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Day ZI, Roberts-Thomson S, Nouri YJ, Dalton NS, Wang SS, Davenport A, Ludlow LE, Hulett MD, Cross RS, Jenkins MR. Defining the extracellular matrix for targeted immunotherapy in adult and pediatric brain cancer. NPJ Precis Oncol 2025; 9:184. [PMID: 40517137 PMCID: PMC12167366 DOI: 10.1038/s41698-025-00956-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 05/21/2025] [Indexed: 06/16/2025] Open
Abstract
High-grade gliomas (HGGs), including glioblastoma (GBM) and pediatric diffuse midline gliomas (DMGs), remain highly fatal despite therapeutic advances. The tumor microenvironment (TME), particularly the extracellular matrix (ECM), plays a crucial role in tumor progression, immune exclusion, and drug resistance. We performed a comprehensive proteomic, transcriptomic, and pathological characterization of the ECM in primary adult and pediatric HGGs. Using cell surface proteomics, TCGA transcriptomics, and immunohistochemistry, we identified key ECM components influencing immune infiltration. We integrated these findings into ImmunoTar, a computational model prioritizing immunotherapeutic targets. Our study presents the first in-depth cell surface proteomic landscape of HGG ECM, identifying CSPG4/5, PTPRZ1, SDC1, TGFBR3, PLG, and GPC2 as key targets. We validate ECM-targeted CAR T cell therapy, including Glypican-2 (GPC2), which shows strong efficacy against pediatric DIPG. These findings highlight ECM-focused immunotherapy as a promising strategy to overcome HGGs' immunosuppressive TME, particularly in pediatric patients.
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Affiliation(s)
- Zoe I Day
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC, Australia
| | | | - Yasmin J Nouri
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
| | - Nathan S Dalton
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
| | - Stacie S Wang
- The Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
- Children's Cancer Centre, Royal Children's Hospital, Melbourne, VIC, Australia
- Murdoch Children's Research Institute, The Royal Children's Hospital, Flemington Road, Parkville, VIC, Australia
| | - Alexander Davenport
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Anatomical Pathology, Royal Melbourne Hospital, Melbourne, VIC, Australia
| | - Louise E Ludlow
- Children's Cancer Centre, Royal Children's Hospital, Melbourne, VIC, Australia
- Murdoch Children's Research Institute, The Royal Children's Hospital, Flemington Road, Parkville, VIC, Australia
| | - Mark D Hulett
- Department of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC, Australia
| | - Ryan S Cross
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Anatomical Pathology, Royal Melbourne Hospital, Melbourne, VIC, Australia
| | - Misty R Jenkins
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
- Department of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC, Australia.
- Department of Anatomical Pathology, Royal Melbourne Hospital, Melbourne, VIC, Australia.
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Stucchi S, Borea R, Garcia-Recio S, Zingarelli M, Rädler PD, Camerini E, Marnata Pellegry C, O'Connor S, Earp HS, Carey LA, Perou CM, Savoldo B, Dotti G. B7-H3 and CSPG4 co-targeting as Pan-CAR-T cell treatment of triple-negative breast cancer. J Immunother Cancer 2025; 13:e011533. [PMID: 40425233 PMCID: PMC12107568 DOI: 10.1136/jitc-2025-011533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Accepted: 05/12/2025] [Indexed: 05/29/2025] Open
Abstract
PURPOSE Chimeric antigen receptor T (CAR-T) cell therapy is under clinical investigation in patients with metastatic triple-negative breast cancer (TNBC). However, the identification of targetable antigens remains a high priority to avoid toxicity and prevent tumor escape. EXPERIMENTAL DESIGN Here we analyzed the gene expression of B7-H3 (CD276) and chondroitin sulfate proteoglycan 4 (CSPG4) in 98 TNBC samples identified in the AURORA US Network and Rapid Autopsy RNA sequencing data set at University of North Carolina (UNC). We then performed immunohistochemistry analysis for B7-H3 and CSPG4 protein expression in 151 TNBC samples collected at UNC. Finally, the validity of the proposed B7-H3 and CSGP4 co-targeting was tested in clinically relevant TNBC patient derived xenograft (PDX) models. RESULTS We observed that CD276 and CSPG4 genes are broadly and comparably expressed in TNBC samples, and gene expression is generally conserved in tumor metastases. None of the TNBC analyzed met the criteria for simultaneous low expression of CSPG4 and CD276 genes. Immunohistochemistry analysis showed a median H-score of 138 (105-168, lower and upper quartile, respectively) for B7-H3 expression and a median H-score of 33 (14-78 lower and upper quartile, respectively) for CSPG4 expression. Notably, 49% of the TNBC cores with B7-H3 H-score ≤105 exhibited a CSPG4 H-score exceeding its median value, and 37% and 18% of the TNBC cores with low B7-H3 expression scored CSPG4 expression above its median H-score or exceeded its upper quartile, respectively, confirming that at least one of these two proteins is expressed in 94% of the analyzed tumors. Finally, optimized dual-specific B7-H3 and CSPG4 CAR-T cells eradicated tumors with mixed antigen expression in TNBC PDX models. CONCLUSIONS These data highlight the clinical potential of the proposed approach that could be applicable to the great majority of patients with TNBC as well as most of patients with breast cancer in general.
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Affiliation(s)
- Simone Stucchi
- Lineberger Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Roberto Borea
- Lineberger Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Susana Garcia-Recio
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Manuela Zingarelli
- Lineberger Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Patrick D Rädler
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Elena Camerini
- Lineberger Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA
| | | | - Siobhan O'Connor
- Pathology & Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - H Shelton Earp
- Lineberger Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Lisa A Carey
- Division of Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Charles M Perou
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Barbara Savoldo
- Lineberger Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA
- Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Gianpietro Dotti
- Lineberger Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA
- Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, USA
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Bhutani B, Sharma V, Ganguly NK, Rana R. Unravelling the modified T cell receptor through Gen-Next CAR T cell therapy in Glioblastoma: Current status and future challenges. Biomed Pharmacother 2025; 186:117987. [PMID: 40117901 DOI: 10.1016/j.biopha.2025.117987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 03/05/2025] [Accepted: 03/10/2025] [Indexed: 03/23/2025] Open
Abstract
PURPOSE Despite current technological advancements in the treatment of glioma, immediate alleviation of symptoms can be catered by therapeutic modalities, including surgery, chemotherapy, and combinatorial radiotherapy that exploit aberrations of glioma. Additionally, a small number of target antigens, their heterogeneity, and immune evasion are the potential reasons for developing targeted therapies. This oncologic milestone has catalyzed interest in developing immunotherapies against Glioblastoma to improve overall survival and cure patients with high-grade glioma. The next-gen CAR-T Cell therapy is one of the effective immunotherapeutic strategies in which autologous T cells have been modified to express receptors against GBM and it modulates cytotoxicity. METHODS In this review article, we examine preclinical and clinical outcomes, and limitations as well as present cutting-edge techniques to improve the function of CAR-T cell therapy and explore the possibility of combination therapy. FINDINGS To date, several CAR T-cell therapies are being evaluated in clinical trials for GBM and other brain malignancies and multiple preclinical studies have demonstrated encouraging outcomes. IMPLICATIONS CAR-T cell therapy represents a promising therapeutic paradigm in the treatment of solid tumors but a few limitations include, the blood-brain barrier (BBB), antigen escape, tumor microenvironment (TME), tumor heterogeneity, and its plasticity that suppresses immune responses weakens the ability of this therapy. Additional investigation is required that can accurately identify the targets and reflect the similar architecture of glioblastoma, thus optimizing the efficiency of CAR-T cell therapy; allowing for the selection of patients most likely to benefit from immuno-based treatments.
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Affiliation(s)
- Bhavya Bhutani
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India
| | - Vyoma Sharma
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India
| | - Nirmal Kumar Ganguly
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India
| | - Rashmi Rana
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India.
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Huang Y, Wang H. Tonic signaling in CAR-T therapy: the lever long enough to move the planet. Front Med 2025:10.1007/s11684-025-1130-x. [PMID: 40117019 DOI: 10.1007/s11684-025-1130-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Accepted: 12/16/2024] [Indexed: 03/23/2025]
Abstract
Chimeric antigen receptor (CAR) T-cell therapy has shown remarkable efficacy in treating hematological malignancies and is expanding into other indications such as autoimmune diseases, fibrosis, aging and viral infection. However, clinical challenges persist in treating solid tumors, including physical barriers, tumor heterogeneity, poor in vivo persistence, and T-cell exhaustion, all of which hinder therapeutic efficacy. This review focuses on the critical role of tonic signaling in CAR-T therapy. Tonic signaling is a low-level constitutive signaling occurring in both natural and engineered antigen receptors without antigen stimulation. It plays a pivotal role in regulating immune cell homeostasis, exhaustion, persistence, and effector functions. The "Peak Theory" suggests an optimal level of tonic signaling for CAR-T function: while weak tonic signaling may result in poor proliferation and persistence, excessively strong signaling can cause T cell exhaustion. This review also summarizes the recent progress in mechanisms underlying the tonic signaling and strategies to fine-tune the CAR tonic signaling. By understanding and precisely modulating tonic signaling, the efficacy of CAR-T therapies can be further optimized, offering new avenues for treatment across a broader spectrum of diseases. These findings have implications beyond CAR-T cells, potentially impacting other engineered immune cell therapies such as CAR-NK and CAR-M.
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Affiliation(s)
- Yuwei Huang
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
- Lingang Laboratory, Shanghai, 200031, China
| | - Haopeng Wang
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
- Shanghai Clinical Research and Trial Center, Shanghai, 201210, China.
- State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai, 201210, China.
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5
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Soko GF, Kosgei BK, Meena SS, Ng YJ, Liang H, Zhang B, Liu Q, Xu T, Hou X, Han RPS. Extracellular matrix re-normalization to improve cold tumor penetration by oncolytic viruses. Front Immunol 2025; 15:1535647. [PMID: 39845957 PMCID: PMC11751056 DOI: 10.3389/fimmu.2024.1535647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 12/18/2024] [Indexed: 01/24/2025] Open
Abstract
Immunologically inert or cold tumors pose a substantial challenge to the effectiveness of immunotherapy. The use of oncolytic viruses (OVs) to induce immunogenic cell death (ICD) in tumor cells is a well-established strategy for initiating the cancer immunity cycle (CIC). This process promotes the trafficking and infiltration of CD8+ T cells into tumors, thereby eliciting a tumor-specific immune response. Despite the potential of OVs for handling cold tumors, clinical outcomes have fallen short of expectations. To better understand the obstacles faced by oncolytic virus immunotherapy (OVI), we would like to revisit the OV issue. Growing evidence indicates that limited intratumoral penetration and inadequate intratumoral distribution of OVs are critical factors contributing to the suboptimal response to OVI. Aberrant expressions of matrix proteins by cancer-associated fibroblasts (CAFs) alter the mechanical properties of the tumor extracellular matrix (ECM). This results in increased ECM desmoplasia and elevated intratumoral interstitial fluid pressure (IFP), creating physical barriers that impede the penetration and dissemination of OVs within tumors. This review explores the latest advancements in strategies designed to improve the intratumoral penetration of OVs to facilitate the penetration of tumor-infiltrating lymphocytes (TILs) into cold tumors. Additionally, we investigated current clinical trials and challenges associated with translating these strategies into clinical practice to improve patient outcomes.
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Affiliation(s)
- Geofrey F. Soko
- Jiangzhong Cancer Research Center, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China & Jiangxi Engineering Research Center for Translational Cancer Technology, Jiangxi University of Chinese Medicine, Nanchang, China
- Ocean Road Cancer Institute, Dar es Salaam, Tanzania
| | - Benson K. Kosgei
- Jiangzhong Cancer Research Center, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China & Jiangxi Engineering Research Center for Translational Cancer Technology, Jiangxi University of Chinese Medicine, Nanchang, China
| | - Stephene S. Meena
- Jiangzhong Cancer Research Center, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China & Jiangxi Engineering Research Center for Translational Cancer Technology, Jiangxi University of Chinese Medicine, Nanchang, China
- Ocean Road Cancer Institute, Dar es Salaam, Tanzania
| | - Ying Jing Ng
- Jiangzhong Cancer Research Center, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China & Jiangxi Engineering Research Center for Translational Cancer Technology, Jiangxi University of Chinese Medicine, Nanchang, China
| | - Huihui Liang
- Jiangzhong Cancer Research Center, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China & Jiangxi Engineering Research Center for Translational Cancer Technology, Jiangxi University of Chinese Medicine, Nanchang, China
| | - Bing Zhang
- The Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, China
| | - Qingjun Liu
- Biosensor National Special Laboratory & Key Laboratory for Biomedical Engineering of Education Ministry, Dept. of Biomedical Engineering, Zhejiang University, Hangzhou, China
| | - Tielong Xu
- Evidence-based Medicine Research Center, Jiangxi University of Chinese Medicine, Nanchang, China
| | - Xinju Hou
- Jiangzhong Cancer Research Center, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China & Jiangxi Engineering Research Center for Translational Cancer Technology, Jiangxi University of Chinese Medicine, Nanchang, China
- Dept. of Rehabilitation, Nanchang Hongdu Hospital of Chinese Medicine, Nanchang, China
| | - Ray P. S. Han
- Jiangzhong Cancer Research Center, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China & Jiangxi Engineering Research Center for Translational Cancer Technology, Jiangxi University of Chinese Medicine, Nanchang, China
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Milan M, Maiullari F, Chirivì M, Ceraolo MG, Zigiotto R, Soluri A, Maiullari S, Landoni E, Silvestre DD, Brambilla F, Mauri P, De Paolis V, Fratini N, Crosti MC, Cordiglieri C, Parisi C, Calogero A, Seliktar D, Torrente Y, Lanzuolo C, Dotti G, Toccafondi M, Bombaci M, De Falco E, Bearzi C, Rizzi R. Macrophages producing chondroitin sulfate proteoglycan-4 induce neuro-cardiac junction impairment in Duchenne muscular dystrophy. J Pathol 2025; 265:1-13. [PMID: 39523812 PMCID: PMC11638662 DOI: 10.1002/path.6362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 08/12/2024] [Accepted: 10/01/2024] [Indexed: 11/16/2024]
Abstract
Duchenne muscular dystrophy (DMD) is caused by the absence of the full form of the dystrophin protein, which is essential for maintaining the structural integrity of muscle cells, including those in the heart and respiratory system. Despite progress in understanding the molecular mechanisms associated with DMD, myocardial insufficiency persists as the primary cause of mortality, and existing therapeutic strategies remain limited. This study investigates the hypothesis that a dysregulation of the biological communication between infiltrating macrophages (MPs) and neurocardiac junctions exists in dystrophic cardiac tissue. In a mouse model of DMD (mdx), this phenomenon is influenced by the over-release of chondroitin sulfate proteoglycan-4 (CSPG4), a key inhibitor of nerve sprouting and a modulator of the neural function, by MPs infiltrating the cardiac tissue and associated with dilated cardiomyopathy, a hallmark of DMD. Givinostat, the histone deacetylase inhibitor under current development as a clinical treatment for DMD, is effective at both restoring a physiological microenvironment at the neuro-cardiac junction and cardiac function in mdx mice in addition to a reduction in cardiac fibrosis, MP-mediated inflammation, and tissue CSPG4 content. This study provides novel insight into the pathophysiology of DMD in the heart, identifying potential new biological targets. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Marika Milan
- Neurology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore PoliclinicoMilanItaly
- Fondazione Istituto Nazionale di Genetica Molecolare (INGM) ‘Romeo ed Enrica Invernizzi’MilanItaly
| | - Fabio Maiullari
- Fondazione Istituto Nazionale di Genetica Molecolare (INGM) ‘Romeo ed Enrica Invernizzi’MilanItaly
- PhD Program in Cellular and Molecular Biology, Department of BiologyUniversity of Rome ‘Tor Vergata’RomeItaly
| | - Maila Chirivì
- Neurology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore PoliclinicoMilanItaly
- Department of Molecular MedicineSapienza UniversityRomeItaly
| | - Maria Grazia Ceraolo
- Neurology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore PoliclinicoMilanItaly
- Fondazione Istituto Nazionale di Genetica Molecolare (INGM) ‘Romeo ed Enrica Invernizzi’MilanItaly
| | - Rebecca Zigiotto
- Fondazione Istituto Nazionale di Genetica Molecolare (INGM) ‘Romeo ed Enrica Invernizzi’MilanItaly
| | - Andrea Soluri
- Unit of Molecular NeurosciencesUniversity Campus Bio‐Medico, RomeRomeItaly
- Institute of Biochemistry and Cell BiologyNational Research CouncilRomeItaly
| | - Silvia Maiullari
- Institute of Biochemistry and Cell BiologyNational Research CouncilRomeItaly
| | - Elisa Landoni
- Lineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel HillChapel HillNCUSA
| | | | | | - Pierluigi Mauri
- Institute of Biomedical TechnologiesNational Research CouncilMilanItaly
| | - Veronica De Paolis
- Institute of Biochemistry and Cell BiologyNational Research CouncilRomeItaly
| | - Nicole Fratini
- Department of Molecular MedicineSapienza UniversityRomeItaly
| | - Maria Cristina Crosti
- Fondazione Istituto Nazionale di Genetica Molecolare (INGM) ‘Romeo ed Enrica Invernizzi’MilanItaly
| | - Chiara Cordiglieri
- Fondazione Istituto Nazionale di Genetica Molecolare (INGM) ‘Romeo ed Enrica Invernizzi’MilanItaly
| | - Chiara Parisi
- Institute of Biochemistry and Cell BiologyNational Research CouncilRomeItaly
| | - Antonella Calogero
- Department of Medical‐Surgical Sciences and BiotechnologiesSapienza University of RomeLatinaItaly
| | - Dror Seliktar
- Department of Biomedical EngineeringTechnion InstituteHaifaIsrael
| | - Yvan Torrente
- Neurology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore PoliclinicoMilanItaly
| | - Chiara Lanzuolo
- Fondazione Istituto Nazionale di Genetica Molecolare (INGM) ‘Romeo ed Enrica Invernizzi’MilanItaly
- Institute of Biomedical TechnologiesNational Research CouncilMilanItaly
| | - Gianpietro Dotti
- Lineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel HillChapel HillNCUSA
| | - Mirco Toccafondi
- Fondazione Istituto Nazionale di Genetica Molecolare (INGM) ‘Romeo ed Enrica Invernizzi’MilanItaly
| | - Mauro Bombaci
- Fondazione Istituto Nazionale di Genetica Molecolare (INGM) ‘Romeo ed Enrica Invernizzi’MilanItaly
| | - Elena De Falco
- Department of Medical‐Surgical Sciences and BiotechnologiesSapienza University of RomeLatinaItaly
| | - Claudia Bearzi
- Fondazione Istituto Nazionale di Genetica Molecolare (INGM) ‘Romeo ed Enrica Invernizzi’MilanItaly
- Institute of Biomedical TechnologiesNational Research CouncilMilanItaly
| | - Roberto Rizzi
- Fondazione Istituto Nazionale di Genetica Molecolare (INGM) ‘Romeo ed Enrica Invernizzi’MilanItaly
- Department of Medical‐Surgical Sciences and BiotechnologiesSapienza University of RomeLatinaItaly
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Zhang P, Li C, Wang Y, Chi X, Sun T, Zhang Q, Zhang Y, Ji N. Expression features of targets for anti-glioma CAR-T cell immunotherapy. J Neurooncol 2025; 171:179-189. [PMID: 39467936 DOI: 10.1007/s11060-024-04855-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 10/15/2024] [Indexed: 10/30/2024]
Abstract
OBJECTIVE To investigate the expression features of common anti-glioma CAR-T targets (B7H3, CSPG4, EGFRv III, HER2 and IL-13Ra2) in gliomas with different grades and molecular subtypes, and explore the association of target expression with glioma malignant or immune phenotypes including immune evasion, stemness, antigen presentation, and tumor angiogenesis. METHODS Opal™ Multiplex immunofluorescence staining was performed on glioma tissues to detect the expression of targets, and biomarkers related to the phenotypes. RESULTS High variety of CAR-T target expression among glioma subtypes was observed. GBMs exhibited the highest expression level of all the examined targets among glioma subtypes. In all glioma cases, CSPG4 was the most prevalent target covering over 84% glioma cases, followed by B7H3 at over 64%. B7H3 exhibited the highest coverage (94%) in GBMs while CSPG4 was the most popular target in both oligodendrogliomas and astrocytomas, covering 94% and 80% cases, respectively. Bi or tri-target combination strategies markedly expanded the tumor coverage across glioma cases while increased tumor-cell coverage within tumor. PD-L1 expression was significantly enriched in all the target-positive cells (except the EGFRvIII+ cells); CD133 expression was higher in the CSPG4+ or IL-13Ra2+ cells, and CD31 elevated in the B7H3+ cells, as compared with their negative cell populations. CONCLUSION Anti-glioma CAR-T targets have heterogenous expression and distinct tumor coverage among glioma subtypes, and closely correlate with glioma malignant or immune phenotypes.
