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Liu L, He P, Wang Y, Ma F, Li D, Bai Z, Qu Y, Zhu L, Yoon CW, Yu X, Huang Y, Liang Z, Zhang Y, Liu K, Guo T, Zeng Y, Zhou Q, Chung HK, Fan R, Wang Y. Engineering sonogenetic EchoBack-CAR T cells. Cell 2025; 188:2621-2636.e20. [PMID: 40179881 DOI: 10.1016/j.cell.2025.02.035] [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: 07/18/2024] [Revised: 12/13/2024] [Accepted: 02/27/2025] [Indexed: 04/05/2025]
Abstract
Chimeric antigen receptor (CAR) T cell therapy for solid tumors encounters challenges such as on-target off-tumor toxicity, exhaustion, and limited T cell persistence. Here, we engineer sonogenetic EchoBack-CAR T cells using an ultrasensitive heat-shock promoter screened from a library and integrated with a positive feedback loop from CAR signaling, enabling long-lasting CAR expression upon focused-ultrasound (FUS) stimulation. EchoBack-hGD2CAR T cells, targeting disialoganglioside GD2, exhibited potent cytotoxicity and persistence in 3D glioblastoma (GBM) models. In mice, EchoBack-hGD2CAR T cells suppressed GBM without off-tumor toxicity and outperformed their constitutive counterparts. Single-cell RNA sequencing revealed enhanced cytotoxicity and reduced exhaustion in EchoBack-CAR T cells compared with the standard CAR T cells. This EchoBack design was further adapted to target prostate-specific membrane antigen (EchoBack-PSMACAR) for prostate cancer treatment, demonstrating long-lasting tumor suppression with minimal off-tumor toxicity. Thus, the sonogenetic EchoBack-CAR T cells can serve as a versatile, efficient, and safe strategy for solid tumor treatment.
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Affiliation(s)
- Longwei Liu
- Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA.
| | - Peixiang He
- Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA; Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Yuxuan Wang
- Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA
| | - Fengyi Ma
- Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA
| | - Dulei Li
- Acoustic Cell Therapy, Inc., San Diego, CA 92130, USA
| | - Zhiliang Bai
- Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA
| | - Yunjia Qu
- Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA; Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Linshan Zhu
- Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA
| | - Chi Woo Yoon
- Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA
| | - Xi Yu
- Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA
| | - Yixuan Huang
- Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA
| | - Zhengyu Liang
- Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Yiming Zhang
- Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA
| | - Kunshu Liu
- Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA
| | - Tianze Guo
- Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA
| | - Yushun Zeng
- Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA
| | - Qifa Zhou
- Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA
| | - H Kay Chung
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Cell Biology & Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Rong Fan
- Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA
| | - Yingxiao Wang
- Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA; Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
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2
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Ghosh N, Chatterjee D, Datta A. Tumor heterogeneity and resistance in glioblastoma: the role of stem cells. Apoptosis 2025:10.1007/s10495-025-02123-y. [PMID: 40375039 DOI: 10.1007/s10495-025-02123-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/25/2025] [Indexed: 05/18/2025]
Abstract
Glioblastoma multiforme (GBM) is one of the most aggressive and treatment-resistant brain tumor, characterized by its heterogeneity and the presence of glioblastoma stem cells (GSCs). GSCs are a subpopulation of cells within the tumor that possess self-renewal and differentiation capabilities, contributing to tumor initiation, progression, and recurrence. This review explores the unique biological properties of GSCs, including their molecular markers, signalling pathways, and interactions with the tumor microenvironment. We discuss the mechanisms by which GSCs evade conventional therapies, such as enhanced DNA repair and metabolic plasticity, which complicate treatment outcomes. Furthermore, we highlight recent advancements in identifying novel biomarkers and therapeutic targets that may improve the efficacy of treatments aimed at GSCs. The potential of targeted therapies, including immunotherapy and combination strategies, is also examined to overcome the challenges posed by GSCs. Ultimately, a deeper understanding of GSC biology is essential for developing personalized treatment approaches that can enhance patient outcomes in glioblastoma.
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Affiliation(s)
- Nikita Ghosh
- Department of Neuroscience Technology, School of Allied Health Sciences, Yenepoya, Mangalore, Karnataka, India
| | | | - Aparna Datta
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata, India.
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3
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Song KW, Lim M, Monje M. Complex neural-immune interactions shape glioma immunotherapy. Immunity 2025; 58:1140-1160. [PMID: 40324379 DOI: 10.1016/j.immuni.2025.04.017] [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: 02/20/2025] [Revised: 04/14/2025] [Accepted: 04/15/2025] [Indexed: 05/07/2025]
Abstract
Rich neural-immune interactions in the central nervous system (CNS) shape its function and create a unique immunological microenvironment for immunotherapy in CNS malignancies. Far from the now-debunked concept of CNS "immune privilege," it is now understood that unique immunological niches and constant immune surveillance of the brain contribute in multifaceted ways to brain health and robustly influence immunotherapy approaches for CNS cancers. Challenges include immune-suppressive and neurotoxicity-promoting crosstalk between brain, immune, and tumor cells. Developing effective immunotherapies for cancers of the nervous system will require a deeper understanding of these neural-immune-malignant cell interactions. Here, we review progress and challenges in immunotherapy for gliomas of the brain and spinal cord in light of these unique neural-immune interactions and highlight future work needed to optimize promising immunotherapies for gliomas.
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Affiliation(s)
- Kun-Wei Song
- Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, CA, USA
| | - Michael Lim
- Department of Neurosurgery, Stanford University, Palo Alto, CA, USA
| | - Michelle Monje
- Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, CA, USA; Department of Neurosurgery, Stanford University, Palo Alto, CA, USA; Howard Hughes Medical Institute, Stanford University, Palo Alto, CA, USA.
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4
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Politis A, Stavrinou L, Kalyvas A, Boviatsis E, Piperi C. Glioblastoma: molecular features, emerging molecular targets and novel therapeutic strategies. Crit Rev Oncol Hematol 2025; 212:104764. [PMID: 40368035 DOI: 10.1016/j.critrevonc.2025.104764] [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: 03/04/2025] [Revised: 05/01/2025] [Accepted: 05/09/2025] [Indexed: 05/16/2025] Open
Abstract
Glioblastomas (GBMs) constitute the most common malignant tumors of the Central Nervous System (CNS) with a complex molecular, genetic and histological profile and extensive heterogenicity. GBMs are notoriously difficult to treat, with morbidity and mortality rate that remain high and practically unchanged, despite the aggressive and multimodal treatment strategies. Keeping up with current research and emerging scientific data is of primary importance for the detection of new molecular targets, enabling the design of novel therapeutic strategies. Herein, we discuss current data on the cellular and molecular features that contribute to GBM pathophysiological mechanisms in an effort to reveal emerging molecular targets with therapeutic potential as well as effective immunotherapeutic approaches, including chimeric antigen receptor (CAR) T-cell therapy and adaptive immune modulation with immune checkpoint inhibitors. Enhanced drug delivery strategies such as ultrasound-assisted technologies to overcome drug resistance are also discussed, aiming to provide an overall translational perspective that bridges molecular insights with practical therapeutic implications.
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Affiliation(s)
- Anastasios Politis
- Second Department of Neurosurgery, "Attikon" University Hospital, National and Kapodistrian University of Athens, 15772 Athens, Greece; Department of Biological Chemistry, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Lampis Stavrinou
- Second Department of Neurosurgery, "Attikon" University Hospital, National and Kapodistrian University of Athens, 15772 Athens, Greece
| | - Aristotelis Kalyvas
- Second Department of Neurosurgery, "Attikon" University Hospital, National and Kapodistrian University of Athens, 15772 Athens, Greece; Division of Neurosurgery, Department of Surgery, Temetry Faculty of Medicine, University of Toronto, Toronto, Canada
| | - Efstathios Boviatsis
- Second Department of Neurosurgery, "Attikon" University Hospital, National and Kapodistrian University of Athens, 15772 Athens, Greece
| | - Christina Piperi
- Department of Biological Chemistry, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece.
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5
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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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6
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Fu M, Xue B, Miao X, Gao Z. Overcoming immunotherapy resistance in glioblastoma: challenges and emerging strategies. Front Pharmacol 2025; 16:1584688. [PMID: 40223940 PMCID: PMC11987931 DOI: 10.3389/fphar.2025.1584688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Accepted: 03/21/2025] [Indexed: 04/15/2025] Open
Abstract
Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults, characterized by rapid proliferation, extensive infiltration, and significant intratumoral heterogeneity. Despite advancements in conventional treatments, including surgery, radiotherapy, and chemotherapy, the prognosis for GBM patients remains poor, with a median survival of approximately 15 months. Immunotherapy has emerged as a promising alternative; however, the unique biological and immunological features, including its immunosuppressive tumor microenvironment (TME) and low mutational burden, render it resistant to many immunotherapeutic strategies. This review explores the key challenges in GBM immunotherapy, focusing on immune evasion mechanisms, the blood-brain barrier (BBB), and the TME. Immune checkpoint inhibitors and CAR-T cells have shown promise in preclinical models but have limited clinical success due to antigen heterogeneity, immune cell exhaustion, and impaired trafficking across the BBB. Emerging strategies, including dual-targeting CAR-T cells, engineered immune cells secreting therapeutic molecules, and advanced delivery systems to overcome the BBB, show potential for enhancing treatment efficacy. Addressing these challenges is crucial for improving GBM immunotherapy outcomes.
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Affiliation(s)
- Maowu Fu
- Department of Neurosurgery, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Bing Xue
- Department of Neurosurgery, Jinan Third People’s Hospital, Jinan, Shandong, China
| | - Xiuming Miao
- Department of Pathology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Zong Gao
- Department of Neurosurgery, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
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7
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Begley SL, O'Rourke DM, Binder ZA. CAR T cell therapy for glioblastoma: A review of the first decade of clinical trials. Mol Ther 2025:S1525-0016(25)00178-9. [PMID: 40057825 DOI: 10.1016/j.ymthe.2025.03.004] [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: 01/06/2025] [Revised: 02/13/2025] [Accepted: 03/05/2025] [Indexed: 03/22/2025] Open
Abstract
Glioblastoma (GBM) is an aggressive primary brain tumor with a poor prognosis and few effective treatment options. Focus has shifted toward using immunotherapies, such as chimeric antigen receptor (CAR) T cells, to selectively target tumor antigens and mediate cytotoxic activity within an otherwise immunosuppressive tumor microenvironment. Between 2015 and 2024, the results of eight completed and two ongoing phase I clinical trials have been published. The majority of studies have treated recurrent GBM patients, although the inter- and intra-patient tumor heterogeneity has been historically challenging to overcome. Molecular targets have included EGFR, HER2, and IL13Rα2 and there has been continued development in improving receptor constructs, identifying novel targets, and adding adjuvant enhancers to increase efficacy. CAR T cells have been safely administered through both peripheral and locoregional routes but with variable clinical and radiographic efficacy. Most trials utilized autologous T cell products to avoid immune rejection yet were unable to consistently show robust engraftment and persistence within patients. Nonetheless, targeted immunotherapies such as CAR T cell therapy remain the next frontier for GBM treatment, and the popularity and complexity of this undertaking is evident in the past, present, and future landscape of clinical trials.
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Affiliation(s)
- Sabrina L Begley
- GBM Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Donald M O'Rourke
- GBM Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Zev A Binder
- GBM Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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8
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Kuroda H, Kijima N, Tachi T, Ikeda S, Murakami K, Nakagawa T, Yaga M, Nakagawa K, Utsugi R, Hirayama R, Okita Y, Kagawa N, Hosen N, Kishima H. Prostaglandin F2 receptor negative regulator as a potential target for chimeric antigen receptor-T cell therapy for glioblastoma. Cancer Immunol Immunother 2025; 74:136. [PMID: 40047938 PMCID: PMC11885767 DOI: 10.1007/s00262-025-03979-4] [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: 06/22/2024] [Accepted: 02/11/2025] [Indexed: 03/09/2025]
Abstract
BACKGROUND Chimeric antigen receptor (CAR)-T cell therapy targeting novel glioblastoma (GBM)-specific cell surface antigens is a promising approach. However, transcriptome analyses have revealed few GBM-specific target antigens. METHODS A library of monoclonal antibodies (mAbs) against tumor cell lines derived from patients with GBM was generated. mAbs reacting with tumor cells in resected tissues from patients with GBM but not with nonmalignant human brain cells were detected. The antigens that were recognized were identified through expression cloning. CAR-T cells derived from a candidate mAb were generated, and their functionality was tested in vitro and in vivo. RESULTS Approximately 3,200 clones were established. Among them, 5E17 reacted with tumor cells in six of seven patients with GBM, but not with nonmalignant human brain cells. Prostaglandin F2 receptor negative regulator (PTGFRN) was identified as an antigen recognized by 5E17. CAR-T cells derived from 5E17 produced cytokines and exerted cytotoxicity upon co-culture with tumor cells from patients with GBM. Furthermore, intracranial injection of 5E17-CAR-T cells demonstrated antitumor effects in an orthotopic xenograft murine model with patient-derived GBM cells. CONCLUSIONS Cell surface PTGFRN is a candidate target for intracranial CAR-T cell therapy for GBM. On-target off-tumor toxicity in alternative normal tissues needs to be carefully tested.
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Affiliation(s)
- Hideki Kuroda
- Department of Neurosurgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, 5650871, Japan
| | - Noriyuki Kijima
- Department of Neurosurgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, 5650871, Japan.
| | - Tetsuro Tachi
- Department of Neurosurgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, 5650871, Japan
| | - Shunya Ikeda
- World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan
| | - Koki Murakami
- Department of Neurosurgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, 5650871, Japan
| | - Tomoyoshi Nakagawa
- Department of Neurosurgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, 5650871, Japan
| | - Moto Yaga
- Department of Respiratory Medicine, Osaka General Hospital, Osaka, Osaka, Japan
| | - Kanji Nakagawa
- Department of Neurosurgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, 5650871, Japan
| | - Reina Utsugi
- Department of Neurosurgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, 5650871, Japan
| | - Ryuichi Hirayama
- Department of Neurosurgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, 5650871, Japan
| | - Yoshiko Okita
- Department of Neurosurgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, 5650871, Japan
| | - Naoki Kagawa
- Department of Neurosurgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, 5650871, Japan
| | - Naoki Hosen
- World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
- Department of Hematology and Oncology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, 5650871, Japan.
| | - Haruhiko Kishima
- Department of Neurosurgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, 5650871, Japan
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Pfeffer LK, Fischbach F, Heesen C, Friese MA. Current state and perspectives of CAR T cell therapy in central nervous system diseases. Brain 2025; 148:723-736. [PMID: 39530593 DOI: 10.1093/brain/awae362] [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: 07/19/2024] [Revised: 10/03/2024] [Accepted: 10/20/2024] [Indexed: 11/16/2024] Open
Abstract
B cell-directed CAR T cell therapy has fundamentally changed the treatment of haematological malignancies, and its scope of application is rapidly expanding to include other diseases such as solid tumours or autoimmune disorders. Therapy-refractoriness remains an important challenge in various inflammatory and non-inflammatory disorders of the CNS. The reasons for therapy failure are diverse and include the limited access current therapies have to the CNS, as well as enormous inter- and intra-individual disease heterogeneity. The tissue-penetrating properties of CAR T cells make them a promising option for overcoming this problem and tackling pathologies directly within the CNS. First application of B cell-directed CAR T cells in neuromyelitis optica spectrum disorder and multiple sclerosis patients has recently revealed promising outcomes, expanding the potential of CAR T cell therapy to encompass CNS diseases. Additionally, the optimization of CAR T cells for the therapy of gliomas is a growing field. As a further prospect, preclinical data reveal the potential benefits of CAR T cell therapy in the treatment of primary neurodegenerative diseases such as Alzheimer's disease. Considering the biotechnological optimizations in the field of T cell engineering, such as extension to target different antigens or variation of the modified T cell subtype, new and promising fields of CAR T cell application are rapidly opening up. These innovations offer the potential to address the complex pathophysiological properties of CNS diseases. To use CAR T cell therapy optimally to treat CNS diseases in the future while minimizing therapy risks, further mechanistic research and prospective controlled trials are needed to assess seriously the disease and patient-specific risk-benefit ratio.
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Affiliation(s)
- Lena Kristina Pfeffer
- Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
- Department of Neurology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Felix Fischbach
- Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
- Department of Neurology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Christoph Heesen
- Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
- Department of Neurology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Manuel A Friese
- Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
- Department of Neurology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
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10
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Dong J, Wu J, Jin Y, Zheng Z, Su T, Shao L, Bei J, Chen S. In-depth analysis of the safety of CAR-T cell therapy for solid tumors. Front Immunol 2025; 16:1548979. [PMID: 40066440 PMCID: PMC11891211 DOI: 10.3389/fimmu.2025.1548979] [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: 12/20/2024] [Accepted: 01/30/2025] [Indexed: 05/13/2025] Open
Abstract
In recent years, the rapid progress in oncology, immunology, and molecular biology has dramatically advanced cancer immunotherapy, particularly CAR-T cell therapy. This innovative approach involves engineering a patient's T cells to express receptors that specifically target tumor antigens, enhancing their ability to identify and eliminate cancer cells. However, the effectiveness of CAR-T therapy in solid tumors is often hampered by the challenging tumor microenvironment (TME). The complex TME includes dense stroma that obstructs T cell infiltration, abnormal blood vessel structures leading to hypoxia, and an acidic pH, all of which hinder CAR-T cell function. Additionally, the presence of immunosuppressive factors in the TME reduces the efficacy of CAR-T cells, making successful targeting of tumors more difficult. The safety of CAR-T therapy has gained interest, especially CAR-T therapy has shown considerable effectiveness in various cancers, with notable results in multiple myeloma and hepatocellular carcinoma, among others. Nonetheless, CAR-T cell therapy is associated with several adverse reactions primarily driven by heightened levels of proinflammatory cytokines. These reactions include cytokine release syndrome (CRS), neurotoxicity (CANS), and organ toxicity, often leading to serious complications. CRS, characterized by systemic inflammation due to cytokine release, can escalate to severe organ dysfunction. It typically occurs within the first week post-infusion, correlating with CAR-T cell expansion and often presents with fever and hypotension. Meanwhile, CANS encompasses neurological issues ranging from mild symptoms to severe seizures, possibly exacerbated by CRS. Organ toxicity can also arise from CAR-T therapy, with potential damage affecting the gastrointestinal tract, kidneys, liver, and lungs, often tied to shared antigens found in both tumor and healthy tissues. Moreover, long-term effects like cytokine-associated hematotoxicity (CAHT) and secondary malignancies represent significant concerns that could affect the patient's quality of life post-treatment. The long-term adverse effects and challenges in treating solid tumors underscore the need for ongoing research. Strategies to improve CAR-T cell efficacy, minimize adverse reactions, and enhance patient safety are critical. Future explorations could include designing CAR-T cells to better navigate the TME, identifying specific target antigen profiles to minimize off-target damage, and developing adjunct therapies to mitigate cytokine-related toxicity. Continued monitoring for long-term effects will also be paramount in improving patient outcomes and maintaining their quality of life. Overall, while CAR-T therapy holds great promise, it must be administered with careful consideration of potential side effects and rigorous management strategies to ensure patient safety and treatment efficacy.
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Affiliation(s)
- Jiayi Dong
- Department of Immuno-Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Key Laboratory of Monitoring Adverse Reactions Associated with Chimeric Antigen Receptor T-Cell Therapy, Guangdong Higher Education Institutions, Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Provincial Engineering Research Center for Precision Medicine in Esophageal Cancer, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Key Laboratory of Cancer Immunotherapy, Guangdong Higher Education Institutions, Guangdong Pharmaceutical University, Guangzhou, China
| | - Jiexiong Wu
- School of Clinical Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Ye Jin
- Department of Immuno-Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Key Laboratory of Monitoring Adverse Reactions Associated with Chimeric Antigen Receptor T-Cell Therapy, Guangdong Higher Education Institutions, Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Provincial Engineering Research Center for Precision Medicine in Esophageal Cancer, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Key Laboratory of Cancer Immunotherapy, Guangdong Higher Education Institutions, Guangdong Pharmaceutical University, Guangzhou, China
- School of Clinical Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Zhu Zheng
- Department of Immuno-Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Key Laboratory of Monitoring Adverse Reactions Associated with Chimeric Antigen Receptor T-Cell Therapy, Guangdong Higher Education Institutions, Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Provincial Engineering Research Center for Precision Medicine in Esophageal Cancer, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Key Laboratory of Cancer Immunotherapy, Guangdong Higher Education Institutions, Guangdong Pharmaceutical University, Guangzhou, China
- School of Clinical Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Ting Su
- Department of Immuno-Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Key Laboratory of Monitoring Adverse Reactions Associated with Chimeric Antigen Receptor T-Cell Therapy, Guangdong Higher Education Institutions, Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Provincial Engineering Research Center for Precision Medicine in Esophageal Cancer, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Key Laboratory of Cancer Immunotherapy, Guangdong Higher Education Institutions, Guangdong Pharmaceutical University, Guangzhou, China
- School of Clinical Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Lijuan Shao
- Department of Immuno-Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Key Laboratory of Monitoring Adverse Reactions Associated with Chimeric Antigen Receptor T-Cell Therapy, Guangdong Higher Education Institutions, Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Provincial Engineering Research Center for Precision Medicine in Esophageal Cancer, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Key Laboratory of Cancer Immunotherapy, Guangdong Higher Education Institutions, Guangdong Pharmaceutical University, Guangzhou, China
- School of Clinical Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Jiaxin Bei
- Department of Immuno-Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Key Laboratory of Monitoring Adverse Reactions Associated with Chimeric Antigen Receptor T-Cell Therapy, Guangdong Higher Education Institutions, Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Provincial Engineering Research Center for Precision Medicine in Esophageal Cancer, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Key Laboratory of Cancer Immunotherapy, Guangdong Higher Education Institutions, Guangdong Pharmaceutical University, Guangzhou, China
| | - Size Chen
- Department of Immuno-Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Key Laboratory of Monitoring Adverse Reactions Associated with Chimeric Antigen Receptor T-Cell Therapy, Guangdong Higher Education Institutions, Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Provincial Engineering Research Center for Precision Medicine in Esophageal Cancer, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Key Laboratory of Cancer Immunotherapy, Guangdong Higher Education Institutions, Guangdong Pharmaceutical University, Guangzhou, China
- School of Clinical Medicine, Guangdong Pharmaceutical University, Guangzhou, China
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11
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Gallus M, Young JS, Cook Quackenbush S, Khasraw M, de Groot J, Okada H. Chimeric antigen receptor T-cell therapy in patients with malignant glioma-From neuroimmunology to clinical trial design considerations. Neuro Oncol 2025; 27:352-368. [PMID: 39450490 PMCID: PMC11812040 DOI: 10.1093/neuonc/noae203] [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] [Indexed: 10/26/2024] Open
Abstract
Clinical trials evaluating chimeric antigen receptor (CAR) T-cell therapy in patients with malignant gliomas have shown some early promise in pediatric and adult patients. However, the long-term benefits and safety for patients remain to be established. The ultimate success of CAR T-cell therapy for malignant glioma will require the integration of an in-depth understanding of the immunology of the central nervous system (CNS) parenchyma with strategies to overcome the paucity and heterogeneous expression of glioma-specific antigens. We also need to address the cold (immunosuppressive) microenvironment, exhaustion of the CAR T-cells, as well as local and systemic immunosuppression. Here, we discuss the basics and scientific considerations for CAR T-cell therapies and highlight recent clinical trials. To help identify optimal CAR T-cell administration routes, we summarize our current understanding of CNS immunology and T-cell homing to the CNS. We also discuss challenges and opportunities related to clinical trial design and patient safety/monitoring. Finally, we provide our perspective on future prospects in CAR T-cell therapy for malignant gliomas by discussing combinations and novel engineering strategies to overcome immuno-regulatory mechanisms. We hope this review will serve as a basis for advancing the field in a multiple discipline-based and collaborative manner.
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Affiliation(s)
- Marco Gallus
- Department of Neurological Surgery, Unversity of California San Fracisco, San Francisco, California, USA
| | - Jacob S Young
- Department of Neurological Surgery, Unversity of California San Fracisco, San Francisco, California, USA
| | | | - Mustafa Khasraw
- The Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA
| | - John de Groot
- Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA
- Department of Neurological Surgery, Unversity of California San Fracisco, San Francisco, California, USA
| | - Hideho Okada
- The Parker Institute for Cancer Immunotherapy, San Francisco, California, USA
- Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA
- Department of Neurological Surgery, Unversity of California San Fracisco, San Francisco, California, USA
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12
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Logun M, Wang X, Sun Y, Bagley SJ, Li N, Desai A, Zhang DY, Nasrallah MP, Pai ELL, Oner BS, Plesa G, Siegel D, Binder ZA, Ming GL, Song H, O'Rourke DM. Patient-derived glioblastoma organoids as real-time avatars for assessing responses to clinical CAR-T cell therapy. Cell Stem Cell 2025; 32:181-190.e4. [PMID: 39657679 PMCID: PMC11808387 DOI: 10.1016/j.stem.2024.11.010] [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: 04/20/2024] [Revised: 08/19/2024] [Accepted: 11/11/2024] [Indexed: 12/12/2024]
Abstract
Patient-derived tumor organoids have been leveraged for disease modeling and preclinical studies but rarely applied in real time to aid with interpretation of patient treatment responses in clinics. We recently demonstrated early efficacy signals in a first-in-human, phase 1 study of dual-targeting chimeric antigen receptor (CAR)-T cells (EGFR-IL13Rα2 CAR-T cells) in patients with recurrent glioblastoma. Here, we analyzed six sets of patient-derived glioblastoma organoids (GBOs) treated concurrently with the same autologous CAR-T cell products as patients in our phase 1 study. We found that CAR-T cell treatment led to target antigen reduction and cytolysis of tumor cells in GBOs, the degree of which correlated with CAR-T cell engraftment detected in patients' cerebrospinal fluid (CSF). Furthermore, cytokine release patterns in GBOs mirrored those in patient CSF samples over time. Our findings highlight a unique trial design and GBOs as a valuable platform for real-time assessment of CAR-T cell bioactivity and insights into immunotherapy efficacy.