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Affiliation(s)
- Peng Zhang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Nan Si Huan Xi Lu 119, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
| | - Chunzhao Li
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Nan Si Huan Xi Lu 119, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
| | - Yi Wang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Nan Si Huan Xi Lu 119, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
| | - Xiaohan Chi
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Nan Si Huan Xi Lu 119, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
| | - Tai Sun
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Nan Si Huan Xi Lu 119, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
| | - Qianhe Zhang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Nan Si Huan Xi Lu 119, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
| | - Yang Zhang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Nan Si Huan Xi Lu 119, Beijing, 100070, China.
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.
| | - Nan Ji
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Nan Si Huan Xi Lu 119, Beijing, 100070, China.
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.
- Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Beihang University, Beijing, 100191, China.
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8
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Carcopino C, Erdogan E, Henrich M, Kobold S. Armoring chimeric antigen receptor (CAR) T cells as micropharmacies for cancer therapy. IMMUNO-ONCOLOGY TECHNOLOGY 2024; 24:100739. [PMID: 39711794 PMCID: PMC11659983 DOI: 10.1016/j.iotech.2024.100739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/24/2024]
Abstract
Chimeric antigen receptor (CAR)-T-cell therapy has emerged as a powerful weapon in the fight against cancer. However, its efficacy is often hindered by challenges such as limited tumor penetration, antigen escape, and immune suppression within the tumor microenvironment. This review explores the potential of armored CAR-T cells, or 'micropharmacies', in overcoming these obstacles and enhancing the therapeutic outcomes of adoptive T-cell (ATC) therapy. We delve into the engineering strategies behind these advanced therapies and the mechanisms through which they improve CAR-T-cell efficacy. Additionally, we discuss the latest advancements and research findings in the field, providing a comprehensive understanding of the role of armored CAR-T cells in cancer treatment. Ultimately, this review highlights the promising future of integrating micropharmacies into ATC therapy, paving the way for more effective and targeted cancer treatments.
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Affiliation(s)
- C. Carcopino
- Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig Maximilian University (LMU) of Munich, Munich, Germany
| | - E. Erdogan
- Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig Maximilian University (LMU) of Munich, Munich, Germany
| | - M. Henrich
- Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig Maximilian University (LMU) of Munich, Munich, Germany
| | - S. Kobold
- Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig Maximilian University (LMU) of Munich, Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, a partnership between the DKFZ Heidelberg and the University Hospital of the LMU, Heidelberg, Germany
- Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
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Zhou D, Zhu X, Xiao Y. Advances in CAR-T therapy for central nervous system tumors. Biomark Res 2024; 12:132. [PMID: 39506843 PMCID: PMC11539471 DOI: 10.1186/s40364-024-00679-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 10/27/2024] [Indexed: 11/08/2024] Open
Abstract
The application of chimeric antigen receptor T-cell therapy in central nervous system tumors has significantly advanced; however, challenges pertaining to the blood-brain barrier, immunosuppressive microenvironment, and antigenic heterogeneity continue to be encountered, unlike its success in hematological malignancies such as acute lymphoblastic leukemia and diffuse large B-cell lymphomas. This review examined the research progress of chimeric antigen receptor T-cell therapy in gliomas, medulloblastomas, and lymphohematopoietic tumors of the central nervous system, focusing on chimeric antigen receptor T-cells targeting antigens such as EGFRvIII, HER2, B7H3, GD2, and CD19 in preclinical and clinical studies. It synthesized current research findings to offer valuable insights for future chimeric antigen receptor T-cell therapeutic strategies for central nervous system tumors and advance the development and application of this therapeutic modality in this domain.
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Affiliation(s)
- Delian Zhou
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Xiaojian Zhu
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
| | - Yi Xiao
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
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10
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Chen X, Habib S, Alexandru M, Chauhan J, Evan T, Troka JM, Rahimi A, Esapa B, Tull TJ, Ng WZ, Fitzpatrick A, Wu Y, Geh JLC, Lloyd-Hughes H, Palhares LCGF, Adams R, Bax HJ, Whittaker S, Jacków-Malinowska J, Karagiannis SN. Chondroitin Sulfate Proteoglycan 4 (CSPG4) as an Emerging Target for Immunotherapy to Treat Melanoma. Cancers (Basel) 2024; 16:3260. [PMID: 39409881 PMCID: PMC11476251 DOI: 10.3390/cancers16193260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 09/18/2024] [Accepted: 09/20/2024] [Indexed: 10/20/2024] Open
Abstract
Immunotherapies, including checkpoint inhibitor antibodies, have precipitated significant improvements in clinical outcomes for melanoma. However, approximately half of patients do not benefit from approved treatments. Additionally, apart from Tebentafusp, which is approved for the treatment of uveal melanoma, there is a lack of immunotherapies directly focused on melanoma cells. This is partly due to few available targets, especially those expressed on the cancer cell surface. Chondroitin sulfate proteoglycan 4 (CSPG4) is a cell surface molecule overexpressed in human melanoma, with restricted distribution and low expression in non-malignant tissues and involved in several cancer-promoting and dissemination pathways. Here, we summarize the current understanding of the expression and functional significance of CSPG4 in health and melanoma, and we outline immunotherapeutic strategies. These include monoclonal antibodies, antibody-drug conjugates (ADCs), chimeric-antigen receptor (CAR) T cells, and other strategies such as anti-idiotypic and mimotope vaccines to raise immune responses against CSPG4-expressing melanomas. Several showed promising functions in preclinical models of melanoma, yet few have reached clinical testing, and none are approved for therapeutic use. Obstacles preventing that progress include limited knowledge of CSPG4 function in human cancer and a lack of in vivo models that adequately represent patient immune responses and human melanoma biology. Despite several challenges, immunotherapy directed to CSPG4-expressing melanoma harbors significant potential to transform the treatment landscape.
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Affiliation(s)
- Xinyi Chen
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
| | - Shabana Habib
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
| | - Madalina Alexandru
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
| | - Jitesh Chauhan
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
| | - Theodore Evan
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
| | - Joanna M. Troka
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
| | - Avigail Rahimi
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
| | - Benjamina Esapa
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
| | - Thomas J. Tull
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
| | - Wen Zhe Ng
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
| | - Amanda Fitzpatrick
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
- Oncology Department, Guy’s and St Thomas’ Hospitals, London SE1 9RT, UK
- Breast Cancer Now Research Unit, School of Cancer & Pharmaceutical Sciences, King’s College London, Innovation Hub, Guy’s Hospital, London SE1 9RT, UK
| | - Yin Wu
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
- Breast Cancer Now Research Unit, School of Cancer & Pharmaceutical Sciences, King’s College London, Innovation Hub, Guy’s Hospital, London SE1 9RT, UK
- Peter Gorer Department of Immunobiology, Centre for Inflammation Biology and Cancer Immunology, School of Immunology and Microbial Sciences, King’s College London, London SE1 9RT, UK
| | - Jenny L. C. Geh
- St John’s Institute of Dermatology, Guy’s, King’s and St. Thomas’ Hospitals NHS Foundation Trust, London SE1 9RT, UK
- Department of Plastic Surgery, Guy’s, King’s and St. Thomas’ Hospitals, London SE1 9RT, UK
| | - Hawys Lloyd-Hughes
- Department of Plastic Surgery, Guy’s, King’s and St. Thomas’ Hospitals, London SE1 9RT, UK
| | - Lais C. G. F. Palhares
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
| | - Rebecca Adams
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
| | - Heather J. Bax
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
| | - Sean Whittaker
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
| | - Joanna Jacków-Malinowska
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
| | - Sophia N. Karagiannis
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
- Breast Cancer Now Research Unit, School of Cancer & Pharmaceutical Sciences, King’s College London, Innovation Hub, Guy’s Hospital, London SE1 9RT, UK
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11
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Kang X, Mita N, Zhou L, Wu S, Yue Z, Babu RJ, Chen P. Nanotechnology in Advancing Chimeric Antigen Receptor T Cell Therapy for Cancer Treatment. Pharmaceutics 2024; 16:1228. [PMID: 39339264 PMCID: PMC11435308 DOI: 10.3390/pharmaceutics16091228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 09/09/2024] [Accepted: 09/13/2024] [Indexed: 09/30/2024] Open
Abstract
Chimeric antigen receptor (CAR) T cell therapy has emerged as a groundbreaking treatment for hematological cancers, yet it faces significant hurdles, particularly regarding its efficacy in solid tumors and concerning associated adverse effects. This review provides a comprehensive analysis of the advancements and ongoing challenges in CAR-T therapy. We highlight the transformative potential of nanotechnology in enhancing CAR-T therapy by improving targeting precision, modulating the immune-suppressive tumor microenvironment, and overcoming physical barriers. Nanotechnology facilitates efficient CAR gene delivery into T cells, boosting transfection efficiency and potentially reducing therapy costs. Moreover, nanotechnology offers innovative solutions to mitigate cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Cutting-edge nanotechnology platforms for real-time monitoring of CAR-T cell activity and cytokine release are also discussed. By integrating these advancements, we aim to provide valuable insights and pave the way for the next generation of CAR-T cell therapies to overcome current limitations and enhance therapeutic outcomes.
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Affiliation(s)
- Xuejia Kang
- Materials Research and Education Center, Materials Engineering, Department of Mechanical Engineering, Auburn University, Auburn, AL 36849, USA; (L.Z.); (S.W.)
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USA; (N.M.); (Z.Y.); (R.J.B.)
| | - Nur Mita
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USA; (N.M.); (Z.Y.); (R.J.B.)
- Faculty of Pharmacy, Mulawarman University, Samarinda 75119, Kalimantan Timur, Indonesia
| | - Lang Zhou
- Materials Research and Education Center, Materials Engineering, Department of Mechanical Engineering, Auburn University, Auburn, AL 36849, USA; (L.Z.); (S.W.)
| | - Siqi Wu
- Materials Research and Education Center, Materials Engineering, Department of Mechanical Engineering, Auburn University, Auburn, AL 36849, USA; (L.Z.); (S.W.)
| | - Zongliang Yue
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USA; (N.M.); (Z.Y.); (R.J.B.)
| | - R. Jayachandra Babu
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USA; (N.M.); (Z.Y.); (R.J.B.)
| | - Pengyu Chen
- Materials Research and Education Center, Materials Engineering, Department of Mechanical Engineering, Auburn University, Auburn, AL 36849, USA; (L.Z.); (S.W.)
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12
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Feng H, Li J, Wang H, Wei Z, Feng S. Senescence- and Immunity-Related Changes in the Central Nervous System: A Comprehensive Review. Aging Dis 2024:AD.2024.0755. [PMID: 39325939 DOI: 10.14336/ad.2024.0755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 08/26/2024] [Indexed: 09/28/2024] Open
Abstract
Senescence is a cellular state characterized by an irreversible halt in the cell cycle, accompanied by alterations in cell morphology, function, and secretion. Senescent cells release a plethora of inflammatory and growth factors, extracellular matrix proteins, and other bioactive substances, collectively known as the senescence-associated secretory phenotype (SASP). These excreted substances serve as crucial mediators of senescent tissues, while the secretion of SASP by senescent neurons and glial cells in the central nervous system modulates the activity of immune cells. Senescent immune cells also influence the physiological activities of various cells in the central nervous system. Further, the interaction between cellular senescence and immune regulation collectively affects the physiological and pathological processes of the central nervous system. Herein, we explore the role of senescence in the physiological and pathological processes underlying embryonic development, aging, degeneration, and injury of the central nervous system, through the immune response. Further, we elucidate the role of senescence in the physiological and pathological processes of the central nervous system, proposing a new theoretical foundation for treating central nervous system diseases.
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Affiliation(s)
- Haiwen Feng
- Tianjin Key Laboratory of Spine and Spinal Cord, International Science and Technology Cooperation Base of Spinal Cord Injury, Department of Orthopedics, International Chinese Musculoskeletal Research Society Collaborating Center for Spinal Cord Injury, Tianjin Medical University General Hospital, Tianjin 300070, China
| | - Junjin Li
- Tianjin Key Laboratory of Spine and Spinal Cord, International Science and Technology Cooperation Base of Spinal Cord Injury, Department of Orthopedics, International Chinese Musculoskeletal Research Society Collaborating Center for Spinal Cord Injury, Tianjin Medical University General Hospital, Tianjin 300070, China
| | - Hongda Wang
- Tianjin Key Laboratory of Spine and Spinal Cord, International Science and Technology Cooperation Base of Spinal Cord Injury, Department of Orthopedics, International Chinese Musculoskeletal Research Society Collaborating Center for Spinal Cord Injury, Tianjin Medical University General Hospital, Tianjin 300070, China
| | - Zhijian Wei
- Orthopedic Research Center of Shandong University and Department of Orthopedics, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
| | - Shiqing Feng
- Tianjin Key Laboratory of Spine and Spinal Cord, International Science and Technology Cooperation Base of Spinal Cord Injury, Department of Orthopedics, International Chinese Musculoskeletal Research Society Collaborating Center for Spinal Cord Injury, Tianjin Medical University General Hospital, Tianjin 300070, China
- Orthopedic Research Center of Shandong University and Department of Orthopedics, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
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13
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Lin H, Liu C, Hu A, Zhang D, Yang H, Mao Y. Understanding the immunosuppressive microenvironment of glioma: mechanistic insights and clinical perspectives. J Hematol Oncol 2024; 17:31. [PMID: 38720342 PMCID: PMC11077829 DOI: 10.1186/s13045-024-01544-7] [Citation(s) in RCA: 59] [Impact Index Per Article: 59.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Accepted: 04/10/2024] [Indexed: 05/12/2024] Open
Abstract
Glioblastoma (GBM), the predominant and primary malignant intracranial tumor, poses a formidable challenge due to its immunosuppressive microenvironment, thereby confounding conventional therapeutic interventions. Despite the established treatment regimen comprising surgical intervention, radiotherapy, temozolomide administration, and the exploration of emerging modalities such as immunotherapy and integration of medicine and engineering technology therapy, the efficacy of these approaches remains constrained, resulting in suboptimal prognostic outcomes. In recent years, intensive scrutiny of the inhibitory and immunosuppressive milieu within GBM has underscored the significance of cellular constituents of the GBM microenvironment and their interactions with malignant cells and neurons. Novel immune and targeted therapy strategies have emerged, offering promising avenues for advancing GBM treatment. One pivotal mechanism orchestrating immunosuppression in GBM involves the aggregation of myeloid-derived suppressor cells (MDSCs), glioma-associated macrophage/microglia (GAM), and regulatory T cells (Tregs). Among these, MDSCs, though constituting a minority (4-8%) of CD45+ cells in GBM, play a central component in fostering immune evasion and propelling tumor progression, angiogenesis, invasion, and metastasis. MDSCs deploy intricate immunosuppressive mechanisms that adapt to the dynamic tumor microenvironment (TME). Understanding the interplay between GBM and MDSCs provides a compelling basis for therapeutic interventions. This review seeks to elucidate the immune regulatory mechanisms inherent in the GBM microenvironment, explore existing therapeutic targets, and consolidate recent insights into MDSC induction and their contribution to GBM immunosuppression. Additionally, the review comprehensively surveys ongoing clinical trials and potential treatment strategies, envisioning a future where targeting MDSCs could reshape the immune landscape of GBM. Through the synergistic integration of immunotherapy with other therapeutic modalities, this approach can establish a multidisciplinary, multi-target paradigm, ultimately improving the prognosis and quality of life in patients with GBM.
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Affiliation(s)
- Hao Lin
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Chaxian Liu
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Ankang Hu
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Duanwu Zhang
- Children's Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, People's Republic of China.
| | - Hui Yang
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, People's Republic of China.
- Institute for Translational Brain Research, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
| | - Ying Mao
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, People's Republic of China.
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
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14
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Deng Y, Kumar A, Xie K, Schaaf K, Scifo E, Morsy S, Li T, Ehninger A, Bano D, Ehninger D. Targeting senescent cells with NKG2D-CAR T cells. Cell Death Discov 2024; 10:217. [PMID: 38704364 PMCID: PMC11069534 DOI: 10.1038/s41420-024-01976-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 04/17/2024] [Accepted: 04/18/2024] [Indexed: 05/06/2024] Open
Abstract
This study investigates the efficacy of NKG2D chimeric antigen receptor (CAR) engineered T cells in targeting and eliminating stress-induced senescent cells in vitro. Cellular senescence contributes to age-related tissue decline and is characterized by permanent cell cycle arrest and the senescence-associated secretory phenotype (SASP). Immunotherapy, particularly CAR-T cell therapy, emerges as a promising approach to selectively eliminate senescent cells. Our focus is on the NKG2D receptor, which binds to ligands (NKG2DLs) upregulated in senescent cells, offering a target for CAR-T cells. Using mouse embryonic fibroblasts (MEFs) and astrocytes (AST) as senescence models, we demonstrate the elevated expression of NKG2DLs in response to genotoxic and oxidative stress. NKG2D-CAR T cells displayed potent cytotoxicity against these senescent cells, with minimal effects on non-senescent cells, suggesting their potential as targeted senolytics. In conclusion, our research presents the first evidence of NKG2D-CAR T cells' ability to target senescent brain cells, offering a novel approach to manage senescence-associated diseases. The findings pave the way for future investigations into the therapeutic applicability of NKG2D-targeting CAR-T cells in naturally aged organisms and models of aging-associated brain diseases in vivo.
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Affiliation(s)
- Yushuang Deng
- Translational Biogerontology Lab, German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1/99, 53127, Bonn, Germany
| | - Avadh Kumar
- Translational Biogerontology Lab, German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1/99, 53127, Bonn, Germany
- Lonza Netherlands B.V., Geleen, Urmonderbaan 20-B, 6167 RD, Geleen, Netherlands
| | - Kan Xie
- Translational Biogerontology Lab, German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1/99, 53127, Bonn, Germany
| | - Kristina Schaaf
- Translational Biogerontology Lab, German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1/99, 53127, Bonn, Germany
| | - Enzo Scifo
- Translational Biogerontology Lab, German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1/99, 53127, Bonn, Germany
| | - Sarah Morsy
- Translational Biogerontology Lab, German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1/99, 53127, Bonn, Germany
- AvenCell Europe GmbH, Tatzberg 47, 01307, Dresden, Germany
| | - Tao Li
- Department of Neurodegenerative Disease and Geriatric Psychiatry/Neurology, University of Bonn Medical Center, 53127, Bonn, Germany
| | - Armin Ehninger
- AvenCell Europe GmbH, Tatzberg 47, 01307, Dresden, Germany
| | - Daniele Bano
- Aging and Neurodegeneration Lab, German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1/99, 53127, Bonn, Germany
| | - Dan Ehninger
- Translational Biogerontology Lab, German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1/99, 53127, Bonn, Germany.
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15
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Kong D, Kwon D, Moon B, Kim DH, Kim MJ, Choi J, Kang KS. CD19 CAR-expressing iPSC-derived NK cells effectively enhance migration and cytotoxicity into glioblastoma by targeting to the pericytes in tumor microenvironment. Biomed Pharmacother 2024; 174:116436. [PMID: 38508081 DOI: 10.1016/j.biopha.2024.116436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 03/07/2024] [Accepted: 03/15/2024] [Indexed: 03/22/2024] Open
Abstract
In cancer immunotherapy, chimeric antigen receptors (CARs) targeting specific antigens have become a powerful tool for cell-based therapy. CAR-natural killer (NK) cells offer selective anticancer lysis with reduced off-tumor toxicity compared to CAR-T cells, which is beneficial in the heterogeneous milieu of solid tumors. In the tumor microenvironment (TME) of glioblastoma (GBM), pericytes not only support tumor growth but also contribute to immune evasion, underscoring their potential as therapeutic targets in GBM treatment. Given this context, our study aimed to target the GBM TME, with a special focus on pericytes expressing CD19, to evaluate the potential effectiveness of CD19 CAR-iNK cells against GBM. We performed CD19 CAR transduction in induced pluripotent stem cell-derived NK (iNK) cells. To determine whether CD19 CAR targets the TME pericytes in GBM, we developed GBM-blood vessel assembloids (GBVA) by fusing GBM spheroids with blood vessel organoids. When co-cultured with GBVA, CD19 CAR-iNK cells migrated towards the pericytes surrounding the GBM. Using a microfluidic chip, we demonstrated CD19 CAR-iNK cells' targeted action and cytotoxic effects in a perfusion-like environment. GBVA xenografts recapitulated the TME including human CD19-positive pericytes, thereby enabling the application of an in vivo model for validating the efficacy of CD19 CAR-iNK cells against GBM. Compared to GBM spheroids, the presence of pericytes significantly enhanced CD19 CAR-iNK cell migration towards GBM and reduced proliferation. These results underline the efficacy of CD19 CAR-iNK cells in targeting pericytes within the GBM TME, suggesting their potential therapeutic value for GBM treatment.
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Affiliation(s)
- Dasom Kong
- Adult Stem Cell Research Center and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea
| | - Daekee Kwon
- Research Institute in Maru Therapeutics, Seoul 05854, Republic of Korea
| | - Bokyung Moon
- Research Institute in Maru Therapeutics, Seoul 05854, Republic of Korea
| | - Da-Hyun Kim
- Adult Stem Cell Research Center and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea; Department of Biotechnology, Sungshin Women's University, Seoul 01133, Republic of Korea
| | - Min-Ji Kim
- Adult Stem Cell Research Center and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea
| | - Jungju Choi
- Adult Stem Cell Research Center and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea
| | - Kyung-Sun Kang
- Adult Stem Cell Research Center and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea.
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16
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Boewe AS, Wrublewsky S, Hoppstädter J, Götz C, Kiemer AK, Menger MD, Laschke MW, Ampofo E. C-Myc/H19/miR-29b axis downregulates nerve/glial (NG)2 expression in glioblastoma multiforme. MOLECULAR THERAPY. NUCLEIC ACIDS 2024; 35:102120. [PMID: 38318212 PMCID: PMC10839451 DOI: 10.1016/j.omtn.2024.102120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 01/09/2024] [Indexed: 02/07/2024]
Abstract
Nerve/glial antigen (NG)2 is highly expressed in glioblastoma multiforme (GBM). However, the underlying mechanisms of its upregulated expression are largely unknown. In silico analyses reveal that the tumor-suppressive miR-29b targets NG2. We used GBM-based data from The Cancer Genome Atals databases to analyze the expression pattern of miR-29b and different target genes, including NG2. Moreover, we investigated the regulatory function of miR-29b on NG2 expression and NG2-related signaling pathways. We further studied upstream mechanisms affecting miR-29b-dependent NG2 expression. We found that miR-29b downregulates NG2 expression directly and indirectly via the transcription factor Sp1. Furthermore, we identified the NG2 coreceptor platelet-derived growth factor receptor (PDGFR)α as an additional miR-29b target. As shown by a panel of functional cell assays, a reduced miR-29b-dependent NG2 expression suppresses tumor cell proliferation and migration. Signaling pathway analyses revealed that this is associated with a decreased ERK1/2 activity. In addition, we found that the long noncoding RNA H19 and c-Myc act as upstream repressors of miR-29b in GBM cells, resulting in an increased NG2 expression. These findings indicate that the c-Myc/H19/miR-29b axis crucially regulates NG2 expression in GBM and, thus, represents a target for the development of future GBM therapies.
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Affiliation(s)
- Anne S. Boewe
- Institute for Clinical and Experimental Surgery, Saarland University, 66421 Homburg, Germany
| | - Selina Wrublewsky
- Institute for Clinical and Experimental Surgery, Saarland University, 66421 Homburg, Germany
| | - Jessica Hoppstädter
- Department of Pharmacy, Pharmaceutical Biology, Saarland University, 66123 Saarbruecken, Germany
| | - Claudia Götz
- Medical Biochemistry and Molecular Biology, Saarland University, 66421 Homburg, Germany
| | - Alexandra K. Kiemer
- Department of Pharmacy, Pharmaceutical Biology, Saarland University, 66123 Saarbruecken, Germany
| | - Michael D. Menger
- Institute for Clinical and Experimental Surgery, Saarland University, 66421 Homburg, Germany
| | - Matthias W. Laschke
- Institute for Clinical and Experimental Surgery, Saarland University, 66421 Homburg, Germany
| | - Emmanuel Ampofo
- Institute for Clinical and Experimental Surgery, Saarland University, 66421 Homburg, Germany
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17
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Niibori-Nambu A, Yamasaki Y, Kobayashi D, Angata K, Kuno A, Panawan O, Silsirivanit A, Narimatsu H, Araki N. Chondroitin sulfate modification of CSPG4 regulates the maintenance and differentiation of glioma-initiating cells via integrin-associated signaling. J Biol Chem 2024; 300:105706. [PMID: 38309500 PMCID: PMC10958118 DOI: 10.1016/j.jbc.2024.105706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 12/03/2023] [Accepted: 01/15/2024] [Indexed: 02/05/2024] Open
Abstract
Glioma stem cell/glioma-initiating cell (GIC) and their niches are considered responsible for the therapeutic resistance and recurrence of malignant glioma. To clarify the molecular mechanisms of GIC maintenance/differentiation, we performed a unique integrated proteogenomics utilizing GIC clones established from patient tumors having the potential to develop glioblastoma. After the integration and extraction of the transcriptomics/proteomics data, we found that chondroitin sulfate proteoglycan 4 (CSPG4) and its glycobiosynthetic enzymes were significantly upregulated in GICs. Glyco-quantitative PCR array revealed that chondroitin sulfate (CS) biosynthetic enzymes, such as xylosyltransferase 1 (XYLT1) and carbohydrate sulfotransferase 11, were significantly downregulated during serum-induced GIC differentiation. Simultaneously, the CS modification on CSPG4 was characteristically decreased during the differentiation and also downregulated by XYLT1 knockdown. Notably, the CS degradation on CSPG4 by ChondroitinaseABC treatment dramatically induced GIC differentiation, which was significantly inhibited by the addition of CS. GIC growth and differentiation ability were significantly suppressed by CSPG4 knockdown, suggesting that CS-CSPG4 is an important factor in GIC maintenance/differentiation. To understand the molecular function of CS-CSPG4, we analyzed its associating proteins in GICs and found that CSPG4, but not CS-CSPG4, interacts with integrin αV during GIC differentiation. This event sequentially upregulates integrin-extracellular signal-regulated kinase signaling, which can be inhibited by cyclic-RGD (Arg-Gly-Asp) integrin αV inhibitor. These results indicate that CS-CSPG4 regulates the GIC microenvironment for GIC maintenance/differentiation via the CS moiety, which controls integrin signaling. This study demonstrates a novel function of CS on CSPG4 as a niche factor, so-called "glyco-niche" for GICs, and suggests that CS-CSPG4 could be a potential target for malignant glioma.
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Affiliation(s)
- Akiko Niibori-Nambu
- Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, Institute of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Yoshimune Yamasaki
- Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, Institute of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Daiki Kobayashi
- Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, Institute of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Kiyohiko Angata
- Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan
| | - Atsushi Kuno
- Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan
| | - Orasa Panawan
- Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, Institute of Life Sciences, Kumamoto University, Kumamoto, Japan; Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Atit Silsirivanit
- Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, Institute of Life Sciences, Kumamoto University, Kumamoto, Japan; Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Hisashi Narimatsu
- Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan
| | - Norie Araki
- Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, Institute of Life Sciences, Kumamoto University, Kumamoto, Japan.
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18
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Giraudo L, Cattaneo G, Gammaitoni L, Iaia I, Donini C, Massa A, Centomo ML, Basiricò M, Vigna E, Pisacane A, Picciotto F, Berrino E, Marchiò C, Merlini A, Paruzzo L, Poletto S, Caravelli D, Biolato AM, Bortolot V, Landoni E, Ventin M, Ferrone CR, Aglietta M, Dotti G, Leuci V, Carnevale-Schianca F, Sangiolo D. CSPG4 CAR-redirected Cytokine Induced Killer lymphocytes (CIK) as effective cellular immunotherapy for HLA class I defective melanoma. J Exp Clin Cancer Res 2023; 42:310. [PMID: 37993874 PMCID: PMC10664597 DOI: 10.1186/s13046-023-02884-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 11/02/2023] [Indexed: 11/24/2023] Open
Abstract
BACKGROUND Even acknowledging the game-changing results achieved in the treatment of metastatic melanoma with the use of immune checkpoint inhibitors (ICI), a large proportion of patients (40-60%) still fail to respond or relapse due to the development of resistance. Alterations in the expression of Human Leukocyte Antigen class I (HLA-I) molecules are considered to play a major role in clinical resistance to ICI. Cellular immunotherapy with HLA-independent CAR-redirected lymphocytes is a promising alternative in this challenging setting and dedicated translational models are needed. METHODS In this study, we propose an HLA-independent therapeutic strategy with Cytokine Induced Killer lymphocytes (CIK) genetically engineered with a Chimeric Antigen Receptor (CAR) targeting the tumor antigen CSPG4 as effector mechanism. We investigated the preclinical antitumor activity of CSPG4-CAR.CIK in vitro and in a xenograft murine model focusing on patient-derived melanoma cell lines (Mel) with defective expression of HLA-I molecules. RESULTS We successfully generated CSPG4-CAR.CIK from patients with metastatic melanoma and reported their intense activity in vitro against a panel of CSPG4-expressing patient-derived Mel. The melanoma killing activity was intense, even at very low effector to target ratios, and not influenced by the expression level (high, low, defective) of HLA-I molecules on target cells. Furthermore, CAR.CIK conditioned medium was capable of upregulating the expression of HLA-I molecules on melanoma cells. A comparable immunomodulatory effect was replicated by treatment of Mel cells with exogenous IFN-γ and IFN-α. The antimelanoma activity of CSPG4-CAR.CIK was successfully confirmed in vivo, obtaining a significant tumor growth inhibition of an HLA-defective Mel xenograft in immunodeficient mice. CONCLUSIONS In this study we reported the intense preclinical activity of CSPG4-CAR.CIK against melanoma, including those with low or defective HLA-I expression. Our findings support CSPG4 as a valuable CAR target in melanoma and provide translational rationale for clinical studies exploring CAR-CIK cellular immunotherapies within the challenging setting of patients not responsive or relapsing to immune checkpoint inhibitors.
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Affiliation(s)
- Lidia Giraudo
- Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142 Km 3.95, 10060, Candiolo, TO, Italy
| | - Giulia Cattaneo
- Department of Oncology, University of Turin, Regione Gonzole 10, 10043, Orbassano, TO, Italy.
- Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
| | - Loretta Gammaitoni
- Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142 Km 3.95, 10060, Candiolo, TO, Italy
| | - Ilenia Iaia
- Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142 Km 3.95, 10060, Candiolo, TO, Italy
- Department of Oncology, University of Turin, Regione Gonzole 10, 10043, Orbassano, TO, Italy
| | - Chiara Donini
- Department of Oncology, University of Turin, Regione Gonzole 10, 10043, Orbassano, TO, Italy
| | - Annamaria Massa
- Department of Oncology, University of Turin, Regione Gonzole 10, 10043, Orbassano, TO, Italy
| | - Maria Laura Centomo
- Department of Oncology, University of Turin, Regione Gonzole 10, 10043, Orbassano, TO, Italy
| | - Marco Basiricò
- Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142 Km 3.95, 10060, Candiolo, TO, Italy
| | - Elisa Vigna
- Department of Oncology, University of Turin, Regione Gonzole 10, 10043, Orbassano, TO, Italy
| | - Alberto Pisacane
- Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142 Km 3.95, 10060, Candiolo, TO, Italy
| | - Franco Picciotto
- Dermatologic Surgery Section, Department of Surgery, Azienda Ospedaliera Universitaria (AOU) Città Della Salute E Della Scienza, Turin, TO, Italy
| | - Enrico Berrino
- Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142 Km 3.95, 10060, Candiolo, TO, Italy
- Department of Medical Sciences, University of Turin, Corso Dogliotti 14, 10126, Turin, TO, Italy
| | - Caterina Marchiò
- Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142 Km 3.95, 10060, Candiolo, TO, Italy
- Department of Medical Sciences, University of Turin, Corso Dogliotti 14, 10126, Turin, TO, Italy
| | - Alessandra Merlini
- Department of Oncology, University of Turin, Regione Gonzole 10, 10043, Orbassano, TO, Italy
| | - Luca Paruzzo
- Department of Oncology, University of Turin, Regione Gonzole 10, 10043, Orbassano, TO, Italy
| | - Stefano Poletto
- Department of Oncology, University of Turin, Regione Gonzole 10, 10043, Orbassano, TO, Italy
| | - Daniela Caravelli
- Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142 Km 3.95, 10060, Candiolo, TO, Italy
| | - Andrea Michela Biolato
- Department of Oncology, University of Turin, Regione Gonzole 10, 10043, Orbassano, TO, Italy
- Cytoskeleton and Cancer Progression, Department of Oncology, Luxembourg Institute of Health, Luxembourg City, Luxembourg
- Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-Sur-Alzette, Luxembourg
| | - Valentina Bortolot
- Department of Oncology, University of Turin, Regione Gonzole 10, 10043, Orbassano, TO, Italy
| | - Elisa Landoni
- Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA
| | - Marco Ventin
- Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Cristina R Ferrone
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Massimo Aglietta
- Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142 Km 3.95, 10060, Candiolo, TO, Italy
- Department of Oncology, University of Turin, Regione Gonzole 10, 10043, Orbassano, TO, Italy
| | - Gianpietro Dotti
- Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA
| | - Valeria Leuci
- Department of Oncology, University of Turin, Regione Gonzole 10, 10043, Orbassano, TO, Italy
| | | | - Dario Sangiolo
- Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142 Km 3.95, 10060, Candiolo, TO, Italy.