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Affiliation(s)
- Meghan Logun
- Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Xin Wang
- Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Yusha Sun
- Neuroscience Graduate Group, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Stephen J Bagley
- Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Nannan Li
- Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Arati Desai
- Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Daniel Y Zhang
- Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - MacLean P Nasrallah
- Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Emily Ling-Lin Pai
- Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Bike Su Oner
- Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Gabriela Plesa
- Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Donald Siegel
- Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Zev A Binder
- Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
| | - Guo-Li Ming
- Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
| | - Hongjun Song
- Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
| | - Donald M O'Rourke
- Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
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13
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Buono G, Capozzi M, Caputo R, Lauro VD, Cianniello D, Piezzo M, Cocco S, Martinelli C, Verrazzo A, Tafuro M, Calderaio C, Calabrese A, Nuzzo F, Pagliuca M, Laurentiis MD. CAR-T cell therapy for breast cancer: Current status and future perspective. Cancer Treat Rev 2025; 133:102868. [PMID: 39798230 DOI: 10.1016/j.ctrv.2024.102868] [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: 10/29/2024] [Revised: 12/09/2024] [Accepted: 12/23/2024] [Indexed: 01/15/2025]
Abstract
Within the expanding therapeutic landscape for breast cancer (BC), metastatic breast cancer (MBC) remains virtually incurable and tend to develop resistance to conventional treatments ultimately leading to metastatic progression and death. Cellular immunotherapy (CI), particularly chimeric antigen receptor-engineered T (CAR-T) cells, has emerged as a promising approach for addressing this challenge. In the wake of their striking efficacy against hematological cancers, CAR-T cells have also been used where the clinical need is greatest - in patients with aggressive BCs. Unfortunately, current outcomes fall considerably short of replicating that success, primarily owing to the scarcity of tumor-specific antigens and the immunosuppressive microenvironment within BC. Herein, we provide an up-to-date overview of both preclinical and clinical data concerning the application of CAR-T cell therapy in BC. By surveying the existing literature, we discuss the prevailing constrains of this therapeutic approach and overview possible strategies to advance it in the context of breast malignancies. Possible approaches include employing synthetic biology to refine antigen targeting and mitigate off-target toxicity, utilizing logic-gated CAR constructs to enhance specificity, and leveraging armored CARs to remodel the tumor micro-environment. Temporal and spatial regulation of CAR-T cells using inducible gene switches and external triggers further improves safety and functionality. In addition, promoting T cell homing through chemokine receptor engineering and enhancing manufacturing processes with universal CAR platforms expand therapeutic applicability. These innovations not only address antigen escape and T cell exhaustion but also optimize the efficacy and safety profile of CAR-T cell therapy. We, therefore, outline a trajectory wherein CAR-T cells may evolve from a promising experimental approach to a standard modality in BC therapy.
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Affiliation(s)
- Giuseppe Buono
- Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli, Italy
| | - Monica Capozzi
- Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli, Italy
| | - Roberta Caputo
- Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli, Italy
| | - Vincenzo Di Lauro
- Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli, Italy
| | | | - Michela Piezzo
- Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli, Italy
| | - Stefania Cocco
- Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli, Italy
| | - Claudia Martinelli
- Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli, Italy; Clinical and Translational Oncology, Scuola Superiore Meridionale (SSM), Napoli, Italy
| | - Annarita Verrazzo
- Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli, Italy; Clinical and Translational Oncology, Scuola Superiore Meridionale (SSM), Napoli, Italy
| | - Margherita Tafuro
- Clinical and Translational Oncology, Scuola Superiore Meridionale (SSM), Napoli, Italy; Department of Clinical Medicine and Surgery, University of Naples Federico II, Napoli, Italy
| | - Claudia Calderaio
- Clinical and Translational Oncology, Scuola Superiore Meridionale (SSM), Napoli, Italy; Department of Clinical Medicine and Surgery, University of Naples Federico II, Napoli, Italy
| | | | - Francesco Nuzzo
- Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli, Italy
| | - Martina Pagliuca
- Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli, Italy; Clinical and Translational Oncology, Scuola Superiore Meridionale (SSM), Napoli, Italy; Université Paris-Saclay, Gustave Roussy, INSERM, Molecular Predictors and New Targets in Oncology, Villejuif, France.
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14
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Thirumalaisamy R, Vasuki S, Sindhu SM, Mothilal TM, Srimathi V, Poornima B, Bhuvaneswari M, Hariharan M. FDA-Approved Chimeric Antigen Receptor (CAR)-T Cell Therapy for Different Cancers-A Recent Perspective. Mol Biotechnol 2025; 67:469-483. [PMID: 38459361 DOI: 10.1007/s12033-024-01090-0] [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: 11/22/2023] [Accepted: 01/26/2024] [Indexed: 03/10/2024]
Abstract
Cancer is one of the most prevalent diseases in the world, and their rate of occurence has been increased in recent decades. Current review article, summarizes the novel treatment options Chimeric Antigen Receptor-T (CAR-T) cell therapy for various cancers constitute a major health and development challenge, impacting every aspect of sustainable development quoted by goal 3 good health and well-being of UN sustainable goals. WHO estimates that 70% of cancer deaths occur in low- and middle- income countries (LMICs) by 2030, LMICs are expected to bear the brunt of the expected 24.1 million new cancer cases per year. This current review article focuses and discussed about CAR-T cell therapy for various cancers against most prevalent non-communicable disease cancer disease stipulated by WHO and UN sustainable goals. Three literature databases Google scholar, Science Direct, PubMed was utilized to search and collect CAR-T cell treatment options for different cancers published articles sources in between January 2000 and December 2023. There were a total of 18,700 papers found, with 48 of them being found to be eligible focusing various cancer treatment by CAR-T cells utilized for the study. Based on the information gathered, CAR-T cell therapy treating different cancers and their merit and its advantages in heal and improve certain cancers was also discussed in this review article with their detailed molecular mechanisms. This article also gives an insight to utilize CAR-T cell treatment protocols for rejuvenating cancer patient from such ruthless cancer disease condition thereby improving life span of cancer patients and eradication of disease in some cases.
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Affiliation(s)
- R Thirumalaisamy
- Department of Biotechnology, Sona College Arts and Science, Salem (Dt.), Tamil Nadu, 636005, India.
| | - S Vasuki
- Department of Biotechnology, Sona College Arts and Science, Salem (Dt.), Tamil Nadu, 636005, India
| | - S M Sindhu
- Department of Biotechnology, Sona College Arts and Science, Salem (Dt.), Tamil Nadu, 636005, India
- Department of Biotechnology, PSGR Krishnammal College for Women (Autonomous), Coimbatore (Dt.), Tamil Nadu, 641004, India
| | - T M Mothilal
- Department of Biotechnology, Sona College Arts and Science, Salem (Dt.), Tamil Nadu, 636005, India
| | - V Srimathi
- Department of Biotechnology, Sona College Arts and Science, Salem (Dt.), Tamil Nadu, 636005, India
| | - B Poornima
- Department of Biotechnology, Sona College Arts and Science, Salem (Dt.), Tamil Nadu, 636005, India
| | - M Bhuvaneswari
- Department of Biotechnology, Sona College Arts and Science, Salem (Dt.), Tamil Nadu, 636005, India
| | - Mohan Hariharan
- Center for Applied Research, Saveetha School of Engineering, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamilnadu, 602105, India
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15
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Tykocki T. Diffuse Intrinsic Pontine Glioma and Chimeric Antigen Receptor T-Cell Therapy: An Emerging Frontier. World Neurosurg 2025; 194:123579. [PMID: 39694135 DOI: 10.1016/j.wneu.2024.123579] [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: 11/14/2024] [Accepted: 12/10/2024] [Indexed: 12/20/2024]
Abstract
This study explores the integration of chimeric antigen receptor T-cell (CAR-T) therapy with convection-enhanced delivery (CED) as a novel approach for treating diffuse intrinsic pontine glioma, a highly aggressive pediatric brain tumor with limited treatment options. Preliminary clinical results indicate that CED improves CAR-T cell distribution within the tumor microenvironment, leading to promising antitumor responses. However, challenges such as catheter-related complications and potential on-target/off-tumor toxicity remain. Ongoing research is essential to optimize these strategies and address ethical considerations surrounding patient safety and equitable access to innovative therapies. The aim is to assess the safety, efficacy, and distribution of CAR T cells delivered directly to the tumor site via CED, thereby enhancing therapeutic outcomes while minimizing systemic side effects.
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Affiliation(s)
- Tomasz Tykocki
- Department of Paediatric Neurosurgery, Children's Hospital named after Prof. Jan Bogdanowicz in Warsaw, Warsaw, Poland; Maria Sklodowska-Curie Medical Academy, Warsaw, Poland.
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16
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Grewal EP, Nahed BV, Carter BS, Gerstner ER, Curry WT, Maus MV, Choi BD. Clinical progress in the development of CAR T cells to treat malignant glioma. J Neurooncol 2025; 171:571-579. [PMID: 39695004 DOI: 10.1007/s11060-024-04909-7] [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: 10/22/2024] [Accepted: 12/06/2024] [Indexed: 12/20/2024]
Abstract
CONTEXT Chimeric antigen receptor (CAR) T cell therapy is an exciting modality of immunotherapy that has revolutionized the treatment of hematologic malignancies. However, translating this success to malignant gliomas such as glioblastoma (GBM) and diffuse midline glioma (DMG) remains a formidable challenge due to multiple biologic, anatomic, and immunologic factors. Despite these hurdles, a number of clinical trials deployed over the last decade have increased optimism for the potential of CAR T cell therapy in glioma treatment. EVIDENCE SYNTHESIS We highlight historical and ongoing clinical trials of CAR T cell therapy in glioma, with a focus on key tumor-associated antigens such as IL-13Rα2, HER2, EGFR, EGFRvIII, EphA2, GD2, and B7-H3. Early studies established proof-of-concept for antigen-specific CAR T cell targeting, yet immune evasion mechanisms such as antigen downregulation and limited CAR T cell persistence remain significant obstacles. Recent approaches, including multiantigen targeting, alternative cell sources, and innovations in delivery routes offer promising strategies to overcome these challenges. CONCLUSIONS The rapid evolution of investigational CAR T cell therapies portends great potential for the future of glioma treatment. Future studies will need to refine antigen targeting strategies, optimize CAR T cell persistence, and integrate combinatorial approaches to fully harness the therapeutic potential of this modality and improve the therapeutic window against brain tumors.
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Affiliation(s)
- Eric P Grewal
- Brain Tumor Immunotherapy Laboratory, Massachusetts General Hospital, Boston, MA, USA
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - Brian V Nahed
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA
| | - Bob S Carter
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA
| | | | - William T Curry
- Brain Tumor Immunotherapy Laboratory, Massachusetts General Hospital, Boston, MA, USA
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA
| | - Marcela V Maus
- Cellular Immunotherapy Program, Massachusetts General Hospital, Boston, MA, USA
| | - Bryan D Choi
- Brain Tumor Immunotherapy Laboratory, Massachusetts General Hospital, Boston, MA, USA.
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA.
- Cellular Immunotherapy Program, Massachusetts General Hospital, Boston, MA, USA.
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17
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Sabahi M, Fathi Jouzdani A, Sadeghian Z, Dabbagh Ohadi MA, Sultan H, Salehipour A, Maniakhina L, Rezaei N, Adada B, Mansouri A, Borghei-Razavi H. CAR-engineered NK cells versus CAR T cells in treatment of glioblastoma; strength and flaws. J Neurooncol 2025; 171:495-530. [PMID: 39538038 DOI: 10.1007/s11060-024-04876-z] [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: 09/19/2024] [Accepted: 11/01/2024] [Indexed: 11/16/2024]
Abstract
Glioblastoma (GBM) is a highly aggressive primary brain tumor that carries a grim prognosis. Because of the dearth of treatment options available for treatment of GBM, Chimeric Antigen Receptor (CAR)-engineered T cell and Natural Killer (NK) therapy could provide alternative strategies to address the challenges in GBM treatment. In these approaches, CAR T and NK cells are engineered for cancer-specific immunotherapy by recognizing surface antigens independently of major histocompatibility complex (MHC) molecules. However, the efficacy of CAR T cells is hindered by GBM's downregulation of its targeted antigens. CAR NK cells face similar challenges, but, in contrast, they offer advantages as off-the-shelf allogeneic products, devoid of graft-versus-host disease (GVHD) risk as well as anti-cancer activity beyond CAR specificity, potentially reducing the risk of relapse or resistance. Despite CAR T cell therapies being extensively studied in clinical settings, the use of CAR-modified NK cells in GBM treatment remains largely in the preclinical stage. This review aims to discuss recent advancements in NK cell and CAR T cell therapies for GBM, including methods for introducing CARs into both NK cells and T cells, addressing manufacturing challenges, and providing evidence supporting the efficacy of these approaches from preclinical and early-phase clinical studies. The comprehensive evaluation of CAR-engineered NK cells and CAR T cells seeks to identify the optimal therapeutic approach for GBM, contributing to the development of effective immunotherapies for this devastating disease.