- Department of Oncology, University of Turin, Regione Gonzole 10, 10043, Orbassano, TO, Italy.
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19
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Woodell AS, Landoni E, Valdivia A, Buckley A, Ogunnaike EA, Dotti G, Hingtgen SD. Utilizing induced neural stem cell-based delivery of a cytokine cocktail to enhance chimeric antigen receptor-modified T-cell therapy for brain cancer. Bioeng Transl Med 2023; 8:e10538. [PMID: 38023712 PMCID: PMC10658508 DOI: 10.1002/btm2.10538] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 04/14/2023] [Accepted: 04/17/2023] [Indexed: 12/01/2023] Open
Abstract
Chimeric antigen receptor (CAR)-modified T-cell therapy has shown enormous clinical promise against blood cancers, yet efficacy against solid tumors remains a challenge. Here, we investigated the potential of a new combination cell therapy, where tumor-homing induced neural stem cells (iNSCs) are used to enhance CAR-T-cell therapy and achieve efficacious suppression of brain tumors. Using in vitro and in vivo migration assays, we found iNSC-secreted RANTES/IL-15 increased CAR-T-cell migration sixfold and expansion threefold, resulting in greater antitumor activity in a glioblastoma (GBM) tumor model. Furthermore, multimodal imaging showed iNSC delivery of RANTES/IL-15 in combination with intravenous administration of CAR-T cells reduced established orthotopic GBM xenografts 2538-fold within the first week, followed by durable tumor remission through 60 days post-treatment. By contrast, CAR-T-cell therapy alone only partially controlled tumor growth, with a median survival of only 19 days. Together, these studies demonstrate the potential of combined cell therapy platforms to improve the efficacy of CAR-T-cell therapy for brain tumors.
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Affiliation(s)
- Alex S. Woodell
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of PharmacyUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Elisa Landoni
- Lineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Alain Valdivia
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of PharmacyUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Andrew Buckley
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of PharmacyUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Edikan A. Ogunnaike
- Lineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
- Center for Nanotechnology in Drug Delivery, UNC Eshelman School of PharmacyUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Gianpietro Dotti
- Lineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
- Department of Microbiology and ImmunologyUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Shawn D. Hingtgen
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of PharmacyUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
- Lineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
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20
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Kropp KN, Fatho M, Huduti E, Faust M, Lübcke S, Lennerz V, Paschen A, Theobald M, Wölfel T, Wölfel C. Targeting the melanoma-associated antigen CSPG4 with HLA-C*07:01-restricted T-cell receptors. Front Immunol 2023; 14:1245559. [PMID: 37849763 PMCID: PMC10577170 DOI: 10.3389/fimmu.2023.1245559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 09/14/2023] [Indexed: 10/19/2023] Open
Abstract
Intorduction Chondroitin sulfate proteoglycan 4 (CSPG4), also known as high molecular weight-melanoma associated antigen, is expressed in melanoma but also other tumor entities and constitutes an attractive target for immunotherapeutic approaches. While recent preclinical reports focused on anti-CSPG4 chimeric antigen receptors (CAR), we here explore T-cell receptor (TCR)-based approaches targeting CSPG4. Methods The TCRs of two CSPG4-reactive T-cell clones (11C/73 and 2C/165) restricted by the highly prevalent HLA-C*07:01 allele were isolated and the respective αβTCR pairs were retrovirally expressed in CRISPR/Cas9-edited TCR-knockout T cells for functional testing. We also combined alpha and beta TCR chains derived from 11C/73 and 2C/165 in a cross-over fashion to assess for hemichain dominance. CSPG4+ melanoma, glioblastoma and lung cancer cell lines were identified and, if negative, retrovirally transduced with HLA-C*07:01. Results Functional tests confirmed specific recognition of CSPG4+HLA-C*07:01+ target cells by the αβTCR retrieved from the parental T-cell clones and in part also by the cross-over TCR construct 2Cα-11Cβ. Despite high surface expression, the 11Cα-2Cβ combination, however, was not functional. Discussion Collectively, 11C/73- and 2C/165-expressing T cells specifically and efficiently recognized CSPG4+HLA-C*07:01+ cancer cells which warrants further preclinical and clinical evaluation of these TCRs.
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Affiliation(s)
- Korbinian N. Kropp
- Internal Medicine III, University Cancer Center (UCT), Research Center for Immunotherapy (FZI), University Medical Center (UMC) of the Johannes Gutenberg University and German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Mainz, Germany
| | - Martina Fatho
- Internal Medicine III, University Cancer Center (UCT), Research Center for Immunotherapy (FZI), University Medical Center (UMC) of the Johannes Gutenberg University and German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Mainz, Germany
| | - Enes Huduti
- Internal Medicine III, University Cancer Center (UCT), Research Center for Immunotherapy (FZI), University Medical Center (UMC) of the Johannes Gutenberg University and German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Mainz, Germany
| | - Marilena Faust
- Internal Medicine III, University Cancer Center (UCT), Research Center for Immunotherapy (FZI), University Medical Center (UMC) of the Johannes Gutenberg University and German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Mainz, Germany
| | - Silke Lübcke
- Internal Medicine III, University Cancer Center (UCT), Research Center for Immunotherapy (FZI), University Medical Center (UMC) of the Johannes Gutenberg University and German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Mainz, Germany
| | - Volker Lennerz
- Internal Medicine III, University Cancer Center (UCT), Research Center for Immunotherapy (FZI), University Medical Center (UMC) of the Johannes Gutenberg University and German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Mainz, Germany
| | - Annette Paschen
- Dermatology, University Hospital, University Duisburg/Essen and German Cancer Research Consortium (DKTK), Partner Site Essen/Duesseldorf, Essen, Germany
| | - Matthias Theobald
- Internal Medicine III, University Cancer Center (UCT), Research Center for Immunotherapy (FZI), University Medical Center (UMC) of the Johannes Gutenberg University and German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Mainz, Germany
| | - Thomas Wölfel
- Internal Medicine III, University Cancer Center (UCT), Research Center for Immunotherapy (FZI), University Medical Center (UMC) of the Johannes Gutenberg University and German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Mainz, Germany
| | - Catherine Wölfel
- Internal Medicine III, University Cancer Center (UCT), Research Center for Immunotherapy (FZI), University Medical Center (UMC) of the Johannes Gutenberg University and German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Mainz, Germany
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21
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Mansour A, Trefi A, Mansour M, Shekho A, Salloum S. The complexities of treating brain and spinal cord tumors: a review of current approaches. Ann Med Surg (Lond) 2023; 85:4969-4972. [PMID: 37811056 PMCID: PMC10552955 DOI: 10.1097/ms9.0000000000001213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 08/13/2023] [Indexed: 10/10/2023] Open
Abstract
This article provides an overview of brain and spinal cord tumours, including their types, diagnosis, and treatment approaches. Brain and spinal cord tumours are complex and can be caused by various factors. They can be divided into two main categories, primary and metastatic tumours, which present their own unique challenges and complexities when it comes to treatment. Diagnosing brain and spinal cord tumours requires a careful evaluation of the patient's medical history and symptoms, as well as a variety of diagnostic tools and techniques. Treatment approaches include surgery, radiation therapy, and chemotherapy, each with its own benefits and drawbacks. The choice of treatment depends on the type and location of the tumour, as well as the patient's individual needs and preferences. Despite advances in treatment, there is a pressing need for further research to improve the effectiveness and safety of these treatments.
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Affiliation(s)
| | | | - Majd Mansour
- Faculty of Medicine, Tishreen University, Latakia, Syria
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22
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Nehama D, Woodell AS, Maingi SM, Hingtgen SD, Dotti G. Cell-based therapies for glioblastoma: Promising tools against tumor heterogeneity. Neuro Oncol 2023; 25:1551-1562. [PMID: 37179459 PMCID: PMC10484163 DOI: 10.1093/neuonc/noad092] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Indexed: 05/15/2023] Open
Abstract
Glioblastoma (GBM) is a highly aggressive tumor with a devastating impact on quality-of-life and abysmal survivorship. Patients have very limited effective treatment options. The successes of targeted small molecule drugs and immune checkpoint inhibitors seen in various solid tumors have not translated to GBM, despite significant advances in our understanding of its molecular, immune, and microenvironment landscapes. These discoveries, however, have unveiled GBM's incredible heterogeneity and its role in treatment failure and survival. Novel cellular therapy technologies are finding successes in oncology and harbor characteristics that make them uniquely suited to overcome challenges posed by GBM, such as increased resistance to tumor heterogeneity, modularity, localized delivery, and safety. Considering these advantages, we compiled this review article on cellular therapies for GBM, focusing on cellular immunotherapies and stem cell-based therapies, to evaluate their utility. We categorize them based on their specificity, review their preclinical and clinical data, and extract valuable insights to help guide future cellular therapy development.
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Affiliation(s)
- Dean Nehama
- Department of Internal Medicine, Montefiore Medical Center, New York, New York, USA
| | - Alex S Woodell
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - Spencer M Maingi
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - Shawn D Hingtgen
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - Gianpietro Dotti
- Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
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23
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Lin YC, Chu YH, Liao WC, Chen CH, Hsiao WC, Ho YJ, Yang MY, Liu CH. CHST11-modified chondroitin 4-sulfate as a potential therapeutic target for glioblastoma. Am J Cancer Res 2023; 13:2998-3012. [PMID: 37559985 PMCID: PMC10408464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 06/23/2023] [Indexed: 08/11/2023] Open
Abstract
Aberrant chondroitin sulfate (CS) accumulation in glioblastoma (GBM) tissue has been documented, but the role of excessive CS in GBM progression and whether it can be a druggable target are largely unknown. The aim of this study is to clarify the biological functions of CHST11 in GBM cells, and evaluate therapeutic effects of blocking CHST11-derived chondroitin 4-sulfate (C4S). We investigated the expression of CHST11 in glioma tissue by immunohistochemistry, and analyzed CHST11 associated genes using public RNA sequencing datasets. The effects of CHST11 on aggressive cell behaviors have been studied in vitro and in vivo. We demonstrated that CHST11 is frequently overexpressed in GBM tissue, promoting GBM cell mobility and modulating C4S on GBM cells. We further discovered that CSPG4 is positively correlated with CHST11, and CSPG4 involved in CHST11-mediated cell invasiveness. In addition, GBM patients with high expression of CHST11 and CSPG4 have a significantly shorter survival time. We examined the effects of treating C4S-specific binding peptide (C4Sp) as a therapeutic agent in vitro and in vivo. C4Sp treatment attenuated GBM cell invasiveness and, notably, improved survival rate of orthotopic glioma cell transplant mice. Our results propose a possible mechanism of CHST11 in regulating GBM malignancy and highlight a novel strategy for targeting aberrant chondroitin sulfate in GBM cells.
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Affiliation(s)
- You-Cheng Lin
- Doctoral Program in Tissue Engineering and Regenerative Medicine, College of Medicine, National Chung Hsing UniversityTaichung, Taiwan
| | - Yin-Hung Chu
- Doctoral Program in Tissue Engineering and Regenerative Medicine, College of Medicine, National Chung Hsing UniversityTaichung, Taiwan
| | - Wen-Chieh Liao
- Doctoral Program in Tissue Engineering and Regenerative Medicine, College of Medicine, National Chung Hsing UniversityTaichung, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing UniversityTaichung, Taiwan
| | - Chia-Hua Chen
- Molecular Medicine Research Center, Chang Gung UniversityTaoyuan, Taiwan
| | - Wen-Chuan Hsiao
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing UniversityTaichung, Taiwan
| | - Ying-Jui Ho
- Department of Psychology, Chung Shan Medical UniversityTaichung, Taiwan
| | - Meng-Yin Yang
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing UniversityTaichung, Taiwan
- Department of Neurosurgery, Neurological Institute, Taichung Veterans General HospitalTaichung, Taiwan
| | - Chiung-Hui Liu
- Doctoral Program in Tissue Engineering and Regenerative Medicine, College of Medicine, National Chung Hsing UniversityTaichung, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing UniversityTaichung, Taiwan
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24
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Xiong Q, Zhu J, Zhang Y, Deng H. CAR-NK cell therapy for glioblastoma: what to do next? Front Oncol 2023; 13:1192128. [PMID: 37404752 PMCID: PMC10315652 DOI: 10.3389/fonc.2023.1192128] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 05/29/2023] [Indexed: 07/06/2023] Open
Abstract
Glioblastoma is a malignant tumor with the highest morbidity and mortality in the central nervous system. Conventional surgical resection combined with radiotherapy or chemotherapy has a high recurrence rate and poor prognosis. The 5-year survival rate of patients is less than 10%. In tumor immunotherapy, CAR-T cell therapy represented by chimeric antigen receptor-modified T cells has achieved great success in hematological tumors. However, the application of CAR-T cells in solid tumors such as glioblastoma still faces many challenges. CAR-NK cells are another potential adoptive cell therapy strategy after CAR-T cells. Compared with CAR-T cell therapy, CAR-NK cells have similar anti-tumor effects. CAR-NK cells can also avoid some deficiencies in CAR-T cell therapy, a research hotspot in tumor immunity. This article summarizes the preclinical research status of CAR-NK cells in glioblastoma and the problems and challenges faced by CAR-NK in glioblastoma.
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Märkl F, Benmebarek MR, Keyl J, Cadilha BL, Geiger M, Karches C, Obeck H, Schwerdtfeger M, Michaelides S, Briukhovetska D, Stock S, Jobst J, Müller PJ, Majed L, Seifert M, Klüver AK, Lorenzini T, Grünmeier R, Thomas M, Gottschlich A, Klaus R, Marr C, von Bergwelt-Baildon M, Rothenfusser S, Levesque MP, Heppt MV, Endres S, Klein C, Kobold S. Bispecific antibodies redirect synthetic agonistic receptor modified T cells against melanoma. J Immunother Cancer 2023; 11:jitc-2022-006436. [PMID: 37208128 DOI: 10.1136/jitc-2022-006436] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/16/2023] [Indexed: 05/21/2023] Open
Abstract
BACKGROUND Melanoma is an immune sensitive disease, as demonstrated by the activity of immune check point blockade (ICB), but many patients will either not respond or relapse. More recently, tumor infiltrating lymphocyte (TIL) therapy has shown promising efficacy in melanoma treatment after ICB failure, indicating the potential of cellular therapies. However, TIL treatment comes with manufacturing limitations, product heterogeneity, as well as toxicity problems, due to the transfer of a large number of phenotypically diverse T cells. To overcome said limitations, we propose a controlled adoptive cell therapy approach, where T cells are armed with synthetic agonistic receptors (SAR) that are selectively activated by bispecific antibodies (BiAb) targeting SAR and melanoma-associated antigens. METHODS Human as well as murine SAR constructs were generated and transduced into primary T cells. The approach was validated in murine, human and patient-derived cancer models expressing the melanoma-associated target antigens tyrosinase-related protein 1 (TYRP1) and melanoma-associated chondroitin sulfate proteoglycan (MCSP) (CSPG4). SAR T cells were functionally characterized by assessing their specific stimulation and proliferation, as well as their tumor-directed cytotoxicity, in vitro and in vivo. RESULTS MCSP and TYRP1 expression was conserved in samples of patients with treated as well as untreated melanoma, supporting their use as melanoma-target antigens. The presence of target cells and anti-TYRP1 × anti-SAR or anti-MCSP × anti-SAR BiAb induced conditional antigen-dependent activation, proliferation of SAR T cells and targeted tumor cell lysis in all tested models. In vivo, antitumoral activity and long-term survival was mediated by the co-administration of SAR T cells and BiAb in a syngeneic tumor model and was further validated in several xenograft models, including a patient-derived xenograft model. CONCLUSION The SAR T cell-BiAb approach delivers specific and conditional T cell activation as well as targeted tumor cell lysis in melanoma models. Modularity is a key feature for targeting melanoma and is fundamental towards personalized immunotherapies encompassing cancer heterogeneity. Because antigen expression may vary in primary melanoma tissues, we propose that a dual approach targeting two tumor-associated antigens, either simultaneously or sequentially, could avoid issues of antigen heterogeneity and deliver therapeutic benefit to patients.