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Affiliation(s)
- Mohammadmahdi Sabahi
- Department of Neurological Surgery, Pauline Braathen Neurological Center, Cleveland Clinic Florida, Weston, FL, USA
| | - Ali Fathi Jouzdani
- Neurosurgery Research Group (NRG), Hamadan University of Medical Sciences, Hamadan, Iran
- Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Zohre Sadeghian
- Department of Pathology & Laboratory Medicine, Cleveland Clinic Florida, Weston, FL, USA
| | | | - Hadi Sultan
- Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, USA
| | - Arash Salehipour
- Neurosurgery Research Group (NRG), Hamadan University of Medical Sciences, Hamadan, Iran
- Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Lana Maniakhina
- Department of Neurosurgery, Geisinger and Geisinger Commonwealth School of Medicine, Wilkes-Barre, PA, USA
| | - Nima Rezaei
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Badih Adada
- Department of Neurological Surgery, Pauline Braathen Neurological Center, Cleveland Clinic Florida, Weston, FL, USA
| | - Alireza Mansouri
- Department of Neurosurgery, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA.
| | - Hamid Borghei-Razavi
- Department of Neurological Surgery, Pauline Braathen Neurological Center, Cleveland Clinic Florida, Weston, FL, USA
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18
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Wu H, Liu Q, Wang F, Gao W, Zhou F, Zhao H. Research Progress of NK Cells in Glioblastoma Treatment. Onco Targets Ther 2025; 18:87-106. [PMID: 39845286 PMCID: PMC11752833 DOI: 10.2147/ott.s486411] [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: 08/24/2024] [Accepted: 01/01/2025] [Indexed: 01/24/2025] Open
Abstract
NK cells are a type of antitumor immune cell with promising clinical application, following T cells. The activity of NK cells is primarily regulated by their surface receptors and immune microenvironment. In gliomas, the tumor microenvironment exerts a strong immunosuppressive effect, which significantly reduces the clinical efficacy of NK cell immunotherapy. Therefore, this review aims to discuss the latest research on the role of NK cells in glioma immunotherapy, focusing on aspects such as NK cell development, function, and localization. It summarizes information on the compounds, monoclonal antibodies, and cytokine therapies targeting NK cells while emphasizing the current status and trends of gene-modified NK cells in glioma treatment. Additionally, it explores the molecular mechanisms underlying immune escape in glioma cells, providing a theoretical foundation and new perspectives for NK cell-based immunotherapy in gliomas.
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Affiliation(s)
- Hao Wu
- Department of Neurosurgery, The Second Affiliated Hospital of Xi’an Medical University, Xi’an, People’s Republic of China
| | - Qi Liu
- Department of Neurosurgery, The First Hospital of Yulin, Yulin, People’s Republic of China
| | - Fenglu Wang
- Department of Neurosurgery, The Second Affiliated Hospital of Xi’an Medical University, Xi’an, People’s Republic of China
| | - Wenwen Gao
- Department of Neurosurgery, The Second Affiliated Hospital of Xi’an Medical University, Xi’an, People’s Republic of China
| | - Feng Zhou
- Department of Neurosurgery, The First Hospital of Yulin, Yulin, People’s Republic of China
| | - Haikang Zhao
- Department of Neurosurgery, The Second Affiliated Hospital of Xi’an Medical University, Xi’an, People’s Republic of China
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19
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Ismail FS, Gallus M, Meuth SG, Okada H, Hartung HP, Melzer N. Current and Future Roles of Chimeric Antigen Receptor T-Cell Therapy in Neurology: A Review. JAMA Neurol 2025; 82:93-103. [PMID: 39585688 DOI: 10.1001/jamaneurol.2024.3818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2024]
Abstract
Importance Advancements in molecular engineering have facilitated the creation of engineered T cells that express synthetic receptors, termed chimeric antigen receptors (CARs). This is promising not only in cancer treatment but also in addressing a spectrum of other conditions. This review provides a comprehensive overview of the current approaches and future potential of CAR T-cell therapy in the field of neurology, particularly for primary brain tumors and autoimmune neurological disorders. Observations CAR T-cell therapy for glioblastoma is promising; however, first-in-human trials did not yield significant success or showed only limited success in a subset of patients. To date, the efficacy of CAR T-cell therapies has been demonstrated in animal models of multiple sclerosis, but larger human studies to corroborate the efficacy remain pending. CAR T cells showed efficacy in treatment of patients with relapsed or refractory aquaporin 4-immunoglobulin G-seropositive neuromyelitis optica spectrum disorders. Further studies with larger patient populations are needed to confirm these results. Success was reported also for treatment of cases with generalized myasthenia gravis using CAR T cells. Chimeric autoantibody receptor T cells, representing a modified form of CAR T cells directed against autoreactive B cells secreting autoantibodies, were used to selectively target autoreactive anti-N-methyl-d-aspartate B cells under in vitro and in vivo conditions, providing the basis for human studies and application to other types of autoimmune encephalitis associated with neuronal or glial antibodies. Conclusions and Relevance CAR T cells herald a new era in the therapeutic landscape of neurological disorders. While their application in solid tumors, such as glioblastoma, has not universally yielded robust success, emerging innovative strategies show promise, and there is optimism for their effectiveness in certain autoimmune neurological disorders.
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Affiliation(s)
- Fatme Seval Ismail
- Department of Neurology, Klinikum Vest, Academic Teaching Hospital of the Ruhr University Bochum, Recklinghausen, Germany
| | - Marco Gallus
- Department of Neurological Surgery, University of California, San Francisco
- Department of Neurosurgery, University Hospital Muenster, Muenster, Germany
| | - Sven G Meuth
- Department of Neurology, Medical Faculty and University Hospital, Heinrich-Heine University of Düsseldorf, Düsseldorf, Germany
| | - Hideho Okada
- Department of Neurological Surgery, University of California, San Francisco
- Parker Institute for Cancer Immunotherapy, San Francisco, California
- Helen Diller Family Comprehensive Cancer Center, San Francisco, California
| | - Hans-Peter Hartung
- Department of Neurology, Medical Faculty and University Hospital, Heinrich-Heine University of Düsseldorf, Düsseldorf, Germany
- Brain and Mind Center, University of Sydney, Sydney, New South Wales, Australia
- Department of Neurology, Palacky University Olomouc, Olomouc, Czech Republic
| | - Nico Melzer
- Department of Neurology, Medical Faculty and University Hospital, Heinrich-Heine University of Düsseldorf, Düsseldorf, Germany
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20
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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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21
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Park S, Maus MV, Choi BD. CAR-T cell therapy for the treatment of adult high-grade gliomas. NPJ Precis Oncol 2024; 8:279. [PMID: 39702579 DOI: 10.1038/s41698-024-00753-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 10/30/2024] [Indexed: 12/21/2024] Open
Abstract
Treatment for malignant primary brain tumors, including glioblastoma, remains a significant challenge despite advances in therapy. CAR-T cell immunotherapy represents a promising alternative to conventional treatments. This review discusses the landscape of clinical trials for CAR-T cell therapy targeting brain tumors, highlighting key advancements like novel target antigens and combinatorial strategies designed to address tumor heterogeneity and immunosuppression, with the goal of improving outcomes for patients with these aggressive cancers.
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Affiliation(s)
- Sangwoo Park
- Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Marcela V Maus
- Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Bryan D Choi
- Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
- Brain Tumor Immunotherapy Lab, Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
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22
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Liu Y, Zhou F, Ali H, Lathia JD, Chen P. Immunotherapy for glioblastoma: current state, challenges, and future perspectives. Cell Mol Immunol 2024; 21:1354-1375. [PMID: 39406966 PMCID: PMC11607068 DOI: 10.1038/s41423-024-01226-x] [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: 09/18/2024] [Indexed: 10/19/2024] Open
Abstract
Glioblastoma (GBM) is an aggressive and lethal type of brain tumor in human adults. The standard of care offers minimal clinical benefit, and most GBM patients experience tumor recurrence after treatment. In recent years, significant advancements have been made in the development of novel immunotherapies or other therapeutic strategies that can overcome immunotherapy resistance in many advanced cancers. However, the benefit of immune-based treatments in GBM is limited because of the unique brain immune profiles, GBM cell heterogeneity, and immunosuppressive tumor microenvironment. In this review, we present a detailed overview of current immunotherapeutic strategies and discuss the challenges and potential molecular mechanisms underlying immunotherapy resistance in GBM. Furthermore, we provide an in-depth discussion regarding the strategies that can overcome immunotherapy resistance in GBM, which will likely require combination therapies.
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Affiliation(s)
- Yang Liu
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Fei Zhou
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Heba Ali
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Justin D Lathia
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
- Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, 44195, USA
- Rose Ella Burkhardt Brain Tumor & Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH, 44195, USA
- Case Comprehensive Cancer Center, Cleveland, OH, 44195, USA
| | - Peiwen Chen
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.
- Case Comprehensive Cancer Center, Cleveland, OH, 44195, USA.
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23
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Song KW, Scott BJ. CAR T-cell therapy for gliomas. Curr Opin Neurol 2024; 37:672-681. [PMID: 39498846 DOI: 10.1097/wco.0000000000001318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2024]
Abstract
PURPOSE OF REVIEW To review the landscape of chimeric antigen receptor T-cell (CAR T) therapy for gliomas as seen in recently published trials and discuss on-going challenges with new cancer immunotherapy treatments. RECENT FINDINGS Given how CAR T therapy has revolutionized the treatment of several hematologic malignancies, there has been increasing interest in using immunotherapy, and particularly CAR T therapy for gliomas. Within the past decade, several first in human trials have published early patient experiences showing treatment is generally well tolerated but with limited efficacy, which may be improving with newer evolutions in CAR T design to overcome known resistance mechanisms in glioma treatment. SUMMARY CAR T therapy is a promising avenue of treatment for high-grade gliomas, which have a universally poor prognosis as well as limited therapeutics. There are a growing number of CAR T clinical trials for CNS tumors and thus, an understanding of their treatment strategies, toxicity management, and overcoming resistance mechanisms will be important for both clinical practice and to identify areas for future research.
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Affiliation(s)
- Kun-Wei Song
- Department of Neurology, Stanford University School of Medicine
- Stanford Neuro-Immuno-Oncology (NIO) Program, Stanford, California, USA
| | - Brian J Scott
- Department of Neurology, Stanford University School of Medicine
- Stanford Neuro-Immuno-Oncology (NIO) Program, Stanford, California, USA
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24
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Ronsley R, Bertrand KC, Song EZ, Timpanaro A, Choe M, Tlais D, Vitanza NA, Park JR. CAR T cell therapy for pediatric central nervous system tumors: a review of the literature and current North American trials. Cancer Metastasis Rev 2024; 43:1205-1216. [PMID: 39251462 PMCID: PMC11554695 DOI: 10.1007/s10555-024-10208-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 08/22/2024] [Indexed: 09/11/2024]
Abstract
Central nervous system (CNS) tumors are the leading cause of cancer-related death in children. Typical therapy for CNS tumors in children involves a combination of surgery, radiation, and chemotherapy. While upfront therapy is effective for many high-grade tumors, therapy at the time of relapse remains limited. Furthermore, for diffuse intrinsic pontine glioma (DIPG) and diffuse midline glioma (DMG), there are currently no curative therapies. Chimeric antigen receptor T (CAR T) cell therapy is a promising novel treatment avenue for these tumors. Here, we review the preclinical evidence for CAR T cell use in pediatric brain tumors, the preliminary clinical experience of CNS CAR T cell trials, toxicity associated with systemic and locoregional CAR T cell therapy for CNS tumors, challenges in disease response evaluation with CAR T cell therapy, and the knowledge gained from correlative biologic studies from these trials in the pediatric and young adult population.
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Affiliation(s)
- Rebecca Ronsley
- Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA
- Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA, USA
| | - Kelsey C Bertrand
- Department of Oncology, St. Jude Children's Research Hospital, 262 Danny Thomas Pl, Memphis, TN, 38105, USA
- Division of Neuro-Oncology, Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Edward Z Song
- Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA, USA
| | - Andrea Timpanaro
- Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA, USA
| | - Michelle Choe
- Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Dana Tlais
- Department of Oncology, St. Jude Children's Research Hospital, 262 Danny Thomas Pl, Memphis, TN, 38105, USA
- Division of Neuro-Oncology, Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Nicholas A Vitanza
- Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA
- Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA, USA
| | - Julie R Park
- Department of Oncology, St. Jude Children's Research Hospital, 262 Danny Thomas Pl, Memphis, TN, 38105, USA.
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25
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Palazzo L, Pieri V, Berzero G, Filippi M. CAR-T Cells for the Treatment of Central Nervous System Tumours: Known and Emerging Neurotoxicities. Brain Sci 2024; 14:1220. [PMID: 39766419 PMCID: PMC11727498 DOI: 10.3390/brainsci14121220] [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: 11/01/2024] [Revised: 11/24/2024] [Accepted: 11/26/2024] [Indexed: 01/15/2025] Open
Abstract
The advent of chimeric antigen receptor (CAR)-T cells has recently changed the prognosis of relapsing/refractory diffuse large B-cell lymphomas, showing response rates as high as 60 to 80%. Common toxicities reported in the pivotal clinical trials include the cytokine release syndrome (CRS) and the Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS), a stereotyped encephalopathy related to myeloid cell activation and blood-brain barrier dysfunction, presenting with a distinctive cascade of dysgraphia, aphasia, disorientation, attention deficits, vigilance impairment, motor symptoms, seizures, and diffuse brain oedema. The tremendous oncological efficacy of CAR-T cells observed in systemic B-cell malignancies is leading to their growing use in patients with primary or secondary central nervous system (CNS) lymphomas and in patients with solid tumours, including several CNS cancers. Early studies conducted in adult and paediatric patients with solid CNS tumours reported a distinct profile of neurotoxicity referred to as Tumour inflammation-associated neurotoxicity (TIAN), corresponding to local inflammation at the tumour site manifesting with focal neurological deficits or mechanical complications (e.g., obstructive hydrocephalus). The present review summarises available data on the efficacy and safety of CAR-T cells for solid and haematological CNS malignancies, emphasising known and emerging phenotypes, ongoing challenges, and future perspectives.
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Affiliation(s)
- Leonardo Palazzo
- Neurology Unit, IRCCS Ospedale San Raffaele, 20132 Milan, Italy; (L.P.); (V.P.); (M.F.)
- Faculty of Medicine, Vita-Salute San Raffaele University, 20132 Milan, Italy
| | - Valentina Pieri
- Neurology Unit, IRCCS Ospedale San Raffaele, 20132 Milan, Italy; (L.P.); (V.P.); (M.F.)
- Faculty of Medicine, Vita-Salute San Raffaele University, 20132 Milan, Italy
| | - Giulia Berzero
- Neurology Unit, IRCCS Ospedale San Raffaele, 20132 Milan, Italy; (L.P.); (V.P.); (M.F.)
- Faculty of Medicine, Vita-Salute San Raffaele University, 20132 Milan, Italy
| | - Massimo Filippi
- Neurology Unit, IRCCS Ospedale San Raffaele, 20132 Milan, Italy; (L.P.); (V.P.); (M.F.)
- Faculty of Medicine, Vita-Salute San Raffaele University, 20132 Milan, Italy
- Neurorehabilitation Unit, Neurophysiology Unit, Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS Ospedale San Raffaele, 20132 Milan, Italy
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26
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Meeus F, Funeh CN, Awad RM, Zeven K, Autaers D, De Becker A, Van Riet I, Goyvaerts C, Tuyaerts S, Neyns B, Devoogdt N, De Vlaeminck Y, Breckpot K. Preclinical evaluation of antigen-sensitive B7-H3-targeting nanobody-based CAR-T cells in glioblastoma cautions for on-target, off-tumor toxicity. J Immunother Cancer 2024; 12:e009110. [PMID: 39562005 PMCID: PMC11575280 DOI: 10.1136/jitc-2024-009110] [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: 02/21/2024] [Accepted: 10/27/2024] [Indexed: 11/21/2024] Open
Abstract
BACKGROUND Glioblastoma is the most common lethal primary brain tumor, urging evaluation of new treatment options. Chimeric antigen receptor (CAR)-T cells targeting B7 homolog 3 (B7-H3) are promising because of the overexpression of B7-H3 on glioblastoma cells but not on healthy brain tissue. Nanobody-based (nano)CARs are gaining increasing attention as promising alternatives to classical single-chain variable fragment-based (scFv)CARs, because of their single-domain nature and low immunogenicity. Still, B7-H3 nanoCAR-T cells have not been extensively studied in glioblastoma. METHODS B7-H3 nanoCAR- and scFvCAR-T cells were developed and evaluated in human glioblastoma models. NanoCAR-T cells targeting an irrelevant antigen served as control. T cell activation, cytokine secretion and killing capacity were evaluated in vitro using ELISA, live cell imaging and flow cytometry. Antigen-specific killing was assessed by generating B7-H3 knock-out cells using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9-genome editing. The tumor tracing capacity of the B7-H3 nanobody was first evaluated in vivo using nuclear imaging. Then, the therapeutic potential of the nanoCAR-T cells was evaluated in a xenograft glioblastoma model. RESULTS We showed that B7-H3 nanoCAR-T cells were most efficient in lysing B7-H3pos glioblastoma cells in vitro. Lack of glioblastoma killing by control nanoCAR-T cells and lack of B7-H3neg glioblastoma killing by B7-H3 nanoCAR-T cells showed antigen-specificity. We showed in vivo tumor targeting capacity of the B7-H3 nanobody-used for the nanoCAR design-in nuclear imaging experiments. Evaluation of the nanoCAR-T cells in vivo showed tumor control in mice treated with B7-H3 nanoCAR-T cells in contrast to progressive disease in mice treated with control nanoCAR-T cells. However, we observed limiting toxicity in mice treated with B7-H3 nanoCAR-T cells and showed that the B7-H3 nanoCAR-T cells are activated even by low levels of mouse B7-H3 expression. CONCLUSIONS B7-H3 nanoCAR-T cells showed promise for glioblastoma therapy following in vitro characterization, but limiting in vivo toxicity was observed. Off-tumor recognition of healthy mouse tissue by the cross-reactive B7-H3 nanoCAR-T cells was identified as a potential cause for this toxicity, warranting caution when using highly sensitive nanoCAR-T cells, recognizing the low-level expression of B7-H3 on healthy tissue.
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Affiliation(s)
- Fien Meeus
- Translational Oncology Research Center (TORC), Department of Biomedical Sciences, Laboratory for Molecular and Cellular Therapy (LMCT), Vrije Universiteit Brussel, Brussels, Belgium
- Department of Medical Imaging (MIMA), Molecular Imaging and Therapy (MITH) research group, Vrije Universiteit Brussel, Brussels, Belgium
| | - Cyprine Neba Funeh
- Department of Medical Imaging (MIMA), Molecular Imaging and Therapy (MITH) research group, Vrije Universiteit Brussel, Brussels, Belgium
| | - Robin Maximilian Awad
- Translational Oncology Research Center (TORC), Department of Biomedical Sciences, Laboratory for Molecular and Cellular Therapy (LMCT), Vrije Universiteit Brussel, Brussels, Belgium
| | - Katty Zeven
- Department of Medical Imaging (MIMA), Molecular Imaging and Therapy (MITH) research group, Vrije Universiteit Brussel, Brussels, Belgium
| | - Dorien Autaers
- Translational Oncology Research Center (TORC), Department of Biomedical Sciences, Laboratory for Molecular and Cellular Therapy (LMCT), Vrije Universiteit Brussel, Brussels, Belgium
| | - Ann De Becker
- Department of Hematology, Cellular Therapy Laboratory, University Hospital Brussels, Universitair Ziekenhuis Brussel, Brussels, Belgium
| | - Ivan Van Riet
- Department of Hematology, Cellular Therapy Laboratory, University Hospital Brussels, Universitair Ziekenhuis Brussel, Brussels, Belgium
- Translational Oncology Research Center (TORC), Department of Biomedical Sciences, Hematology and Immunology Research Team (HEIM), Vrije Universiteit Brussel, Brussels, Belgium
| | - Cleo Goyvaerts
- Department of Medical Imaging (MIMA), Molecular Imaging and Therapy (MITH) research group, Vrije Universiteit Brussel, Brussels, Belgium
| | - Sandra Tuyaerts
- Department of Medical Oncology, University Hospital Brussels, Universitair Ziekenhuis Brussel, Brussels, Belgium
- Translational Oncology Research Center (TORC), Department of Biomedical Sciences, Laboratory for Medical and Molecular Oncology (LMMO), Vrije Universiteit Brussel, Brussels, Belgium
| | - Bart Neyns
- Department of Medical Oncology, University Hospital Brussels, Universitair Ziekenhuis Brussel, Brussels, Belgium
- Translational Oncology Research Center (TORC), Department of Biomedical Sciences, Laboratory for Medical and Molecular Oncology (LMMO), Vrije Universiteit Brussel, Brussels, Belgium
| | - Nick Devoogdt
- Department of Medical Imaging (MIMA), Molecular Imaging and Therapy (MITH) research group, Vrije Universiteit Brussel, Brussels, Belgium
| | - Yannick De Vlaeminck
- Translational Oncology Research Center (TORC), Department of Biomedical Sciences, Laboratory for Molecular and Cellular Therapy (LMCT), Vrije Universiteit Brussel, Brussels, Belgium
| | - Karine Breckpot
- Translational Oncology Research Center (TORC), Department of Biomedical Sciences, Laboratory for Molecular and Cellular Therapy (LMCT), Vrije Universiteit Brussel, Brussels, Belgium
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27
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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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28
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Liu J, Peng J, Jiang J, Liu Y. Clinical immunotherapy in glioma: current concepts, challenges, and future perspectives. Front Immunol 2024; 15:1476436. [PMID: 39555054 PMCID: PMC11564147 DOI: 10.3389/fimmu.2024.1476436] [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: 08/05/2024] [Accepted: 10/16/2024] [Indexed: 11/19/2024] Open
Abstract
Glioma is one of the common tumors in the central nervous system, and its treatment methods (surgery, radiotherapy, and chemotherapy) lack specificity and have a poor prognosis. With the development of immunology, cell biology, and genomics, tumor immunotherapy has ushered in a new era of tumor therapy, achieving significant results in other invasive cancers such as advanced melanoma and advanced non-small cell lung cancer. Currently, the clinical trials of immunotherapy in glioma are also progressing rapidly. Here, this review summarizes promising immunotherapy methods in recent years, reviews the current status of clinical trials, and discusses the challenges and prospects of glioma immunotherapy.
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Affiliation(s)
- Jun Liu
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of Neurosurgery, Jiujiang No. 1 People’s Hospital, Jiujiang, China
| | - Jingjian Peng
- Department of Neurosurgery, Jiujiang No. 1 People’s Hospital, Jiujiang, China
| | - Jian Jiang
- Department of Neurosurgery, Jiujiang No. 1 People’s Hospital, Jiujiang, China
| | - Yanhui Liu
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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29
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Del Baldo G, Carai A, Mastronuzzi A. Chimeric antigen receptor adoptive immunotherapy in central nervous system tumors: state of the art on clinical trials, challenges, and emerging strategies to addressing them. Curr Opin Oncol 2024; 36:545-553. [PMID: 38989708 PMCID: PMC11460750 DOI: 10.1097/cco.0000000000001076] [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] [Indexed: 07/12/2024]
Abstract
PURPOSE OF REVIEW Central nervous system (CNS) tumors represent a significant unmet medical need due to their enduring burden of high mortality and morbidity. Chimeric antigen receptor (CAR) T-cell therapy emerges as a groundbreaking approach, offering hope for improved treatment outcomes. However, despite its successes in hematological malignancies, its efficacy in solid tumors, including CNS tumors, remains limited. Challenges such as the intricate tumor microenvironment (TME), antigenic heterogeneity, and CAR T-cell exhaustion hinder its effectiveness. This review aims to explore the current landscape of CAR T-cell therapy for CNS tumors, highlighting recent advancements and addressing challenges in achieving therapeutic efficacy. RECENT FINDINGS Innovative strategies aim to overcome the barriers posed by the TME and antigen diversity, prevent CAR T-cell exhaustion through engineering approaches and combination therapies with immune checkpoint inhibitors to improving treatment outcomes. SUMMARY Researchers have been actively working to address these challenges. Moreover, addressing the unique challenges associated with neurotoxicity in CNS tumors requires specialized management strategies. These may include the development of grading systems, monitoring devices, alternative cell platforms and incorporation of suicide genes. Continued research efforts and clinical advancements are paramount to overcoming the existing challenges and realizing the full potential of CAR T-cell therapy in treating CNS tumors.