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Affiliation(s)
- Florian Märkl
- Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Mohamed-Reda Benmebarek
- Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Julius Keyl
- Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Bruno L Cadilha
- Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Martina Geiger
- Roche Innovation Center Zurich, Roche Pharma Research & Early Development, Schlieren, Switzerland
| | - Clara Karches
- Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Hannah Obeck
- Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Melanie Schwerdtfeger
- Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Stefanos Michaelides
- Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Daria Briukhovetska
- Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Sophia Stock
- Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
- Department of Medicine III, Klinikum der Universität München, Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Jakob Jobst
- Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Philipp Jie Müller
- Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Lina Majed
- Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Matthias Seifert
- Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Anna-Kristina Klüver
- Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Theo Lorenzini
- Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Ruth Grünmeier
- Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Moritz Thomas
- Institute of AI for Health, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
- Institute of Computational Biology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
- School of Life Sciences Weihenstephan, Technical University of Munich, Munich, Freising, Germany
| | - Adrian Gottschlich
- Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Richard Klaus
- Division of Pediatric Nephrology, Department of Pediatrics, Dr. v. Haunersches Kinderspital, Klinikum der Universität München, Munich, Germany
| | - Carsten Marr
- Institute of AI for Health, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
- Institute of Computational Biology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Michael von Bergwelt-Baildon
- Department of Medicine III, Klinikum der Universität München, Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Simon Rothenfusser
- Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Mitchell P Levesque
- Department of Dermatology, University Hospital Zurich, Schlieren, Switzerland
| | - Markus Vincent Heppt
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Stefan Endres
- Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
- Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Christian Klein
- Roche Innovation Center Zurich, Roche Pharma Research & Early Development, Schlieren, Switzerland
| | - Sebastian Kobold
- Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
- Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
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Chauhan J, Grandits M, Palhares LCGF, Mele S, Nakamura M, López-Abente J, Crescioli S, Laddach R, Romero-Clavijo P, Cheung A, Stavraka C, Chenoweth AM, Sow HS, Chiaruttini G, Gilbert AE, Dodev T, Koers A, Pellizzari G, Ilieva KM, Man F, Ali N, Hobbs C, Lombardi S, Lionarons DA, Gould HJ, Beavil AJ, Geh JLC, MacKenzie Ross AD, Healy C, Calonje E, Downward J, Nestle FO, Tsoka S, Josephs DH, Blower PJ, Karagiannis P, Lacy KE, Spicer J, Karagiannis SN, Bax HJ. Anti-cancer pro-inflammatory effects of an IgE antibody targeting the melanoma-associated antigen chondroitin sulfate proteoglycan 4. Nat Commun 2023; 14:2192. [PMID: 37185332 PMCID: PMC10130092 DOI: 10.1038/s41467-023-37811-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 03/31/2023] [Indexed: 05/17/2023] Open
Abstract
Outcomes for half of patients with melanoma remain poor despite standard-of-care checkpoint inhibitor therapies. The prevalence of the melanoma-associated antigen chondroitin sulfate proteoglycan 4 (CSPG4) expression is ~70%, therefore effective immunotherapies directed at CSPG4 could benefit many patients. Since IgE exerts potent immune-activating functions in tissues, we engineer a monoclonal IgE antibody with human constant domains recognizing CSPG4 to target melanoma. CSPG4 IgE binds to human melanomas including metastases, mediates tumoricidal antibody-dependent cellular cytotoxicity and stimulates human IgE Fc-receptor-expressing monocytes towards pro-inflammatory phenotypes. IgE demonstrates anti-tumor activity in human melanoma xenograft models engrafted with human effector cells and is associated with enhanced macrophage infiltration, enriched monocyte and macrophage gene signatures and pro-inflammatory signaling pathways in the tumor microenvironment. IgE prolongs the survival of patient-derived xenograft-bearing mice reconstituted with autologous immune cells. No ex vivo activation of basophils in patient blood is measured in the presence of CSPG4 IgE. Our findings support a promising IgE-based immunotherapy for melanoma.
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Affiliation(s)
- Jitesh Chauhan
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, London, SE1 9RT, UK
- School of Cancer & Pharmaceutical Sciences, King's College London, Guy's Hospital, London, SE1 9RT, UK
| | - Melanie Grandits
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, London, SE1 9RT, UK
| | - Lais C G F Palhares
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, London, SE1 9RT, UK
| | - Silvia Mele
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, London, SE1 9RT, UK
| | - Mano Nakamura
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, London, SE1 9RT, UK
| | - Jacobo López-Abente
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, London, SE1 9RT, UK
| | - Silvia Crescioli
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, London, SE1 9RT, UK
| | - Roman Laddach
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, London, SE1 9RT, UK
- Department of Informatics, Faculty of Natural, Mathematical and Engineering Sciences, King's College London, Bush House, London, WC2B 4BG, UK
| | - Pablo Romero-Clavijo
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, London, SE1 9RT, UK
- Oncogene Biology Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
| | - Anthony Cheung
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, London, SE1 9RT, UK
- Breast Cancer Now Research Unit, School of Cancer & Pharmaceutical Sciences, King's College London, Guy's Hospital, London, SE1 9RT, UK
| | - Chara Stavraka
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, London, SE1 9RT, UK
- School of Cancer & Pharmaceutical Sciences, King's College London, Guy's Hospital, London, SE1 9RT, UK
- Cancer Centre at Guy's, Guy's and St. Thomas' NHS Foundation Trust, London, SE1 9RT, UK
| | - Alicia M Chenoweth
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, London, SE1 9RT, UK
- Breast Cancer Now Research Unit, School of Cancer & Pharmaceutical Sciences, King's College London, Guy's Hospital, London, SE1 9RT, UK
| | - Heng Sheng Sow
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, London, SE1 9RT, UK
| | - Giulia Chiaruttini
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, London, SE1 9RT, UK
| | - Amy E Gilbert
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, London, SE1 9RT, UK
| | - Tihomir Dodev
- Randall Centre for Cell and Molecular Biophysics, School of Basic and Medical Biosciences, King's College London, London, SE1 9RT, UK
- Asthma UK Centre, Allergic Mechanisms in Asthma, King's College London, London, SE1 9RT, UK
| | - Alexander Koers
- School of Biomedical Engineering and Imaging Sciences, King's College London, London, SE1 7EH, UK
| | - Giulia Pellizzari
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, London, SE1 9RT, UK
| | - Kristina M Ilieva
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, London, SE1 9RT, UK
- Breast Cancer Now Research Unit, School of Cancer & Pharmaceutical Sciences, King's College London, Guy's Hospital, London, SE1 9RT, UK
| | - Francis Man
- School of Biomedical Engineering and Imaging Sciences, King's College London, London, SE1 7EH, UK
- Institute of Pharmaceutical Science, School of Cancer & Pharmaceutical Sciences, King's College London, London, SE1 9NH, UK
| | - Niwa Ali
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, SE1 9RT, UK
- Centre for Gene Therapy and Regenerative Medicine, School of Basic and Medical Biosciences, Faculty of Life Sciences and Medicine, King's College London, London, SE1 9RT, UK
| | - Carl Hobbs
- Wolfson Centre for Age-Related Diseases, King's College London, London, SE1 1UL, UK
| | - Sara Lombardi
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, London, SE1 9RT, UK
- Guy's and St. Thomas' Oncology & Haematology Clinical Trials (OHCT), Cancer Centre at Guy's, London, SE1 9RT, UK
| | - Daniël A Lionarons
- Oncogene Biology Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
| | - Hannah J Gould
- Randall Centre for Cell and Molecular Biophysics, School of Basic and Medical Biosciences, King's College London, London, SE1 9RT, UK
- Asthma UK Centre, Allergic Mechanisms in Asthma, King's College London, London, SE1 9RT, UK
| | - Andrew J Beavil
- Randall Centre for Cell and Molecular Biophysics, School of Basic and Medical Biosciences, King's College London, London, SE1 9RT, UK
- Asthma UK Centre, Allergic Mechanisms in Asthma, King's College London, London, SE1 9RT, UK
| | - Jenny L C Geh
- Department of Plastic Surgery, Guy's and St. Thomas' NHS Foundation Trust, London, SE1 7EH, UK
- Skin Tumour Unit, St. John's Institute of Dermatology, Guy's Hospital, London, SE1 9RT, UK
| | | | - Ciaran Healy
- Department of Plastic Surgery, Guy's and St. Thomas' NHS Foundation Trust, London, SE1 7EH, UK
| | - Eduardo Calonje
- Dermatopathology Department, St. John's Institute of Dermatology, St. Thomas' Hospital, London, SE1 7EH, UK
| | - Julian Downward
- Oncogene Biology Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
| | - Frank O Nestle
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, London, SE1 9RT, UK
- Sanofi US, Cambridge, Massachusetts, USA
| | - Sophia Tsoka
- Department of Informatics, Faculty of Natural, Mathematical and Engineering Sciences, King's College London, Bush House, London, WC2B 4BG, UK
| | - Debra H Josephs
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, London, SE1 9RT, UK
- School of Cancer & Pharmaceutical Sciences, King's College London, Guy's Hospital, London, SE1 9RT, UK
- Cancer Centre at Guy's, Guy's and St. Thomas' NHS Foundation Trust, London, SE1 9RT, UK
| | - Philip J Blower
- School of Biomedical Engineering and Imaging Sciences, King's College London, London, SE1 7EH, UK
| | - Panagiotis Karagiannis
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, London, SE1 9RT, UK
- Department of Oncology, Haematology and Bone Marrow Transplantation, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Katie E Lacy
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, London, SE1 9RT, UK
| | - James Spicer
- School of Cancer & Pharmaceutical Sciences, King's College London, Guy's Hospital, London, SE1 9RT, UK
- Cancer Centre at Guy's, Guy's and St. Thomas' NHS Foundation Trust, London, SE1 9RT, UK
| | - Sophia N Karagiannis
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, London, SE1 9RT, UK.
- Breast Cancer Now Research Unit, School of Cancer & Pharmaceutical Sciences, King's College London, Guy's Hospital, London, SE1 9RT, UK.
| | - Heather J Bax
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, London, SE1 9RT, UK.
- School of Cancer & Pharmaceutical Sciences, King's College London, Guy's Hospital, London, SE1 9RT, UK.
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27
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Luksik AS, Yazigi E, Shah P, Jackson CM. CAR T Cell Therapy in Glioblastoma: Overcoming Challenges Related to Antigen Expression. Cancers (Basel) 2023; 15:cancers15051414. [PMID: 36900205 PMCID: PMC10000604 DOI: 10.3390/cancers15051414] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 02/10/2023] [Accepted: 02/20/2023] [Indexed: 02/25/2023] Open
Abstract
Glioblastoma (GBM) is the most common primary brain tumor, yet prognosis remains dismal with current treatment. Immunotherapeutic strategies have had limited effectiveness to date in GBM, but recent advances hold promise. One such immunotherapeutic advance is chimeric antigen receptor (CAR) T cell therapy, where autologous T cells are extracted and engineered to express a specific receptor against a GBM antigen and are then infused back into the patient. There have been numerous preclinical studies showing promising results, and several of these CAR T cell therapies are being tested in clinical trials for GBM and other brain cancers. While results in tumors such as lymphomas and diffuse intrinsic pontine gliomas have been encouraging, early results in GBM have not shown clinical benefit. Potential reasons for this are the limited number of specific antigens in GBM, their heterogenous expression, and their loss after initiating antigen-specific therapy due to immunoediting. Here, we review the current preclinical and clinical experiences with CAR T cell therapy in GBM and potential strategies to develop more effective CAR T cells for this indication.
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Huang Z, Dewanjee S, Chakraborty P, Jha NK, Dey A, Gangopadhyay M, Chen XY, Wang J, Jha SK. CAR T cells: engineered immune cells to treat brain cancers and beyond. Mol Cancer 2023; 22:22. [PMID: 36721153 PMCID: PMC9890802 DOI: 10.1186/s12943-022-01712-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 12/29/2022] [Indexed: 02/01/2023] Open
Abstract
Malignant brain tumors rank among the most challenging type of malignancies to manage. The current treatment protocol commonly entails surgery followed by radiotherapy and/or chemotherapy, however, the median patient survival rate is poor. Recent developments in immunotherapy for a variety of tumor types spark optimism that immunological strategies may help patients with brain cancer. Chimeric antigen receptor (CAR) T cells exploit the tumor-targeting specificity of antibodies or receptor ligands to direct the cytolytic capacity of T cells. Several molecules have been discovered as potential targets for immunotherapy-based targeting, including but not limited to EGFRvIII, IL13Rα2, and HER2. The outstanding clinical responses to CAR T cell-based treatments in patients with hematological malignancies have generated interest in using this approach to treat solid tumors. Research results to date support the astounding clinical response rates of CD19-targeted CAR T cells, early clinical experiences in brain tumors demonstrating safety and evidence for disease-modifying activity, and the promise for further advances to ultimately assist patients clinically. However, several variable factors seem to slow down the progress rate regarding treating brain cancers utilizing CAR T cells. The current study offers a thorough analysis of CAR T cells' promise in treating brain cancer, including design and delivery considerations, current strides in clinical and preclinical research, issues encountered, and potential solutions.
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Affiliation(s)
- Zoufang Huang
- grid.452437.3Department of Hematology, Ganzhou Key Laboratory of Hematology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Saikat Dewanjee
- grid.216499.10000 0001 0722 3459Advanced Pharmacognosy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, 700032 India
| | - Pratik Chakraborty
- grid.216499.10000 0001 0722 3459Advanced Pharmacognosy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, 700032 India
| | - Niraj Kumar Jha
- grid.412552.50000 0004 1764 278XDepartment of Biotechnology, School of Engineering & Technology, Sharda University, Greater Noida, Uttar Pradesh 201310 India
| | - Abhijit Dey
- grid.412537.60000 0004 1768 2925Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata, West Bengal 700032 India
| | - Moumita Gangopadhyay
- grid.502979.00000 0004 6087 8632Department of Biotechnology, School of Life Science and Biotechnology, Adamas University, Barasat, Kolkata, West Bengal 700126 India
| | - Xuan-Yu Chen
- grid.264091.80000 0001 1954 7928Institute for Biotechnology, St. John’s University, Queens, New York, 11439 USA
| | - Jian Wang
- Department of Radiotherapy, the Affiliated Jiangyin People’s Hospital of Nantong University, Jiangyin, 214400 China
| | - Saurabh Kumar Jha
- grid.412552.50000 0004 1764 278XDepartment of Biotechnology, School of Engineering & Technology, Sharda University, Greater Noida, Uttar Pradesh 201310 India ,grid.448792.40000 0004 4678 9721Department of Biotechnology Engineering and Food Technology, Chandigarh University, Mohali, 140413 India ,grid.449906.60000 0004 4659 5193Department of Biotechnology, School of Applied & Life Sciences (SALS), Uttaranchal University, Dehradun, 248007 India
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Bassotti G, Fruganti A, Stracci F, Marconi P, Fettucciari K. Cytotoxic synergism of Clostridioides difficile toxin B with proinflammatory cytokines in subjects with inflammatory bowel diseases. World J Gastroenterol 2023; 29:582-596. [PMID: 36742168 PMCID: PMC9896618 DOI: 10.3748/wjg.v29.i4.582] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 12/03/2022] [Accepted: 12/27/2022] [Indexed: 01/20/2023] Open
Abstract
Clostridioides difficile (C. difficile) is progressively colonizing humans and animals living with humans. During this process, hypervirulent strains and mutated toxin A and B of C. difficile (TcdA and TcdB) are originating and developing. While in healthy subjects colonization by C. difficile becomes a risk after the use of antibiotics that alter the microbiome, other categories of people are more susceptible to infection and at risk of relapse, such as those with inflammatory bowel disease (IBD). Recent in vitro studies suggest that this increased susceptibility could be due to the strong cytotoxic synergism between TcdB and proinflammatory cytokines the tumor necrosis factor-alpha and interferon-gamma (CKs). Therefore, in subjects with IBD the presence of an inflammatory state in the colon could be the driver that increases the susceptibility to C. difficile infection and its progression and relapses. TcdB is internalized in the cell via three receptors: chondroitin sulphate proteoglycan 4; poliovirus receptor-like 3; and Wnt receptor frizzled family. Chondroitin sulphate proteoglycan 4 and Wnt receptor frizzled family are involved in cell death by apoptosis or necrosis depending on the concentration of TcdB and cell types, while poliovirus receptor-like 3 induces only necrosis. It is possible that cytokines could also induce a greater expression of receptors for TcdB that are more involved in necrosis than in apoptosis. Therefore, in subjects with IBD there are the conditions: (1) For greater susceptibility to C. difficile infection, such as the inflammatory state, and abnormalities of the microbiome and of the immune system; (2) for the enhancement of the cytotoxic activity of TcdB +Cks; and (3) for a greater expression of TcdB receptors stimulated by cytokines that induce cell death by necrosis rather than apoptosis. The only therapeutic approach currently possible in IBD patients is monitoring of C. difficile colonization for interventions aimed at reducing tumor necrosis factor-alpha and interferon-gamma levels when the infection begins. The future perspective is to generate bacteriophages against C. difficile for targeted therapy.
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Affiliation(s)
- Gabrio Bassotti
- Department of Medicine and Surgery, Gastroenterology, Hepatology & Digestive Endoscopy Section University of Perugia Medical School, Piazza Lucio Severi, Perugia 06132, Italy, and Santa Maria della Misericordia Hospital, Gastroenterology & Hepatology Unit Perugia 06156, Italy
| | - Alessandro Fruganti
- School of Biosciences and Veterinary Medicine, University of Camerino, Matelica 62024, Italy
| | - Fabrizio Stracci
- Medicine and Surgery, Hygiene and Public Health Section, University of Perugia, Perugia 06123, Italy
| | - Pierfrancesco Marconi
- Medicine and Surgery, Biosciences & Medical Embryology Section, University of Perugia, Perugia 06132, Italy
| | - Katia Fettucciari
- Medicine and Surgery, Biosciences & Medical Embryology Section, University of Perugia, Perugia 06132, Italy
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30
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Boudin L, de Nonneville A, Finetti P, Mescam L, Le Cesne A, Italiano A, Blay JY, Birnbaum D, Mamessier E, Bertucci F. CSPG4 expression in soft tissue sarcomas is associated with poor prognosis and low cytotoxic immune response. Lab Invest 2022; 20:464. [PMID: 36221119 PMCID: PMC9552405 DOI: 10.1186/s12967-022-03679-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Accepted: 09/29/2022] [Indexed: 11/10/2022]
Abstract
Background Soft tissue sarcomas (STS) are heterogeneous and pro-metastatic tumors. Identification of accurate prognostic factors and novel therapeutic targets are crucial. CSPG4 is a cell surface proteoglycan with oncogenic functions. It recently emerged as a potential target for immunotherapy, including cell therapy based on CSPG4-specific chimeric antigen receptor (CAR)-redirected cytokine-induced killer lymphocytes (CSPG4-CAR.CIKs) in STS. However, expression of CSPG4 is poorly known in STS so far. Methods We analyzed CSPG4 gene expression in 1378 localized STS clinical samples, and searched for correlations with clinicopathological data, including disease-free survival (DFS), and with tumor immune features. Results CSPG4 expression was heterogeneous across samples. High expression was associated with younger patients’ age, more frequent undifferentiated pleomorphic sarcoma and myxofibrosarcoma pathological subtypes, more frequent internal trunk tumor site, and more CINSARC high-risk samples. No correlation existed with pathological tumor size and grade, and tumor depth. Patients with high CSPG4 expression displayed 49% (95% CI 42–57) 5-year DFS versus 61% (95% CI 56–68) in patients with low expression (p = 3.17E−03), representing a 49% increased risk of event in the “CSPG4-high” group (HR = 1.49, 95% CI 1.14–1.94). This unfavorable prognostic value persisted in multivariate analysis, independently from other variables. There were significant differences in immune variables between “CSPG4-high” and “CSPG4-low” tumors. The "CSPG4-low" tumors displayed profiles suggesting higher anti-tumor cytotoxic immune response and higher potential vulnerability to immune checkpoint inhibitors (ICI). By contrast, the "CSPG4-high" tumors displayed profiles implying an immune-excluded tumor microenvironment, potentially induced by hypoxia, resulting from an immature chaotic microvasculature, and/or the presence of contractile myofibroblasts. Conclusions Patients with “CSPG4-high” STS, theoretically candidate for CAR.CIKs, display shorter DFS and an immune environment unfavorable to vulnerability to CAR.CIKs, which could be improved by combining anti-angiogenic drugs able to normalize the tumor vasculature. By contrast, “CSPG4-low” STS are better candidates for immune therapy involving ICI. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-022-03679-y.
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Affiliation(s)
- Laurys Boudin
- Laboratory of Predictive Oncology, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, Aix-Marseille Université, INSERM UMR1068, CNRS UMR725, Marseille, France
| | - A de Nonneville
- Laboratory of Predictive Oncology, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, Aix-Marseille Université, INSERM UMR1068, CNRS UMR725, Marseille, France.,Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France
| | - Pascal Finetti
- Laboratory of Predictive Oncology, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, Aix-Marseille Université, INSERM UMR1068, CNRS UMR725, Marseille, France
| | - Léna Mescam
- French Sarcoma Group, Lyon, France.,Department of Pathology, Institut Paoli-Calmettes, 232 Bd. Sainte-Marguerite, 13009, Marseille, France
| | - A Le Cesne
- French Sarcoma Group, Lyon, France.,Department of Medical Oncology, Gustave Roussy, Villejuif, France
| | - Antoine Italiano
- French Sarcoma Group, Lyon, France.,Department of Medical Oncology, Institut Bergonie, Bordeaux, France
| | - Jean-Yves Blay
- French Sarcoma Group, Lyon, France.,Department of Medical Oncology, Centre Léon Bérard, UNICANCER &, Université Claude Bernard Lyon I, Lyon, France
| | - Daniel Birnbaum
- Laboratory of Predictive Oncology, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, Aix-Marseille Université, INSERM UMR1068, CNRS UMR725, Marseille, France
| | - Emilie Mamessier
- Laboratory of Predictive Oncology, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, Aix-Marseille Université, INSERM UMR1068, CNRS UMR725, Marseille, France
| | - François Bertucci
- Laboratory of Predictive Oncology, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, Aix-Marseille Université, INSERM UMR1068, CNRS UMR725, Marseille, France. .,Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France. .,French Sarcoma Group, Lyon, France.
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31
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Gimple RC, Yang K, Halbert ME, Agnihotri S, Rich JN. Brain cancer stem cells: resilience through adaptive plasticity and hierarchical heterogeneity. Nat Rev Cancer 2022; 22:497-514. [PMID: 35710946 DOI: 10.1038/s41568-022-00486-x] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/03/2022] [Indexed: 02/07/2023]
Abstract
Malignant brain tumours are complex ecosystems containing neoplastic and stromal components that generate adaptive and evolutionarily driven aberrant tissues in the central nervous system. Brain cancers are cultivated by a dynamic population of stem-like cells that enforce intratumoural heterogeneity and respond to intrinsic microenvironment or therapeutically guided insults through proliferation, plasticity and restructuring of neoplastic and stromal components. Far from a rigid hierarchy, heterogeneous neoplastic populations transition between cellular states with differential self-renewal capacities, endowing them with powerful resilience. Here we review the biological machinery used by brain tumour stem cells to commandeer tissues in the intracranial space, evade immune responses and resist chemoradiotherapy. Through recent advances in single-cell sequencing, improved models to investigate the role of the tumour microenvironment and a deeper understanding of the fundamental role of the immune system in cancer biology, we are now better equipped to explore mechanisms by which these processes can be exploited for therapeutic benefit.
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Affiliation(s)
- Ryan C Gimple
- Department of Pathology, Case Western Reserve University, Cleveland, OH, USA
| | - Kailin Yang
- Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA
| | - Matthew E Halbert
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Sameer Agnihotri
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Jeremy N Rich
- University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA.
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
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32
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Barish ME, Weng L, Awabdeh D, Zhai Y, Starr R, D'Apuzzo M, Rockne RC, Li H, Badie B, Forman SJ, Brown CE. Spatial organization of heterogeneous immunotherapy target antigen expression in high-grade glioma. Neoplasia 2022; 30:100801. [PMID: 35550513 PMCID: PMC9108993 DOI: 10.1016/j.neo.2022.100801] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 04/15/2022] [Accepted: 04/18/2022] [Indexed: 11/23/2022]
Abstract
High-grade (WHO grades III-IV) glioma remains one of the most lethal human cancers. Adoptive transfer of tumor-targeting chimeric antigen receptor (CAR)-redirected T cells for high-grade glioma has revealed promising indications of anti-tumor activity, but objective clinical responses remain elusive for most patients. A significant challenge to effective immunotherapy is the highly heterogeneous structure of these tumors, including large variations in the magnitudes and distributions of target antigen expression, observed both within individual tumors and between patients. To obtain a more detailed understanding of immunotherapy target antigens within patient tumors, we immunochemically mapped at single cell resolution three clinically-relevant targets, IL13Rα2, HER2 and EGFR, on tumor samples drawn from a 43-patient cohort. We observed that within individual tumor samples, expression of these antigens was neither random nor uniform, but rather that they mapped into local neighborhoods - phenotypically similar cells within regions of cellular tumor - reflecting not well understood properties of tumor cells and their milieu. Notably, tumor cell neighborhoods of high antigen expression were not arranged independently within regions. For example, in cellular tumor regions, neighborhoods of high IL13Rα2 and HER2 expression appeared to be reciprocal to those of EGFR, while in areas of pseudopalisading necrosis, expression of IL13Rα2 and HER2, but not EGFR, appeared to reflect the radial organization of tumor cells around hypoxic cores. Other structural features affecting expression of immunotherapy target antigens remain to be elucidated. This structured but heterogeneous organization of antigen expression in high grade glioma is highly permissive for antigen escape, and combinatorial antigen targeting is a commonly suggested potential mitigating strategy. Deeper understanding of antigen expression within and between patient tumors will enhance optimization of combination immunotherapies, the most immediate clinical application of the observations presented here being the importance of including (wild-type) EGFR as a target antigen.
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Affiliation(s)
- Michael E Barish
- Department of Stem Cell Biology & Regenerative Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010, United States.
| | - Lihong Weng
- Department of Hematology & Hematopoietic Cell Transplantation, National Medical Center, City of Hope, Duarte, CA 91010, United States
| | - Dina Awabdeh
- Department of Stem Cell Biology & Regenerative Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010, United States
| | - Yubo Zhai
- Department of Hematology & Hematopoietic Cell Transplantation, National Medical Center, City of Hope, Duarte, CA 91010, United States
| | - Renate Starr
- Department of Hematology & Hematopoietic Cell Transplantation, National Medical Center, City of Hope, Duarte, CA 91010, United States
| | - Massimo D'Apuzzo
- Department of Pathology, National Medical Center, City of Hope, Duarte, CA 91010, United States
| | - Russell C Rockne
- Department of Computational and Quantitative Medicine, Division of Mathematical Oncology, Beckman Research Institute, City of Hope, Duarte, CA 91010, United States
| | - Haiqing Li
- Integrative Genomics Core, Division of Translational Bioinformatics, Beckman Research Institute, City of Hope, Duarte, CA 91010, United States
| | - Behnam Badie
- Department of Surgery, Division of Neurosurgery, National Medical Center, City of Hope, Duarte, CA 91010, United States
| | - Stephen J Forman
- Department of Hematology & Hematopoietic Cell Transplantation, National Medical Center, City of Hope, Duarte, CA 91010, United States
| | - Christine E Brown
- Department of Hematology & Hematopoietic Cell Transplantation, National Medical Center, City of Hope, Duarte, CA 91010, United States; Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA 91010, United States.
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Jogalekar MP, Rajendran RL, Khan F, Dmello C, Gangadaran P, Ahn BC. CAR T-Cell-Based gene therapy for cancers: new perspectives, challenges, and clinical developments. Front Immunol 2022; 13:925985. [PMID: 35936003 PMCID: PMC9355792 DOI: 10.3389/fimmu.2022.925985] [Citation(s) in RCA: 106] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 06/27/2022] [Indexed: 12/20/2022] Open
Abstract
Chimeric antigen receptor (CAR)-T cell therapy is a progressive new pillar in immune cell therapy for cancer. It has yielded remarkable clinical responses in patients with B-cell leukemia or lymphoma. Unfortunately, many challenges remain to be addressed to overcome its ineffectiveness in the treatment of other hematological and solidtumor malignancies. The major hurdles of CAR T-cell therapy are the associated severe life-threatening toxicities such as cytokine release syndrome and limited anti-tumor efficacy. In this review, we briefly discuss cancer immunotherapy and the genetic engineering of T cells and, In detail, the current innovations in CAR T-cell strategies to improve efficacy in treating solid tumors and hematologic malignancies. Furthermore, we also discuss the current challenges in CAR T-cell therapy and new CAR T-cell-derived nanovesicle therapy. Finally, strategies to overcome the current clinical challenges associated with CAR T-cell therapy are included as well.
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Affiliation(s)
- Manasi P. Jogalekar
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, United States
| | - Ramya Lakshmi Rajendran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, South Korea
| | - Fatima Khan
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Crismita Dmello
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Prakash Gangadaran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, South Korea
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu, South Korea
| | - Byeong-Cheol Ahn
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, South Korea
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu, South Korea
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Zhang P, Zhang Y, Ji N. Challenges in the Treatment of Glioblastoma by Chimeric Antigen Receptor T-Cell Immunotherapy and Possible Solutions. Front Immunol 2022; 13:927132. [PMID: 35874698 PMCID: PMC9300859 DOI: 10.3389/fimmu.2022.927132] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Accepted: 06/10/2022] [Indexed: 11/24/2022] Open
Abstract
Glioblastoma (GBM), one of the most lethal brain cancers in adults, accounts for 48.6% of all malignant primary CNS tumors diagnosed each year. The 5-year survival rate of GBM patients remains less than 10% even after they receive the standard-of-care treatment, including maximal safe resection, adjuvant radiation, and chemotherapy with temozolomide. Therefore, new therapeutic modalities are urgently needed for this deadly cancer. The last decade has witnessed great advances in chimeric antigen receptor T (CAR-T) cell immunotherapy for the treatment of hematological malignancies. Up to now, the US FDA has approved six CAR-T cell products in treating hematopoietic cancers including B-cell acute lymphoblastic leukemia, lymphoma, and multiple myeloma. Meanwhile, the number of clinical trials on CAR-T cell has increased significantly, with more than 80% from China and the United States. With its achievements in liquid cancers, the clinical efficacy of CAR-T cell therapy has also been explored in a variety of solid malignancies that include GBMs. However, attempts to expand CAR-T cell immunotherapy in GBMs have not yet presented promising results in hematopoietic malignancies. Like other solid tumors, CAR-T cell therapies against GBM still face several challenges, such as tumor heterogeneity, tumor immunosuppressive microenvironment, and CAR-T cell persistence. Hence, developing strategies to overcome these challenges will be necessary to accelerate the transition of CAR-T cell immunotherapy against GBMs from bench to bedside.
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Affiliation(s)
- Peng Zhang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Yang Zhang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Nan Ji
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Beihang University, Beijing, China
- *Correspondence: Nan Ji,
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35
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Maiorano G, Guido C, Russo A, Giglio A, Rizzello L, Testini M, Cortese B, D’Amone S, Gigli G, Palamà IE. Hybrid Polyelectrolyte Nanocomplexes for Non-Viral Gene Delivery with Favorable Efficacy and Safety Profile. Pharmaceutics 2022; 14:pharmaceutics14071310. [PMID: 35890206 PMCID: PMC9323431 DOI: 10.3390/pharmaceutics14071310] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 06/15/2022] [Accepted: 06/18/2022] [Indexed: 12/10/2022] Open
Abstract
The development of nanovectors for precise gene therapy is increasingly focusing on avoiding uncontrolled inflammation while still being able to effectively act on the target sites. Herein, we explore the use of non-viral hybrid polyelectrolyte nanocomplexes (hPECs) for gene delivery, which display good transfection efficacy coupled with non-inflammatory properties. Monodisperse hPECs were produced through a layer-by-layer self-assembling of biocompatible and biodegradable polymers. The resulting nanocomplexes had an inner core characterized by an EGFP-encoding plasmid DNA (pDNA) complexed with linear polyethyleneimine or protamine (PEI or PRM) stabilized with lecithin and poly(vinyl alcohol) (PVA) and an outer layer consisting of medium-molecular-weight chitosan (CH) combined with tripolyphosphate (TPP). PEI- and PRM-hPECs were able to efficiently protect the genetic cargo from nucleases and to perform a stimuli-responsive release of pDNA overtime, thus guaranteeing optimal transfection efficiency. Importantly, hPECs revealed a highly cytocompatible and a non-inflammatory profile in vitro. These results were further supported by evidence of the weak and unspecific interactions of serum proteins with both hPECs, thus confirming the antifouling properties of their outer shell. Therefore, these hPECs represent promising candidates for the development of effective, safe nanotools for gene delivery.
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Affiliation(s)
- Gabriele Maiorano
- Nanotechnology Institute of National Research Council, CNR-NANOTEC, Monteroni Street, 73100 Lecce, Italy; (G.M.); (C.G.); (A.R.); (A.G.); (M.T.); (S.D.); (G.G.)
| | - Clara Guido
- Nanotechnology Institute of National Research Council, CNR-NANOTEC, Monteroni Street, 73100 Lecce, Italy; (G.M.); (C.G.); (A.R.); (A.G.); (M.T.); (S.D.); (G.G.)
- Department of Mathematics and Physics, University of Salento, Monteroni Street, 73100 Lecce, Italy
| | - Annamaria Russo
- Nanotechnology Institute of National Research Council, CNR-NANOTEC, Monteroni Street, 73100 Lecce, Italy; (G.M.); (C.G.); (A.R.); (A.G.); (M.T.); (S.D.); (G.G.)
| | - Andrea Giglio
- Nanotechnology Institute of National Research Council, CNR-NANOTEC, Monteroni Street, 73100 Lecce, Italy; (G.M.); (C.G.); (A.R.); (A.G.); (M.T.); (S.D.); (G.G.)
| | - Loris Rizzello
- Department of Pharmaceutical Sciences (DISFARM), University of Milan, G. Balzaretti 9 Street, 20133 Milan, Italy;
- National Institute of Molecular Genetics (INGM), Francesco Sforza 35 Street, 20122 Milan, Italy
| | - Mariangela Testini
- Nanotechnology Institute of National Research Council, CNR-NANOTEC, Monteroni Street, 73100 Lecce, Italy; (G.M.); (C.G.); (A.R.); (A.G.); (M.T.); (S.D.); (G.G.)
| | - Barbara Cortese
- Nanotechnology Institute of National Research Council, CNR-NANOTEC, c/o La Sapienza University, Piazzale Aldo Moro, 00185 Rome, Italy;
| | - Stefania D’Amone
- Nanotechnology Institute of National Research Council, CNR-NANOTEC, Monteroni Street, 73100 Lecce, Italy; (G.M.); (C.G.); (A.R.); (A.G.); (M.T.); (S.D.); (G.G.)
| | - Giuseppe Gigli
- Nanotechnology Institute of National Research Council, CNR-NANOTEC, Monteroni Street, 73100 Lecce, Italy; (G.M.); (C.G.); (A.R.); (A.G.); (M.T.); (S.D.); (G.G.)
- Department of Mathematics and Physics, University of Salento, Monteroni Street, 73100 Lecce, Italy
| | - Ilaria Elena Palamà
- Nanotechnology Institute of National Research Council, CNR-NANOTEC, Monteroni Street, 73100 Lecce, Italy; (G.M.); (C.G.); (A.R.); (A.G.); (M.T.); (S.D.); (G.G.)