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Affiliation(s)
- Giada Del Baldo
- Department of Pediatric Haematology and Oncology, and Cell and Gene Therapy Bambino Gesù Children's Hospital, IRCCS
- Department of Experimental Medicine, Sapienza University of Rome
| | - Andrea Carai
- Department of Neurosciences, Neurosurgery Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Angela Mastronuzzi
- Department of Pediatric Haematology and Oncology, and Cell and Gene Therapy Bambino Gesù Children's Hospital, IRCCS
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30
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Hasan S, Mahmud Z, Hossain M, Islam S. Harnessing the role of aberrant cell signaling pathways in glioblastoma multiforme: a prospect towards the targeted therapy. Mol Biol Rep 2024; 51:1069. [PMID: 39424705 DOI: 10.1007/s11033-024-09996-3] [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: 06/19/2024] [Accepted: 10/07/2024] [Indexed: 10/21/2024]
Abstract
Glioblastoma Multiforme (GBM), designated as grade IV by the World Health Organization, is the most aggressive and challenging brain tumor within the central nervous system. Around 80% of GBM patients have a poor prognosis, with a median survival of 12-15 months. Approximately 90% of GBM cases originate from normal glial cells via oncogenic processes, while the remainder arise from low-grade tumors. GBM is notorious for its heterogeneity, high recurrence rates, invasiveness, and aggressive behavior. Its malignancy is driven by increased invasive migration, proliferation, angiogenesis, and reduced apoptosis. Throughout various stages of central nervous system (CNS) development, pivotal signaling pathways, including Wnt/β-catenin, Sonic hedgehog signaling (Shh), PI3K/AKT/mTOR, Ras/Raf/MAPK/ERK, STAT3, NF-КB, TGF-β, and Notch signaling, orchestrate the growth, proliferation, differentiation, and migration of neural progenitor cells in the brain. Numerous upstream and downstream regulators within these signaling pathways have been identified as significant contributors to the development of human malignancies. Disruptions or aberrant activations in these pathways are linked to gliomagenesis, enhancing the invasiveness, progression, and aggressiveness of GBM, along with epithelial to mesenchymal transition (EMT) and the presence of glioma stem cells (GSCs). Traditional GBM treatment involves surgery, radiotherapy, and chemotherapy with Temozolomide (TMZ). However, most patients experience tumor recurrence, leading to low survival rates. This review provides an overview of the major cell signaling pathways involved in gliomagenesis. Furthermore, we explore the signaling pathways leading to therapy resistance and target key molecules within these signaling pathways, paving the way for the development of novel therapeutic approaches.
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Affiliation(s)
- Subbrina Hasan
- Laboratory of Neuroscience and Neurogenetics, Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, Bangladesh
| | - Zimam Mahmud
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, Bangladesh.
| | - Mahmud Hossain
- Laboratory of Neuroscience and Neurogenetics, Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, Bangladesh.
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, Bangladesh.
| | - Sohidul Islam
- Department of Biochemistry & Microbiology, North South University, Dhaka, 1229, Bangladesh
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31
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Kandav G, Chandel A. Revolutionizing cancer treatment: an in-depth exploration of CAR-T cell therapies. Med Oncol 2024; 41:275. [PMID: 39400611 DOI: 10.1007/s12032-024-02491-6] [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: 07/02/2024] [Accepted: 08/27/2024] [Indexed: 10/15/2024]
Abstract
Cancer is a leading cause of fatality worldwide. Due to the heterogeneity of cancer cells the effectiveness of various conventional cancer treatment techniques is constrained. Thus, researchers are diligently investigating therapeutic approaches like immunotherapy for effective tumor managements. Immunotherapy harnesses the inherent potential of patient's immune system to achieve desired outcomes. Within the realm of immunotherapy, CAR-T (Chimeric Antigen Receptor T) cells, emerges as a revolutionary innovation for cancer therapy. The process of CAR-T cell therapy entails extracting the patient's T cells, altering them with customized receptors designed to specifically recognize and eradicate the tumor cells, and then reinfusing the altered cells into the patient's body. Although there has been significant progress with CAR-T cell therapy in certain cases of specific B-cell leukemia and lymphoma, its effectiveness is hindered in hematological and solid tumors due to the challenges such as severe toxicities, restricted tumor infiltration, cytokine release syndrome and antigen escape. Overcoming these obstacles requires innovative approaches to design more effective CAR-T cells, which require a competent and diverse team to develop and implement. This comprehensive review addresses numerous therapeutic issues and provides a strategic solution while providing a deep understanding of the structural intricacies and production processes of CAR-T cells. In addition, this review explores the practical aspects of CAR-T cell therapy in clinical settings.
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Affiliation(s)
- Gurpreet Kandav
- Chandigarh College of Pharmacy, Chandigarh Group of Colleges, Landran, Sahibzada Ajit Singh Nagar, Punjab, 140307, India.
| | - Akash Chandel
- Chandigarh College of Pharmacy, Chandigarh Group of Colleges, Landran, Sahibzada Ajit Singh Nagar, Punjab, 140307, India
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32
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Tachi T, Kijima N, Kuroda H, Ikeda S, Murakami K, Nakagawa T, Yaga M, Nakagawa K, Utsugi R, Hirayama R, Okita Y, Kagawa N, Kishima H, Imai C, Hosen N. Antitumor effects of intracranial injection of B7-H3-targeted Car-T and Car-Nk cells in a patient-derived glioblastoma xenograft model. Cancer Immunol Immunother 2024; 73:256. [PMID: 39367952 PMCID: PMC11456075 DOI: 10.1007/s00262-024-03808-0] [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: 04/01/2024] [Accepted: 08/12/2024] [Indexed: 10/07/2024]
Abstract
BACKGROUND Glioblastoma multiforme (GBM) is the most lethal primary brain tumor for which novel therapies are needed. Recently, chimeric antigen receptor (CAR) T cell therapy has been shown to be effective against GBM, but it is a personalized medicine and requires high cost and long time for the cell production. CAR-transduced natural killer (NK) cells can be used for "off-the-shelf" cellular immunotherapy because they do not induce graft-versus-host disease. Therefore, we aimed to analyze the anti-GBM effect of CAR-T or NK cells targeting B7-H3, which is known to be highly expressed in GBM. METHODS CAR-T cells targeting B7-H3 were generated using previously reported anti-B7-H3 scFv sequences. Cord blood (CB)-derived NK cells transduced with the B7-H3 CAR were also generated. Their anti-GBM effect was analyzed in vitro. The antitumor effect of intracranial injection of the B7-H3 CAR-T or NK cells was investigated in an in vivo xenograft model with patient-derived GBM cells. RESULTS Both B7-H3 CAR-T cells and CAR-NK cells exhibited marked cytotoxicity against patient-derived GBM cells in vitro. Furthermore, intracranial injection of CAR-T cells and CAR-NK cells targeting B7-H3 resulted in a significant antitumor effect against patient-derived GBM xenografts. CONCLUSION Not only CAR-T cells but also CB-derived CAR-NK cells targeting B7-H3 may have the potential to eliminate GBM cells.
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Affiliation(s)
- Tetsuro Tachi
- Department of Neurosurgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 5650871, Japan
| | - Noriyuki Kijima
- Department of Neurosurgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 5650871, Japan.
| | - Hideki Kuroda
- Department of Neurosurgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 5650871, Japan
| | - Syunya Ikeda
- World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan
| | - Koki Murakami
- Department of Neurosurgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 5650871, Japan
| | - Tomoyoshi Nakagawa
- Department of Neurosurgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 5650871, Japan
| | - Moto Yaga
- Department of Respiratory Medicine, Osaka General Hospital, Osaka, Japan
| | - Kanji Nakagawa
- Department of Neurosurgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 5650871, Japan
| | - Reina Utsugi
- Department of Neurosurgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 5650871, Japan
| | - Ryuichi Hirayama
- Department of Neurosurgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 5650871, Japan
| | - Yoshiko Okita
- Department of Neurosurgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 5650871, Japan
| | - Naoki Kagawa
- Department of Neurosurgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 5650871, Japan
| | - Haruhiko Kishima
- Department of Neurosurgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 5650871, Japan
| | - Chihaya Imai
- Department of Pediatrics, Faculty of Medicine, University of Toyama, Toyama, Japan
| | - Naoki Hosen
- World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
- Department of Hematology and Oncology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 5650871, Japan.
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33
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Li N, Rodriguez JL, Yin Y, Logun MT, Zhang L, Yu S, Hicks KA, Zhang JV, Zhang L, Xie C, Wang J, Wang T, Xu J, Fraietta JA, Binder ZA, Lin Z, O'Rourke DM. Armored bicistronic CAR T cells with dominant-negative TGF-β receptor II to overcome resistance in glioblastoma. Mol Ther 2024; 32:3522-3538. [PMID: 39086131 PMCID: PMC11489531 DOI: 10.1016/j.ymthe.2024.07.020] [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: 02/02/2024] [Revised: 07/01/2024] [Accepted: 07/28/2024] [Indexed: 08/02/2024] Open
Abstract
Chimeric antigen receptor (CAR) T cells have shown significant efficacy in hematological diseases. However, CAR T therapy has demonstrated limited efficacy in solid tumors, including glioblastoma (GBM). One of the most important reasons is the immunosuppressive tumor microenvironment (TME), which promotes tumor growth and suppresses immune cells used to eliminate tumor cells. The human transforming growth factor β (TGF-β) plays a crucial role in forming the suppressive GBM TME and driving the suppression of the anti-GBM response. To mitigate TGF-β-mediated suppressive activity, we combined a dominant-negative TGF-β receptor II (dnTGFβRII) with our previous bicistronic CART-EGFR-IL13Rα2 construct, currently being evaluated in a clinical trial, to generate CART-EGFR-IL13Rα2-dnTGFβRII, a tri-modular construct we are developing for clinical application. We hypothesized that this approach would more effectively subvert resistance mechanisms observed with GBM. Our data suggest that CART-EGFR-IL13Rα2-dnTGFβRII significantly augments T cell proliferation, enhances functional responses, and improves the fitness of bystander cells, particularly by decreasing the TGF-β concentration in a TGF-β-rich TME. In addition, in vivo studies validate the safety and efficacy of the dnTGFβRII cooperating with CARs in targeting and eradicating GBM in an NSG mouse model.
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Affiliation(s)
- Nannan Li
- Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin 150001, China; Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Jesse L Rodriguez
- Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Yibo Yin
- Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin 150001, China; Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Meghan T Logun
- Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Logan Zhang
- Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Shengkun Yu
- Department of Neurosurgery, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing 211800, China
| | - Kelly A Hicks
- Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Jiasi Vicky Zhang
- Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Laura Zhang
- Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Chuncheng Xie
- Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Jiabin Wang
- Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Tianyu Wang
- Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Jiayi Xu
- Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Joseph A Fraietta
- Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Zev A Binder
- Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Zhiguo Lin
- Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
| | - Donald M O'Rourke
- Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
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Owens K, Rahman A, Bozic I. Spatiotemporal dynamics of tumor - CAR T-cell interaction following local administration in solid cancers. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.29.610392. [PMID: 39257746 PMCID: PMC11384001 DOI: 10.1101/2024.08.29.610392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/12/2024]
Abstract
The success of chimeric antigen receptor (CAR) T-cell therapy in treating hematologic malignancies has generated widespread interest in translating this technology to solid cancers. However, issues like tumor infiltration, the immunosuppressive tumor microenvironment, and tumor heterogeneity limit its efficacy in the solid tumor setting. Recent experimental and clinical studies propose local administration directly into the tumor or at the tumor site to increase CAR T-cell infiltration and improve treatment outcomes. Characteristics of the types of solid tumors that may be the most receptive to this treatment approach remain unclear. In this work, we develop a spatiotemporal model for CAR T-cell treatment of solid tumors, and use numerical simulations to compare the effect of introducing CAR T cells via intratumoral injection versus intracavitary administration in diverse cancer types. We demonstrate that the model can recapitulate tumor and CAR T-cell data from imaging studies of local administration of CAR T cells in mouse models. Our results suggest that locally administered CAR T cells will be most successful against slowly proliferating, highly diffusive tumors, which have the lowest average tumor cell density. These findings affirm the clinical observation that CAR T cells will not perform equally across different types of solid tumors, and suggest that measuring tumor density may be helpful when considering the feasibility of CAR T-cell therapy and planning dosages for a particular patient. We additionally find that local delivery of CAR T cells can result in deep tumor responses, provided that the initial CAR T-cell dose does not contain a significant fraction of exhausted cells.
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Affiliation(s)
- Katherine Owens
- Department of Applied Mathematics, University of Washington, Seattle WA
- Fred Hutchinson Cancer Center, Seattle WA
| | - Aminur Rahman
- Fred Hutchinson Cancer Center, Seattle WA
- Artificial Intelligence Institute in Dynamic Systems, University of Washington, Seattle WA
| | - Ivana Bozic
- Department of Applied Mathematics, University of Washington, Seattle WA
- Fred Hutchinson Cancer Center, Seattle WA
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35
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Ju A, Choi S, Jeon Y, Kim K. Lymphodepletion in Chimeric Antigen Receptor T-Cell Therapy for Solid Tumors: A Focus on Brain Tumors. Brain Tumor Res Treat 2024; 12:208-220. [PMID: 39542517 PMCID: PMC11570086 DOI: 10.14791/btrt.2024.0037] [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: 10/14/2024] [Revised: 10/17/2024] [Accepted: 10/19/2024] [Indexed: 11/17/2024] Open
Abstract
Chimeric antigen receptor (CAR)-T cell therapy, which has demonstrated remarkable efficacy in hematologic malignancies, is being extended to the treatment of refractory solid tumors, including brain tumors. Lymphodepletion (LD) is an essential preconditioning process that enhances CAR-T efficacy by promoting CAR-T cell expansion and persistence in the body, and has become a standard regimen for hematologic cancers. Recent clinical results of CAR-T therapy for solid tumors, including brain tumors, have shown that cyclophosphamide/fludarabine-based preconditioning has potential benefits and is gradually becoming adopted in solid tumor CAR-T trials. Furthermore, some CAR-T trials for solid tumors are attempting to develop LD regimens optimized specifically for solid tumors, distinct from the standard LD regimens used in hematologic cancers. In contrast, CAR-T therapy targeting brain tumors frequently employs locoregionally repeated administration in tumors or cerebrospinal fluid, resulting in less frequent use of LD compared to other solid tumors. Nevertheless, several clinical studies suggest that LD may still provide potential benefits for CAR-T expansion and improvement in clinical responses in systemic CAR-T administration. The studies presented in this review suggest that while LD can be beneficial for enhancing CAR-T efficacy, considerations must be made regarding its compatibility with the CAR-T administration route, potential excessive activation based on CAR-T structural characteristics, and target expression in normal organs. Additionally, given the unique characteristics of brain tumors, optimized selection of LD agents, as well as dosing and regimens, may be required, highlighting the need for further research.
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Affiliation(s)
- Anna Ju
- R&D Center, CellabMED Inc., Seoul, Korea
| | | | | | - Kiwan Kim
- R&D Center, CellabMED Inc., Seoul, Korea.
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36
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Peng L, Sferruzza G, Yang L, Zhou L, Chen S. CAR-T and CAR-NK as cellular cancer immunotherapy for solid tumors. Cell Mol Immunol 2024; 21:1089-1108. [PMID: 39134804 PMCID: PMC11442786 DOI: 10.1038/s41423-024-01207-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 07/22/2024] [Indexed: 10/02/2024] Open
Abstract
In the past decade, chimeric antigen receptor (CAR)-T cell therapy has emerged as a promising immunotherapeutic approach for combating cancers, demonstrating remarkable efficacy in relapsed/refractory hematological malignancies in both pediatric and adult patients. CAR-natural killer (CAR-NK) cell complements CAR-T cell therapy by offering several distinct advantages. CAR-NK cells do not require HLA compatibility and exhibit low safety concerns. Moreover, CAR-NK cells are conducive to "off-the-shelf" therapeutics, providing significant logistic advantages over CAR-T cells. Both CAR-T and CAR-NK cells have shown consistent and promising results in hematological malignancies. However, their efficacy against solid tumors remains limited due to various obstacles including limited tumor trafficking and infiltration, as well as an immuno-suppressive tumor microenvironment. In this review, we discuss the recent advances and current challenges of CAR-T and CAR-NK cell immunotherapies, with a specific focus on the obstacles to their application in solid tumors. We also analyze in depth the advantages and drawbacks of CAR-NK cells compared to CAR-T cells and highlight CAR-NK CAR optimization. Finally, we explore future perspectives of these adoptive immunotherapies, highlighting the increasing contribution of cutting-edge biotechnological tools in shaping the next generation of cellular immunotherapy.
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Affiliation(s)
- Lei Peng
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
- System Biology Institute, Yale University, West Haven, CT, USA.
| | - Giacomo Sferruzza
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
| | - Luojia Yang
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
- Combined Program in the Biological and Biomedical Sciences, Yale University, New Haven, CT, USA
- Molecular Cell Biology, Genetics, and Development Program, Yale University, New Haven, CT, USA
| | - Liqun Zhou
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
- Combined Program in the Biological and Biomedical Sciences, Yale University, New Haven, CT, USA
- Immunobiology Program, Yale University, New Haven, CT, USA
| | - Sidi Chen
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
- System Biology Institute, Yale University, West Haven, CT, USA.
- Combined Program in the Biological and Biomedical Sciences, Yale University, New Haven, CT, USA.
- Molecular Cell Biology, Genetics, and Development Program, Yale University, New Haven, CT, USA.
- Immunobiology Program, Yale University, New Haven, CT, USA.
- Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT, USA.
- Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
- Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, USA.
- Yale Liver Center, Yale University School of Medicine, New Haven, CT, USA.
- Yale Center for Biomedical Data Science, Yale University School of Medicine, New Haven, CT, USA.
- Yale Center for RNA Science and Medicine, Yale University School of Medicine, New Haven, CT, USA.
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Valerius AR, Webb LM, Thomsen A, Lehrer EJ, Breen WG, Campian JL, Riviere-Cazaux C, Burns TC, Sener U. Review of Novel Surgical, Radiation, and Systemic Therapies and Clinical Trials in Glioblastoma. Int J Mol Sci 2024; 25:10570. [PMID: 39408897 PMCID: PMC11477105 DOI: 10.3390/ijms251910570] [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: 08/23/2024] [Revised: 09/25/2024] [Accepted: 09/26/2024] [Indexed: 10/20/2024] Open
Abstract
Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Despite an established standard of care including surgical resection, radiation therapy, and chemotherapy, GBM unfortunately is associated with a dismal prognosis. Therefore, researchers are extensively evaluating avenues to expand GBM therapy and improve outcomes in patients with GBM. In this review, we provide a broad overview of novel GBM therapies that have recently completed or are actively undergoing study in clinical trials. These therapies expand across medical, surgical, and radiation clinical trials. We additionally review methods for improving clinical trial design in GBM.
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Affiliation(s)
| | - Lauren M. Webb
- Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA (U.S.)
| | - Anna Thomsen
- Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA (U.S.)
| | - Eric J. Lehrer
- Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - William G. Breen
- Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Jian L. Campian
- Department of Medical Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | | | - Terry C. Burns
- Department of Neurosurgery, Mayo Clinic, Rochester, MN 55905, USA
| | - Ugur Sener
- Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA (U.S.)
- Department of Medical Oncology, Mayo Clinic, Rochester, MN 55905, USA
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38
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Lu J, Huo W, Ma Y, Wang X, Yu J. Suppressive immune microenvironment and CART therapy for glioblastoma: Future prospects and challenges. Cancer Lett 2024; 600:217185. [PMID: 39142498 DOI: 10.1016/j.canlet.2024.217185] [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: 05/10/2024] [Revised: 08/08/2024] [Accepted: 08/09/2024] [Indexed: 08/16/2024]
Abstract
Glioblastoma, a highly malignant intracranial tumor, has acquired slow progress in treatment. Previous clinical trials involving targeted therapy and immune checkpoint inhibitors have shown no significant benefits in treating glioblastoma. This ineffectiveness is largely due to the complex immunosuppressive environment of glioblastoma. Glioblastoma cells exhibit low immunogenicity and strong heterogeneity and the immune microenvironment is replete with inhibitory cytokines, numerous immunosuppressive cells, and insufficient effective T cells. Fortunately, recent Phase I clinical trials of CART therapy for glioblastoma have confirmed its safety, with a small subset of patients achieving survival benefits. However, CART therapy continues to face challenges, including blood-brain barrier obstruction, antigen loss, and an immunosuppressive tumor microenvironment (TME). This article provides a detailed examination of glioblastoma's immune microenvironment, both from intrinsic and extrinsic tumor cell factors, reviews current clinical and basic research on multi-targets CART treatment, and concludes by outlining the key challenges in using CART cells for glioblastoma therapy.
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Affiliation(s)
- Jie Lu
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong Cancer Hospital and Institute, Jinan, Shandong, China
| | - Wen Huo
- Department of Radiation Oncology, Affiliated Tumor Hospital of Xinjiang Medical University, China
| | - Yingze Ma
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong Cancer Hospital and Institute, Jinan, Shandong, China; Department of Radiation Oncology, Shandong University Cancer Center, Jinan, Shandong, China
| | - Xin Wang
- Department of Radiation Oncology, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong Cancer Hospital and Institute, Jinan, Shandong, China.
| | - Jinming Yu
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong Cancer Hospital and Institute, Jinan, Shandong, China; Research Unit of Radiation Oncology, Chinese Academy of Medical Sciences, Jinan, Shandong, China.
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Ghemrawi R, Abuamer L, Kremesh S, Hussien G, Ahmed R, Mousa W, Khoder G, Khair M. Revolutionizing Cancer Treatment: Recent Advances in Immunotherapy. Biomedicines 2024; 12:2158. [PMID: 39335671 PMCID: PMC11429153 DOI: 10.3390/biomedicines12092158] [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: 06/19/2024] [Revised: 09/20/2024] [Accepted: 09/21/2024] [Indexed: 09/30/2024] Open
Abstract
Cancer immunotherapy has emerged as a transformative approach in oncology, utilizing the body's immune system to specifically target and destroy malignant cells. This review explores the scope and impact of various immunotherapeutic strategies, including monoclonal antibodies, chimeric antigen receptor (CAR)-T cell therapy, checkpoint inhibitors, cytokine therapy, and therapeutic vaccines. Monoclonal antibodies, such as Rituximab and Trastuzumab, have revolutionized treatment paradigms for lymphoma and breast cancer by offering targeted interventions that reduce off-target effects. CAR-T cell therapy presents a potentially curative option for refractory hematologic malignancies, although challenges remain in effectively treating solid tumors. Checkpoint inhibitors have redefined the management of cancers like melanoma and lung cancer; however, managing immune-related adverse events and ensuring durable responses are critical areas of focus. Cytokine therapy continues to play a vital role in modulating the immune response, with advancements in cytokine engineering improving specificity and reducing systemic toxicity. Therapeutic vaccines, particularly mRNA-based vaccines, represent a frontier in personalized cancer treatment, aiming to generate robust, long-lasting immune responses against tumor-specific antigens. Despite these advancements, the field faces significant challenges, including immune resistance, tumor heterogeneity, and the immunosuppressive tumor microenvironment. Future research should address these obstacles through emerging technologies, such as next-generation antibodies, Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-based gene editing, and AI-driven drug discovery. By integrating these novel approaches, cancer immunotherapy holds the promise of offering more durable, less toxic, and highly personalized treatment options, ultimately improving patient outcomes and survival rates.
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Affiliation(s)
- Rose Ghemrawi
- College of Pharmacy, Al Ain University, Abu Dhabi P.O. Box 112612, United Arab Emirates
- AAU Health and Biomedical Research Center, Al Ain University, Abu Dhabi P.O. Box 112612, United Arab Emirates
| | - Lama Abuamer
- College of Pharmacy, Al Ain University, Abu Dhabi P.O. Box 112612, United Arab Emirates
- AAU Health and Biomedical Research Center, Al Ain University, Abu Dhabi P.O. Box 112612, United Arab Emirates
| | - Sedra Kremesh
- College of Pharmacy, Al Ain University, Abu Dhabi P.O. Box 112612, United Arab Emirates
- AAU Health and Biomedical Research Center, Al Ain University, Abu Dhabi P.O. Box 112612, United Arab Emirates
| | - Ghadeer Hussien
- College of Pharmacy, Al Ain University, Abu Dhabi P.O. Box 112612, United Arab Emirates
- AAU Health and Biomedical Research Center, Al Ain University, Abu Dhabi P.O. Box 112612, United Arab Emirates
| | - Rahaf Ahmed
- College of Pharmacy, Al Ain University, Abu Dhabi P.O. Box 112612, United Arab Emirates
- AAU Health and Biomedical Research Center, Al Ain University, Abu Dhabi P.O. Box 112612, United Arab Emirates
| | - Walaa Mousa
- College of Pharmacy, Al Ain University, Abu Dhabi P.O. Box 112612, United Arab Emirates
- AAU Health and Biomedical Research Center, Al Ain University, Abu Dhabi P.O. Box 112612, United Arab Emirates
| | - Ghalia Khoder
- Department of Pharmaceutics and Pharmaceuticals Technology, College of Pharmacy, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates
| | - Mostafa Khair
- Core Technology Platforms, New York University Abu Dhabi, Abu Dhabi P.O. Box 129188, United Arab Emirates
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40
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Holtermann A, Gislon M, Angele M, Subklewe M, von Bergwelt-Baildon M, Lauber K, Kobold S. Prospects of Synergy: Local Interventions and CAR T Cell Therapy in Solid Tumors. BioDrugs 2024; 38:611-637. [PMID: 39080180 PMCID: PMC11358237 DOI: 10.1007/s40259-024-00669-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/17/2024] [Indexed: 08/30/2024]
Abstract
Chimeric antigen receptor T cell therapy has been established in the treatment of various B cell malignancies. However, translating this therapeutic effect to treat solid tumors has been challenging because of their inter-tumoral as well as intratumoral heterogeneity and immunosuppressive microenvironment. Local interventions, such as surgery, radiotherapy, local ablation, and locoregional drug delivery, can enhance chimeric antigen receptor T cell therapy in solid tumors by improving tumor infiltration and reducing systemic toxicities. Additionally, ablation and radiotherapy have proven to (re-)activate systemic immune responses via abscopal effects and reprogram the tumor microenvironment on a physical, cellular, and chemical level. This review highlights the potential synergy of the combined approaches to overcome barriers of chimeric antigen receptor T cell therapy and summarizes recent studies that may pave the way for new treatment regimens.