- Correspondence:
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36
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Zhang J, Siller-Farfán JA. Current and future perspectives of chimeric antigen receptors against glioblastoma. IMMUNOTHERAPY ADVANCES 2022; 2:ltac014. [PMID: 36284838 PMCID: PMC9585667 DOI: 10.1093/immadv/ltac014] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 05/27/2022] [Indexed: 11/14/2022] Open
Abstract
Glioblastoma multiforme (GBM) is the most malignant form of cancer in the central nervous system; even with treatment, it has a 5-year survival rate of 7.2%. The adoptive cell transfer (ACT) of T cells expressing chimeric antigen receptors (CARs) has shown a remarkable success against hematological malignancies, namely leukemia and multiple myeloma. However, CAR T cell therapy against solid tumors, and more specifically GBM, is still riddled with challenges preventing its widespread adoption. Here, we first establish the obstacles in ACT against GBM, including on-target/off-tumor toxicity, antigen modulation, tumor heterogeneity, and the immunosuppressive tumor microenvironment. We then present recent preclinical and clinical studies targeting well-characterized GBM antigens, which include the interleukin-13 receptor α2 and the epidermal growth factor receptor. Afterward, we turn our attention to alternative targets in GBM, including less-explored antigens such as B7-H3 (CD276), carbonic anhydrase IX, and the GD2 ganglioside. We also discuss additional target ligands, namely CD70, and natural killer group 2 member D ligands. Finally, we present the possibilities afforded by novel CAR architectures. In particular, we examine the use of armored CARs to improve the survival and proliferation of CAR T cells. We conclude by discussing the advantages of tandem and synNotch CARs when targeting multiple GBM antigens.
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Affiliation(s)
- Josephine Zhang
- Department of Biology, Johns Hopkins University, 3400 N Charles St , Baltimore 21218, United States
- St Anne’s College, University of Oxford, Woodstock Rd , Oxford OX2 6HS, United Kingdom
| | - Jesús A Siller-Farfán
- Sir William Dunn School of Pathology, University of Oxford, S Parks Rd , Oxford OX1 3DP, United Kingdom
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Karimi-Shahri M, Khorramdel M, Zarei S, Attarian F, Hashemian P, Javid H. Glioblastoma, an opportunity T cell trafficking could bring for the treatment. Mol Biol Rep 2022; 49:9863-9875. [DOI: 10.1007/s11033-022-07510-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 04/22/2022] [Indexed: 01/22/2023]
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Lin YJ, Mashouf LA, Lim M. CAR T Cell Therapy in Primary Brain Tumors: Current Investigations and the Future. Front Immunol 2022; 13:817296. [PMID: 35265074 PMCID: PMC8899093 DOI: 10.3389/fimmu.2022.817296] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 01/20/2022] [Indexed: 12/15/2022] Open
Abstract
Chimeric antigen receptor T cells (CAR T cells) are engineered cells expressing a chimeric antigen receptor (CAR) against a specific tumor antigen (TA) that allows for the identification and elimination of cancer cells. The remarkable clinical effect seen with CAR T cell therapies against hematological malignancies have attracted interest in developing such therapies for solid tumors, including brain tumors. Glioblastoma (GBM) is the most common primary brain tumor in adults and is associated with poor prognosis due to its highly aggressive nature. Pediatric brain cancers are similarly aggressive and thus are a major cause of pediatric cancer-related death. CAR T cell therapy represents a promising avenue for therapy against these malignancies. Several specific TAs, such as EGFR/EGFRvIII, IL13Rα2, B7-H3, and HER2, have been targeted in preclinical studies and clinical trials. Unfortunately, CAR T cells against brain tumors have showed limited efficacy due to TA heterogeneity, difficulty trafficking from blood to tumor sites, and the immunosuppressive tumor microenvironment. Here, we review current CAR T cell approaches in treating cancers, with particular focus on brain cancers. We also describe a novel technique of focused ultrasound controlling the activation of engineered CAR T cells to achieve the safer cell therapies. Finally, we summarize the development of combinational strategies to improve the efficacy and overcome historical limitations of CAR T cell therapy.
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Affiliation(s)
- Ya-Jui Lin
- Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, CA, United States.,Department of Neurosurgery, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
| | - Leila A Mashouf
- Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, CA, United States.,Harvard Medical School, Boston, MA, United States
| | - Michael Lim
- Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, CA, United States
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Mahmoud AB, Ajina R, Aref S, Darwish M, Alsayb M, Taher M, AlSharif SA, Hashem AM, Alkayyal AA. Advances in immunotherapy for glioblastoma multiforme. Front Immunol 2022; 13:944452. [PMID: 36311781 PMCID: PMC9597698 DOI: 10.3389/fimmu.2022.944452] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 09/23/2022] [Indexed: 02/05/2023] Open
Abstract
Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor of the central nervous system and has a very poor prognosis. The current standard of care for patients with GBM involves surgical resection, radiotherapy, and chemotherapy. Unfortunately, conventional therapies have not resulted in significant improvements in the survival outcomes of patients with GBM; therefore, the overall mortality rate remains high. Immunotherapy is a type of cancer treatment that helps the immune system to fight cancer and has shown success in different types of aggressive cancers. Recently, healthcare providers have been actively investigating various immunotherapeutic approaches to treat GBM. We reviewed the most promising immunotherapy candidates for glioblastoma that have achieved encouraging results in clinical trials, focusing on immune checkpoint inhibitors, oncolytic viruses, nonreplicating viral vectors, and chimeric antigen receptor (CAR) immunotherapies.
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Affiliation(s)
- Ahmad Bakur Mahmoud
- College of Applied Medical Sciences, Taibah University, Almadinah Almunwarah, Saudi Arabia
- Strategic Research and Innovation Laboratories, Taibah University, Almadinah Almunwarah, Saudi Arabia
- King Abdullah International Medical Research Centre, King Saud University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
- *Correspondence: Ahmad Bakur Mahmoud, ; Almohanad A. Alkayyal,
| | - Reham Ajina
- King Abdullah International Medical Research Centre, King Saud University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Sarah Aref
- King Abdullah International Medical Research Centre, King Saud University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Manar Darwish
- Strategic Research and Innovation Laboratories, Taibah University, Almadinah Almunwarah, Saudi Arabia
| | - May Alsayb
- College of Applied Medical Sciences, Taibah University, Almadinah Almunwarah, Saudi Arabia
| | - Mustafa Taher
- College of Applied Medical Sciences, Taibah University, Almadinah Almunwarah, Saudi Arabia
- Strategic Research and Innovation Laboratories, Taibah University, Almadinah Almunwarah, Saudi Arabia
| | - Shaker A. AlSharif
- King Fahad Hospital, Ministry of Health, Almadinah Almunwarah, Saudi Arabia
| | - Anwar M. Hashem
- Vaccines and Immunotherapy Unit, King Fahd Medical Research Center; King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Microbiology and Parasitology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Almohanad A. Alkayyal
- Department of Medical Laboratory Technology, University of Tabuk, Tabuk, Saudi Arabia
- Immunology Research Program, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
- *Correspondence: Ahmad Bakur Mahmoud, ; Almohanad A. Alkayyal,
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Thanh Nguyen TD, Marasini R, Aryal S. Re-engineered imaging agent using biomimetic approaches. WILEY INTERDISCIPLINARY REVIEWS. NANOMEDICINE AND NANOBIOTECHNOLOGY 2022; 14:e1762. [PMID: 34698438 PMCID: PMC8758533 DOI: 10.1002/wnan.1762] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 08/25/2021] [Indexed: 01/03/2023]
Abstract
Recent progress in biomedical technology, the clinical bioimaging, has a greater impact on the diagnosis, treatment, and prevention of disease, especially by early intervention and precise therapy. Varieties of organic and inorganic materials either in the form of small molecules or nano-sized materials have been engineered as a contrast agent (CA) to enhance image resolution among different tissues for the detection of abnormalities such as cancer and vascular occlusion. Among different innovative imaging agents, contrast agents coupled with biologically derived endogenous platform shows the promising application in the biomedical field, including drug delivery and bioimaging. Strategy using biocomponents such as cells or products of cells as a delivery system predominantly reduces the toxic behavior of its cargo, as these systems reduce non-specific distribution by navigating its cargo toward the targeted location. The hypothesis is that depending on the original biological role of the naïve cell, the contrast agents carried by such a system can provide corresponding natural designated behavior. Therefore, by combining properties of conventional synthetic molecules and nanomaterials with endogenous cell body, new solutions in the field of bioimaging to overcome biological barriers have been offered as innovative bioengineering. In this review, we will discuss the engineering of cell and cell-derived components as a delivery system for various contrast agents to achieve clinically relevant contrast for diagnosis and study underlining mechanism of disease progression. This article is categorized under: Nanotechnology Approaches to Biology > Cells at the Nanoscale Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.
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Affiliation(s)
- Tuyen Duong Thanh Nguyen
- Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Ramesh Marasini
- Department of Chemistry, Nanotechnology Innovation Center of Kansas State, Kansas State Univeristy, Manhattan, KS
| | - Santosh Aryal
- Department of Pharmaceutical Sciences and Health Outcomes, The Ben and Maytee Fisch College of Pharmacy, University of Texas at Tyler, Tyler, Texas 75799, USA
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Chu YH, Liao WC, Ho YJ, Huang CH, Tseng TJ, Liu CH. Targeting Chondroitin Sulfate Reduces Invasiveness of Glioma Cells by Suppressing CD44 and Integrin β1 Expression. Cells 2021; 10:3594. [PMID: 34944101 PMCID: PMC8700349 DOI: 10.3390/cells10123594] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 12/14/2021] [Accepted: 12/17/2021] [Indexed: 12/18/2022] Open
Abstract
Chondroitin sulfate (CS) is a major component of the extracellular matrix found to be abnormally accumulated in several types of cancer tissues. Previous studies have indicated that CS synthases and modification enzymes are frequently elevated in human gliomas and are associated with poor prognosis. However, the underlying mechanisms of CS in cancer progression and approaches for interrupting its functions in cancer cells remain largely unexplored. Here, we have found that CS was significantly enriched surrounding the vasculature in a subset of glioma tissues, which was akin to the perivascular niche for cancer-initiating cells. Silencing or overexpression of the major CS synthase, chondroitin sulfate synthase 1 (CHSY1), significantly regulated the glioma cell invasive phenotypes and modulated integrin expression. Furthermore, we identified CD44 as a crucial chondroitin sulfate proteoglycan (CSPG) that was modified by CHSY1 on glioma cells, and the suppression of CS formation on CD44 by silencing the CHSY1-inhibited interaction between CD44 and integrin β1 on the adhesion complex. Moreover, we tested the CS-specific binding peptide, resulting in the suppression of glioma cell mobility in a fashion similar to that observed upon the silencing of CHSY1. In addition, the peptide demonstrated significant affinity to CD44, promoted CD44 degradation, and suppressed integrin β1 expression in glioma cells. Overall, this study proposes a potential regulatory loop between CS, CD44, and integrin β1 in glioma cells, and highlights the importance of CS in CD44 stability. Furthermore, the targeting of CS by specific binding peptides has potential as a novel therapeutic strategy for glioma.
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Affiliation(s)
- Yin-Hung Chu
- Department of Anatomy, Faculty of Medicine, Chung Shan Medical University, Taichung 402306, Taiwan; (Y.-H.C.); (W.-C.L.); (C.-H.H.); (T.-J.T.)
| | - Wen-Chieh Liao
- Department of Anatomy, Faculty of Medicine, Chung Shan Medical University, Taichung 402306, Taiwan; (Y.-H.C.); (W.-C.L.); (C.-H.H.); (T.-J.T.)
- Department of Medical Education, Chung Shan Medical University Hospital, Taichung 402306, Taiwan
| | - Ying-Jui Ho
- Department of Psychology, Chung Shan Medical University, Taichung 402306, Taiwan;
| | - Chih-Hsien Huang
- Department of Anatomy, Faculty of Medicine, Chung Shan Medical University, Taichung 402306, Taiwan; (Y.-H.C.); (W.-C.L.); (C.-H.H.); (T.-J.T.)
| | - To-Jung Tseng
- Department of Anatomy, Faculty of Medicine, Chung Shan Medical University, Taichung 402306, Taiwan; (Y.-H.C.); (W.-C.L.); (C.-H.H.); (T.-J.T.)
- Department of Medical Education, Chung Shan Medical University Hospital, Taichung 402306, Taiwan
| | - Chiung-Hui Liu
- Department of Anatomy, Faculty of Medicine, Chung Shan Medical University, Taichung 402306, Taiwan; (Y.-H.C.); (W.-C.L.); (C.-H.H.); (T.-J.T.)
- Department of Medical Education, Chung Shan Medical University Hospital, Taichung 402306, Taiwan
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42
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Kilian M, Bunse T, Wick W, Platten M, Bunse L. Genetically Modified Cellular Therapies for Malignant Gliomas. Int J Mol Sci 2021; 22:12810. [PMID: 34884607 PMCID: PMC8657496 DOI: 10.3390/ijms222312810] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 11/12/2021] [Accepted: 11/22/2021] [Indexed: 01/22/2023] Open
Abstract
Despite extensive preclinical research on immunotherapeutic approaches, malignant glioma remains a devastating disease of the central nervous system for which standard of care treatment is still confined to resection and radiochemotherapy. For peripheral solid tumors, immune checkpoint inhibition has shown substantial clinical benefit, while promising preclinical results have yet failed to translate into clinical efficacy for brain tumor patients. With the advent of high-throughput sequencing technologies, tumor antigens and corresponding T cell receptors (TCR) and antibodies have been identified, leading to the development of chimeric antigen receptors (CAR), which are comprised of an extracellular antibody part and an intracellular T cell receptor signaling part, to genetically engineer T cells for antigen recognition. Due to efficacy in other tumor entities, a plethora of CARs has been designed and tested for glioma, with promising signs of biological activity. In this review, we describe glioma antigens that have been targeted using CAR T cells preclinically and clinically, review their drawbacks and benefits, and illustrate how the emerging field of transgenic TCR therapy can be used as a potent alternative for cell therapy of glioma overcoming antigenic limitations.
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Affiliation(s)
- Michael Kilian
- DKTK (German Cancer Consortium), Clinical Cooperation Unit (CCU), Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Theresa Bunse
- DKTK (German Cancer Consortium), Clinical Cooperation Unit (CCU), Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Department of Neurology, Medical Faculty Mannheim, MCTN, University of Heidelberg, 68167 Mannheim, Germany
| | - Wolfgang Wick
- Neurology Clinic, Heidelberg University Hospital, University of Heidelberg, 69120 Heidelberg, Germany
- DKTK CCU Neurooncology, DKFZ, 69120 Heidelberg, Germany
| | - Michael Platten
- DKTK (German Cancer Consortium), Clinical Cooperation Unit (CCU), Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Department of Neurology, Medical Faculty Mannheim, MCTN, University of Heidelberg, 68167 Mannheim, Germany
- Immune Monitoring Unit, National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany
- Helmholtz-Institute of Translational Oncology (HI-TRON), 55131 Mainz, Germany
| | - Lukas Bunse
- DKTK (German Cancer Consortium), Clinical Cooperation Unit (CCU), Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Department of Neurology, Medical Faculty Mannheim, MCTN, University of Heidelberg, 68167 Mannheim, Germany
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43
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Hirabayashi K, Du H, Xu Y, Shou P, Zhou X, Fucá G, Landoni E, Sun C, Chen Y, Savoldo B, Dotti G. Dual Targeting CAR-T Cells with Optimal Costimulation and Metabolic Fitness enhance Antitumor Activity and Prevent Escape in Solid Tumors. ACTA ACUST UNITED AC 2021; 2:904-918. [PMID: 34746799 DOI: 10.1038/s43018-021-00244-2] [Citation(s) in RCA: 114] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Chimeric antigen receptor (CAR) T cells showed great activity in hematologic malignancies. However, heterogeneous antigen expression in tumor cells and suboptimal CAR-T cell persistence remain critical aspects to achieve clinical responses in patients with solid tumors. Here we show that CAR-T cells targeting simultaneously two tumor-associated antigens and providing transacting CD28 and 4-1BB costimulation, while sharing the sane CD3ζ-chain cause rapid antitumor effects in in vivo stress conditions, protection from tumor re-challenge and prevention of tumor escape due to low antigen density. Molecular and signaling studies indicate that T cells engineered with the proposed CAR design demonstrate sustained phosphorylation of T cell receptor-associated (TCR) signaling molecules and a molecular signature supporting CAR-T cell proliferation and long-term survival. Furthermore, metabolic profiling of CAR-T cells displayed induction of glycolysis that sustains rapid effector T cell function, but also preservation of oxidative functions, which are critical for T cell long-term persistence.
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Affiliation(s)
- Koichi Hirabayashi
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Hongwei Du
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Yang Xu
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Peishun Shou
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Xin Zhou
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Giovanni Fucá
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Elisa Landoni
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Chuang Sun
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Yuhui Chen
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Barbara Savoldo
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.,Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Gianpietro Dotti
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.,Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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44
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Xun Y, Yang H, Kaminska B, You H. Toll-like receptors and toll-like receptor-targeted immunotherapy against glioma. J Hematol Oncol 2021; 14:176. [PMID: 34715891 PMCID: PMC8555307 DOI: 10.1186/s13045-021-01191-2] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 10/13/2021] [Indexed: 02/08/2023] Open
Abstract
Glioma represents a fast proliferating and highly invasive brain tumor which is resistant to current therapies and invariably recurs. Despite some advancements in anti-glioma therapies, patients’ prognosis remains poor. Toll-like receptors (TLRs) act as the first line of defense in the immune system being the detectors of those associated with bacteria, viruses, and danger signals. In the glioma microenvironment, TLRs are expressed on both immune and tumor cells, playing dual roles eliciting antitumoral (innate and adaptive immunity) and protumoral (cell proliferation, migration, invasion, and glioma stem cell maintenance) responses. Up to date, several TLR-targeting therapies have been developed aiming at glioma bulk and stem cells, infiltrating immune cells, the immune checkpoint axis, among others. While some TLR agonists exhibited survival benefit in clinical trials, it attracts more attention when they are involved in combinatorial treatment with radiation, chemotherapy, immune vaccination, and immune checkpoint inhibition in glioma treatment. TLR agonists can be used as immune modulators to enhance the efficacy of other treatment, to avoid dose accumulation, and what brings more interests is that they can potentiate immune checkpoint delayed resistance to PD-1/PD-L1 blockade by upregulating PD-1/PD-L1 overexpression, thus unleash powerful antitumor responses when combined with immune checkpoint inhibitors. Herein, we focus on recent developments and clinical trials exploring TLR-based treatment to provide a picture of the relationship between TLR and glioma and their implications for immunotherapy.
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Affiliation(s)
- Yang Xun
- Department of Basic Medicine and Biomedical Engineering, School of Medicine, Foshan University, Foshan, 528000, Guangdong Province, China
| | - Hua Yang
- Department of Basic Medicine and Biomedical Engineering, School of Medicine, Foshan University, Foshan, 528000, Guangdong Province, China
| | - Bozena Kaminska
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, No.78 Heng-Zhi-Gang Road, Yue Xiu District, Guangzhou, 510095, China.,Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland
| | - Hua You
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, No.78 Heng-Zhi-Gang Road, Yue Xiu District, Guangzhou, 510095, China.
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45
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Ogunnaike EA, Valdivia A, Yazdimamaghani M, Leon E, Nandi S, Hudson H, Du H, Khagi S, Gu Z, Savoldo B, Ligler FS, Hingtgen S, Dotti G. Fibrin gel enhances the antitumor effects of chimeric antigen receptor T cells in glioblastoma. SCIENCE ADVANCES 2021; 7:eabg5841. [PMID: 34613775 PMCID: PMC8494441 DOI: 10.1126/sciadv.abg5841] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 08/16/2021] [Indexed: 05/14/2023]
Abstract
Regional delivery of chimeric antigen receptor (CAR) T cells in glioblastoma represents a rational therapeutic approach as an alternative to intravenous administration to avoid the blood-brain barrier impediment. Here, we developed a fibrin gel that accommodates CAR-T cell loading and promotes their gradual release. Using a model of subtotal glioblastoma resection, we demonstrated that the fibrin-based gel delivery of CAR-T cells within the surgical cavity enables superior antitumor activity compared to CAR-T cells directly inoculated into the tumor resection cavity.
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Affiliation(s)
- Edikan A. Ogunnaike
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
- Joint Department of Biomedical Engineering, North Carolina State University and University of North Carolina at Chapel Hill, Raleigh, NC 27695, USA
- Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Alain Valdivia
- Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Mostafa Yazdimamaghani
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
- Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Ernesto Leon
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Seema Nandi
- Joint Department of Biomedical Engineering, North Carolina State University and University of North Carolina at Chapel Hill, Raleigh, NC 27695, USA
| | - Hannah Hudson
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Hongwei Du
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Simon Khagi
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
- Department of Medicine, Division of Medical Oncology, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Zhen Gu
- Department of Bioengineering, University of California, Los Angeles, CA 90095, USA
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Barbara Savoldo
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
- Department of Pediatrics, University of North Carolina, Chapel Hill, NC 27514, USA
| | - Frances S. Ligler
- Joint Department of Biomedical Engineering, North Carolina State University and University of North Carolina at Chapel Hill, Raleigh, NC 27695, USA
- Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Shawn Hingtgen
- Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Gianpietro Dotti
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
- Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA
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46
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Arnesen VS, Gras Navarro A, Chekenya M. Challenges and Prospects for Designer T and NK Cells in Glioblastoma Immunotherapy. Cancers (Basel) 2021; 13:4986. [PMID: 34638471 PMCID: PMC8507952 DOI: 10.3390/cancers13194986] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/29/2021] [Accepted: 10/01/2021] [Indexed: 12/22/2022] Open
Abstract
Glioblastoma (GBM) is the most prevalent, aggressive primary brain tumour with a dismal prognosis. Treatment at diagnosis has limited efficacy and there is no standardised treatment at recurrence. New, personalised treatment options are under investigation, although challenges persist for heterogenous tumours such as GBM. Gene editing technologies are a game changer, enabling design of novel molecular-immunological treatments to be used in combination with chemoradiation, to achieve long lasting survival benefits for patients. Here, we review the literature on how cutting-edge molecular gene editing technologies can be applied to known and emerging tumour-associated antigens to enhance chimeric antigen receptor T and NK cell therapies for GBM. A tight balance of limiting neurotoxicity, avoiding tumour antigen loss and therapy resistance, while simultaneously promoting long-term persistence of the adoptively transferred cells must be maintained to significantly improve patient survival. We discuss the opportunities and challenges posed by the brain contexture to the administration of the treatments and achieving sustained clinical responses.
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Affiliation(s)
| | - Andrea Gras Navarro
- Department of Biomedicine, University of Bergen, Jonas Lies Vei 91, 5009 Bergen, Norway
| | - Martha Chekenya
- Department of Biomedicine, University of Bergen, Jonas Lies Vei 91, 5009 Bergen, Norway
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Egan CE, Stefanova D, Ahmed A, Raja VJ, Thiesmeyer JW, Chen KJ, Greenberg JA, Zhang T, He B, Finnerty BM, Zarnegar R, Jin MM, Scognamiglio T, Dephoure N, Fahey T, Min IM. CSPG4 Is a Potential Therapeutic Target in Anaplastic Thyroid Cancer. Thyroid 2021; 31:1481-1493. [PMID: 34078123 PMCID: PMC8917884 DOI: 10.1089/thy.2021.0067] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Background: Anaplastic thyroid cancer (ATC) is a rare cancer with poor prognosis and few treatment options. The objective of this study was to investigate new immune-associated therapeutic targets by identifying ATC-derived, human leukocyte antigen (HLA) class II-presenting peptides. One protein that generated multiple peptides in ATC was chondroitin sulfate-proteoglycan-4 (CSPG4), a transmembrane proteoglycan with increased expression in multiple aggressive cancers, but not yet investigated in ATC. Methods: We applied autologous peripheral blood T cells to ATC patient-derived xenografted mice to examine whether ATC induces a tumor-specific T cell response. We then identified peptide antigens eluted from the HLA-DQ complex in ATC patient-derived cells using mass spectrometry, detecting abundant CSPG4-derived peptides specific to the ATC sample. Next, we analyzed the surface expression level of CSPG4 in thyroid cancer cell lines and primary cell culture using flow cytometry. In addition, we used immunohistochemistry to compare the expression level and localization of the CSPG4 protein in ATC, papillary thyroid cancer, and normal thyroid tissue. We then investigated the correlation between CSPG4 expression and clinicopathological features of patients with thyroid cancer. Results: We found that ATC tissue had a high level of HLA-DQ expression and that the patient's CD4+ T cells showed activation when exposed to ATC. By eluting the HLA-DQ complex of ATC tissue, we found that CSPG4 generated one of the most abundant and specific peptides. CSPG4 expression at the cell surface of thyroid cancer was also significantly high when determined by flow cytometry, with the majority of ATC cell lines exhibiting ∼10-fold higher mean fluorescence intensity. Furthermore, most ATC patient cases expressed CSPG4 in the cytoplasm or membrane of the tumor cells. CSPG4 expression was correlated with tumor size, extrathyroidal extension, and intercellular adhesion molecule-1 (ICAM-1) circumferential expression. CSPG4 mRNA overexpression was associated with worse overall survival in patients with ATC and poorly differentiated thyroid cancer. Conclusions: CSPG4 expression is significantly elevated in aggressive thyroid cancers, with a strong correlation with a poor prognosis. The vast number of HLA-DQ eluted CSPG4 peptides was identified in ATC, demonstrating the potential of CSPG4 as a novel immunotherapeutic target for ATC.
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Affiliation(s)
- Caitlin E. Egan
- Department of Surgery, Weill Cornell Medicine, New York, New York, USA
| | | | - Adnan Ahmed
- Department of Biochemistry, Weill Cornell Medicine, New York, New York, USA
| | - Vijay J. Raja
- Department of Biochemistry, Weill Cornell Medicine, New York, New York, USA
| | | | - Kevin J. Chen
- Department of Surgery, Weill Cornell Medicine, New York, New York, USA
| | | | - Taotao Zhang
- Department of Pathology, and Weill Cornell Medicine, New York, New York, USA
| | - Bing He
- Department of Pathology, and Weill Cornell Medicine, New York, New York, USA
| | | | - Rasa Zarnegar
- Department of Surgery, Weill Cornell Medicine, New York, New York, USA
| | - Moonsoo M. Jin
- Department of Surgery, Weill Cornell Medicine, New York, New York, USA
- Department of Radiology, Weill Cornell Medicine, New York, New York, USA
| | | | - Noah Dephoure
- Department of Biochemistry, Weill Cornell Medicine, New York, New York, USA
| | - Thomas Fahey
- Department of Surgery, Weill Cornell Medicine, New York, New York, USA
| | - Irene M. Min
- Department of Surgery, Weill Cornell Medicine, New York, New York, USA
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Yoo HJ, Harapan BN. Chimeric antigen receptor (CAR) immunotherapy: basic principles, current advances, and future prospects in neuro-oncology. Immunol Res 2021; 69:471-486. [PMID: 34554405 PMCID: PMC8580929 DOI: 10.1007/s12026-021-09236-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 08/31/2021] [Indexed: 12/19/2022]
Abstract
With recent advances, chimeric antigen receptor (CAR) immunotherapy has become a promising modality for patients with refractory cancer diseases. The successful results of CAR T cell therapy in relapsed and refractory B-cell malignancies shifted the paradigm of cancer immunotherapy by awakening the scientific, clinical, and commercial interest in translating this technology for the treatment of solid cancers. This review elaborates on fundamental principles of CAR T cell therapy (development of CAR construct, challenges of CAR T cell therapy) and its application on solid tumors as well as CAR T cell therapy potential in the field of neuro-oncology. Glioblastoma (GBM) is identified as one of the most challenging solid tumors with a permissive immunological milieu and dismal prognosis. Standard multimodal treatment using maximal safe resection, radiochemotherapy, and maintenance chemotherapy extends the overall survival beyond a year. Recurrence is, however, inevitable. GBM holds several unique features including its vast intratumoral heterogeneity, immunosuppressive environment, and a partially permissive anatomic blood–brain barrier, which offers a unique opportunity to investigate new treatment approaches. Tremendous efforts have been made in recent years to investigate novel CAR targets and target combinations with standard modalities for solid tumors and GBM to improve treatment efficacy. In this review, we outline the history of CAR immunotherapy development, relevant CAR target antigens validated with CAR T cells as well as preclinical approaches in combination with adjunct approaches via checkpoint inhibition, bispecific antibodies, and second-line systemic therapies that enhance anticancer efficacy of the CAR-based cancer immunotherapy.
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Affiliation(s)
- Hyeon Joo Yoo
- Department of Internal Medicine V, Heidelberg University Hospital, 69120, Heidelberg, Germany
| | - Biyan Nathanael Harapan
- Department of Neurosurgery, University Hospital, Ludwig-Maximilians-University of Munich, 81377, Munich, Germany.
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49
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Man F, Koers A, Karagiannis P, Josephs DH, Bax HJ, Gilbert AE, Dodev TS, Mele S, Chiarruttini G, Crescioli S, Chauhan J, Blower JE, Cooper MS, Spicer J, Karagiannis SN, Blower PJ. In vivo trafficking of a tumor-targeting IgE antibody: molecular imaging demonstrates rapid hepatobiliary clearance compared to IgG counterpart. Oncoimmunology 2021; 10:1966970. [PMID: 34513315 PMCID: PMC8425638 DOI: 10.1080/2162402x.2021.1966970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 07/26/2021] [Accepted: 08/08/2021] [Indexed: 11/30/2022] Open
Abstract
IgE antibodies elicit powerful immune responses, recruiting effector cells to tumors more efficiently and with greater cytotoxicity than IgG antibodies. Consequently, IgE antibodies are a promising alternative to conventional IgG-based therapies in oncology (AllergoOncology). As the pharmacokinetics of IgE antibodies are less well understood, we used molecular imaging in mice to compare the distribution and elimination of IgE and IgG antibodies targeting the human tumor-associated antigen chondroitin sulfate proteoglycan 4 (CSPG4). Anti-CSPG4 IgE and IgG1 antibodies with human Fc domains were radiolabeled with 111In. CSPG4-expressing A375 human melanoma xenografts implanted in NOD-scid IL2rg-/- mice were also engrafted with human immune cells by intravenous administration. 111In-anti-CSPG4 antibodies were administered intravenously. Their distribution was determined by single-photon emission computed tomography (SPECT) and ex vivo gamma-counting over 120 h. SPECT imaging was conducted from 0 to 60 min after antibody administration to precisely measure the early phase of IgE distribution. 111In-labeled anti-CSPG4 IgG and IgE showed serum stability in vitro of >92% after 5 days. In A375 xenograft-bearing mice, anti-CSPG4 IgE showed much faster blood clearance and higher accumulation in the liver compared to anti-CSPG4 IgG. However, tumor-to-blood and tumor-to-muscle ratios were similar between the antibody isotypes and higher compared with a non-tumor-targeting isotype control IgE. IgE excretion was much faster than IgG. In non-tumor-bearing animals, early SPECT imaging revealed a blood clearance half-life of 10 min for IgE. Using image-based quantification, we demonstrated that the blood clearance of IgE is much faster than that of IgG while the two isotypes showed comparable tumor-to-blood ratios.
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Affiliation(s)
- Francis Man
- School of Biomedical Engineering & Imaging Sciences, King’s College London, London, UK
- School of Cancer & Pharmaceutical Sciences, Institute of Pharmaceutical Science, King’s College London, London, UK
| | - Alexander Koers
- School of Biomedical Engineering & Imaging Sciences, King’s College London, London, UK
| | - Panagiotis Karagiannis
- School of Basic & Medical Biosciences, St John’s Institute of Dermatology, King’s College London, London, UK
| | - Debra H. Josephs
- School of Basic & Medical Biosciences, St John’s Institute of Dermatology, King’s College London, London, UK
- School of Cancer & Pharmaceutical Sciences, Guy’s Hospital, King’s College London, London, UK
| | - Heather J. Bax
- School of Basic & Medical Biosciences, St John’s Institute of Dermatology, King’s College London, London, UK
- School of Cancer & Pharmaceutical Sciences, Guy’s Hospital, King’s College London, London, UK
| | - Amy E. Gilbert
- School of Basic & Medical Biosciences, St John’s Institute of Dermatology, King’s College London, London, UK
| | - Tihomir S. Dodev
- School of Cancer & Pharmaceutical Sciences, Guy’s Hospital, King’s College London, London, UK
- School of Basic and Medical Biosciences, Randall Centre for Cell and Molecular Biophysics, King’s College London, London, UK
- Allergic Mechanisms in Asthma, Asthma UK Centre, King’s College London, London, UK
| | - Silvia Mele
- School of Basic & Medical Biosciences, St John’s Institute of Dermatology, King’s College London, London, UK
| | - Giulia Chiarruttini
- School of Basic & Medical Biosciences, St John’s Institute of Dermatology, King’s College London, London, UK
| | - Silvia Crescioli
- School of Basic & Medical Biosciences, St John’s Institute of Dermatology, King’s College London, London, UK
| | - Jitesh Chauhan
- School of Basic & Medical Biosciences, St John’s Institute of Dermatology, King’s College London, London, UK
- School of Cancer & Pharmaceutical Sciences, Guy’s Hospital, King’s College London, London, UK
| | - Julia E. Blower
- School of Biomedical Engineering & Imaging Sciences, King’s College London, London, UK
| | - Margaret S. Cooper
- School of Biomedical Engineering & Imaging Sciences, King’s College London, London, UK
| | - James Spicer
- School of Cancer & Pharmaceutical Sciences, Guy’s Hospital, King’s College London, London, UK
- Cancer Centre at Guy’s, Guy’s and St Thomas’ NHS Foundation Trust, London, UK
| | - Sophia N. Karagiannis
- School of Basic & Medical Biosciences, St John’s Institute of Dermatology, King’s College London, London, UK
- School of Cancer & Pharmaceutical Sciences, Breast Cancer Now Research Unit, King’s College London, Guy’s Hospital, London, UK
| | - Philip J. Blower
- School of Biomedical Engineering & Imaging Sciences, King’s College London, London, UK
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Inhibition of post-surgery tumour recurrence via a hydrogel releasing CAR-T cells and anti-PDL1-conjugated platelets. Nat Biomed Eng 2021; 5:1038-1047. [PMID: 33903744 PMCID: PMC9102991 DOI: 10.1038/s41551-021-00712-1] [Citation(s) in RCA: 189] [Impact Index Per Article: 47.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 03/09/2021] [Indexed: 02/07/2023]
Abstract
The immunosuppressive microenvironment of solid tumours reduces the antitumour activity of chimeric antigen receptor T cells (CAR-T cells). Here, we show that the release-through the implantation of a hyaluronic acid hydrogel-of CAR-T cells targeting the human chondroitin sulfate proteoglycan 4, polymer nanoparticles encapsulating the cytokine interleukin-15 and platelets conjugated with the checkpoint inhibitor programmed death-ligand 1 into the tumour cavity of mice with a resected subcutaneous melanoma tumour inhibits the local recurrence of the tumour as well as the growth of distant tumours, through the abscopal effect. The hydrogel, which functions as a reservoir, facilitates the enhanced distribution of the CAR-T cells within the surgical bed, and the inflammatory microenvironment triggers platelet activation and the subsequent release of platelet-derived microparticles. The post-surgery local delivery of combination immunotherapy through a biocompatible hydrogel reservoir could represent a translational route for preventing the recurrence of cancers with resectable tumours.
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