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Affiliation(s)
- Anne Holtermann
- Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig Maximilian University (LMU) of Munich, Lindwurmstrasse 2a, 80336, Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, a partnership between the DKFZ Heidelberg and the University Hospital of the LMU, Munich, Germany
| | - Mila Gislon
- Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig Maximilian University (LMU) of Munich, Lindwurmstrasse 2a, 80336, Munich, Germany
| | - Martin Angele
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Marion Subklewe
- Department of Medicine III, 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, Munich, Germany
| | - Michael von Bergwelt-Baildon
- Department of Medicine III, 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, Munich, Germany
| | - Kirsten Lauber
- Department of Radiation Oncology, LMU University Hospital, LMU Munich, Munich, Germany
| | - Sebastian Kobold
- Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig Maximilian University (LMU) of Munich, Lindwurmstrasse 2a, 80336, Munich, Germany.
- German Cancer Consortium (DKTK), Partner Site Munich, a partnership between the DKFZ Heidelberg and the University Hospital of the LMU, Munich, Germany.
- Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München-German Research Center for Environmental Health Neuherberg, Munich, Germany.
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41
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Chang PS, Chen YC, Hua WK, Hsu JC, Tsai JC, Huang YW, Kao YH, Wu PH, Wang PN, Chang YF, Chang MC, Chang YC, Jian SL, Lai JS, Lai MT, Yang WC, Shen CN, Wen KLK, Wu SCY. Manufacturing CD20/CD19-targeted iCasp9 regulatable CAR-TSCM cells using a Quantum pBac-based CAR-T engineering system. PLoS One 2024; 19:e0309245. [PMID: 39190688 DOI: 10.1371/journal.pone.0309245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Accepted: 08/07/2024] [Indexed: 08/29/2024] Open
Abstract
CD19-targeted chimeric antigen receptor (CAR) T cell therapies have driven a paradigm shift in the treatment of relapsed/refractory B-cell malignancies. However, >50% of CD19-CAR-T-treated patients experience progressive disease mainly due to antigen escape and low persistence. Clinical prognosis is heavily influenced by CAR-T cell function and systemic cytokine toxicities. Furthermore, it remains a challenge to efficiently, cost-effectively, and consistently manufacture clinically relevant numbers of virally engineered CAR-T cells. Using a highly efficient piggyBac transposon-based vector, Quantum pBac™ (qPB), we developed a virus-free cell-engineering system for development and production of multiplex CAR-T therapies. Here, we demonstrate in vitro and in vivo that consistent, robust and functional CD20/CD19 dual-targeted CAR-T stem cell memory (CAR-TSCM) cells can be efficiently produced for clinical application using qPB™. In particular, we showed that qPB™-manufactured CAR-T cells from cancer patients expanded efficiently, rapidly eradicated tumors, and can be safely controlled via an iCasp9 suicide gene-inducing drug. Therefore, the simplicity of manufacturing multiplex CAR-T cells using the qPB™ system has the potential to improve efficacy and broaden the accessibility of CAR-T therapies.
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Affiliation(s)
- Peter S Chang
- GenomeFrontier Therapeutics TW Co., Ltd., Taipei City, Taiwan (R.O.C.)
| | - Yi-Chun Chen
- GenomeFrontier Therapeutics TW Co., Ltd., Taipei City, Taiwan (R.O.C.)
| | - Wei-Kai Hua
- GenomeFrontier Therapeutics TW Co., Ltd., Taipei City, Taiwan (R.O.C.)
| | - Jeff C Hsu
- GenomeFrontier Therapeutics TW Co., Ltd., Taipei City, Taiwan (R.O.C.)
| | - Jui-Cheng Tsai
- GenomeFrontier Therapeutics TW Co., Ltd., Taipei City, Taiwan (R.O.C.)
| | - Yi-Wun Huang
- GenomeFrontier Therapeutics TW Co., Ltd., Taipei City, Taiwan (R.O.C.)
| | - Yi-Hsin Kao
- GenomeFrontier Therapeutics TW Co., Ltd., Taipei City, Taiwan (R.O.C.)
| | - Pei-Hua Wu
- GenomeFrontier Therapeutics TW Co., Ltd., Taipei City, Taiwan (R.O.C.)
| | - Po-Nan Wang
- Division of Hematology, Chang Gung Medical Foundation, Linkou Branch, Taipei City, Taiwan (R.O.C.)
| | - Yi-Fang Chang
- Division of Hematology and Oncology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan (R.O.C.)
- Department of Medical Research, Laboratory of Good Clinical Research Center, Mackay Memorial Hospital, Tamsui District, New Taipei City, Taiwan (R.O.C.)
- Department of Medicine, Mackay Medical College, New Taipei City, Taiwan (R.O.C.)
| | - Ming-Chih Chang
- Division of Hematology and Oncology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan (R.O.C.)
| | - Yu-Cheng Chang
- Division of Hematology and Oncology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan (R.O.C.)
- Department of Medical Research, Laboratory of Good Clinical Research Center, Mackay Memorial Hospital, Tamsui District, New Taipei City, Taiwan (R.O.C.)
| | | | | | | | | | - Chia-Ning Shen
- Biomedical Translation Research Center, Academia Sinica, Taipei, Taiwan (R.O.C.)
- Genomics Research Center, Academia Sinica, Taipei, Taiwan (R.O.C.)
| | - Kuo-Lan Karen Wen
- GenomeFrontier Therapeutics TW Co., Ltd., Taipei City, Taiwan (R.O.C.)
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42
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Testa U, Castelli G, Pelosi E. CAR-T Cells in the Treatment of Nervous System Tumors. Cancers (Basel) 2024; 16:2913. [PMID: 39199683 PMCID: PMC11352247 DOI: 10.3390/cancers16162913] [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: 07/18/2024] [Revised: 08/18/2024] [Accepted: 08/20/2024] [Indexed: 09/01/2024] Open
Abstract
Chimeric antigen receptor T cells (CAR-Ts) have shown a remarkable efficacy in hematological malignancies but limited responses in solid tumors. Among solid tumors, CAR-T cell therapy has been particularly explored in brain tumors. CAR-T cells have shown a limited clinical efficacy in various types of brain tumors due to several factors that have hampered their activity, including tumor antigen heterogeneity, the limited access of CAR-T cells to brain tumor cells, limited CAR-T cell trafficking and in vivo persistence and the presence of a highly immunosuppressive tumor microenvironment. Despite these considerations, some recent studies have shown promising antitumor activity of GD2-CAR-T cells on diffuse midline gliomas and neuroblastomas and of CARv3-TEAM-E cells in glioblastomas. However, strategies are required to improve the effect of CAR-T cells in brain tumors, including advanced CAR-T cell design with multiple antigenic targeting and incorporation of combination therapies.
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Affiliation(s)
- Ugo Testa
- Department of Oncology, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy; (G.C.); (E.P.)
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43
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Mongeon B, Hébert-Doutreloux J, Surendran A, Karimi E, Fiset B, Quail DF, Walsh LA, Jenner AL, Craig M. Spatial computational modelling illuminates the role of the tumour microenvironment for treating glioblastoma with immunotherapies. NPJ Syst Biol Appl 2024; 10:91. [PMID: 39155294 PMCID: PMC11330976 DOI: 10.1038/s41540-024-00419-4] [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: 11/23/2023] [Accepted: 08/07/2024] [Indexed: 08/20/2024] Open
Abstract
Glioblastoma is the most common and deadliest brain tumour in adults, with a median survival of 15 months under the current standard of care. Immunotherapies like immune checkpoint inhibitors and oncolytic viruses have been extensively studied to improve this endpoint. However, most thus far have failed. To improve the efficacy of immunotherapies to treat glioblastoma, new single-cell imaging modalities like imaging mass cytometry can be leveraged and integrated with computational models. This enables a better understanding of the tumour microenvironment and its role in treatment success or failure in this hard-to-treat tumour. Here, we implemented an agent-based model that allows for spatial predictions of combination chemotherapy, oncolytic virus, and immune checkpoint inhibitors against glioblastoma. We initialised our model with patient imaging mass cytometry data to predict patient-specific responses and found that oncolytic viruses drive combination treatment responses determined by intratumoral cell density. We found that tumours with higher tumour cell density responded better to treatment. When fixing the number of cancer cells, treatment efficacy was shown to be a function of CD4 + T cell and, to a lesser extent, of macrophage counts. Critically, our simulations show that care must be put into the integration of spatial data and agent-based models to effectively capture intratumoral dynamics. Together, this study emphasizes the use of predictive spatial modelling to better understand cancer immunotherapy treatment dynamics, while highlighting key factors to consider during model design and implementation.
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Affiliation(s)
- Blanche Mongeon
- Sainte-Justine University Hospital Azrieli Research Centre, Montréal, QC, Canada
- Department of Mathematics and Statistics, Université de Montréal, Montréal, QC, Canada
| | | | - Anudeep Surendran
- Center for Advanced Systems Understanding, Görlitz, Germany
- Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany
| | - Elham Karimi
- Rosalind and Morris Goodman Cancer Institute, McGill University, Montréal, QC, Canada
| | - Benoit Fiset
- Rosalind and Morris Goodman Cancer Institute, McGill University, Montréal, QC, Canada
| | - Daniela F Quail
- Rosalind and Morris Goodman Cancer Institute, McGill University, Montréal, QC, Canada
- Department of Physiology, Faculty of Medicine, McGill University, Montréal, QC, Canada
- Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, QC, Canada
| | - Logan A Walsh
- Rosalind and Morris Goodman Cancer Institute, McGill University, Montréal, QC, Canada
- Department of Human Genetics, McGill University, Montréal, QC, Canada
| | - Adrianne L Jenner
- School of Mathematical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
| | - Morgan Craig
- Sainte-Justine University Hospital Azrieli Research Centre, Montréal, QC, Canada.
- Department of Mathematics and Statistics, Université de Montréal, Montréal, QC, Canada.
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44
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Shanley M, Daher M, Dou J, Li S, Basar R, Rafei H, Dede M, Gumin J, Pantaleόn Garcίa J, Nunez Cortes AK, He S, Jones CM, Acharya S, Fowlkes NW, Xiong D, Singh S, Shaim H, Hicks SC, Liu B, Jain A, Zaman MF, Miao Q, Li Y, Uprety N, Liu E, Muniz-Feliciano L, Deyter GM, Mohanty V, Zhang P, Evans SE, Shpall EJ, Lang FF, Chen K, Rezvani K. Interleukin-21 engineering enhances NK cell activity against glioblastoma via CEBPD. Cancer Cell 2024; 42:1450-1466.e11. [PMID: 39137729 PMCID: PMC11370652 DOI: 10.1016/j.ccell.2024.07.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 05/31/2024] [Accepted: 07/17/2024] [Indexed: 08/15/2024]
Abstract
Glioblastoma (GBM) is an aggressive brain cancer with limited therapeutic options. Natural killer (NK) cells are innate immune cells with strong anti-tumor activity and may offer a promising treatment strategy for GBM. We compared the anti-GBM activity of NK cells engineered to express interleukin (IL)-15 or IL-21. Using multiple in vivo models, IL-21 NK cells were superior to IL-15 NK cells both in terms of safety and long-term anti-tumor activity, with locoregionally administered IL-15 NK cells proving toxic and ineffective at tumor control. IL-21 NK cells displayed a unique chromatin accessibility signature, with CCAAT/enhancer-binding proteins (C/EBP), especially CEBPD, serving as key transcription factors regulating their enhanced function. Deletion of CEBPD resulted in loss of IL-21 NK cell potency while its overexpression increased NK cell long-term cytotoxicity and metabolic fitness. These results suggest that IL-21, through C/EBP transcription factors, drives epigenetic reprogramming of NK cells, enhancing their anti-tumor efficacy against GBM.
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Affiliation(s)
- Mayra Shanley
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - May Daher
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Jinzhuang Dou
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Sufang Li
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Rafet Basar
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Hind Rafei
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Merve Dede
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Joy Gumin
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Jezreel Pantaleόn Garcίa
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Ana Karen Nunez Cortes
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Shan He
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Corry M Jones
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Sunil Acharya
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Natalie W Fowlkes
- Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Donghai Xiong
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Sanjay Singh
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Hila Shaim
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Samantha Claire Hicks
- Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Bin Liu
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Abhinav Jain
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Mohammad Fayyad Zaman
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Qi Miao
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Ye Li
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Nadima Uprety
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Enli Liu
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Luis Muniz-Feliciano
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Gary M Deyter
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Vakul Mohanty
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Patrick Zhang
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Scott E Evans
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Elizabeth J Shpall
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Frederick F Lang
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Ken Chen
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
| | - Katayoun Rezvani
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA.
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45
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Lin FY, Stuckert A, Tat C, White M, Ruggieri L, Zhang H, Mehta B, Lapteva N, Mei Z, Major A, Thakkar S, Shum T, Parikh K, Wu MF, Lindsay HB, Scherer L, Shekar M, Baxter P, Wang T, Grilley B, Moeller K, Hicks J, Roy A, Anastas J, Malbari F, Aldave G, Chintagumpala M, Blaney S, Parsons DW, Brenner MK, Heslop HE, Rooney CM, Omer B. Phase I Trial of GD2.CART Cells Augmented With Constitutive Interleukin-7 Receptor for Treatment of High-Grade Pediatric CNS Tumors. J Clin Oncol 2024; 42:2769-2779. [PMID: 38771986 PMCID: PMC11305939 DOI: 10.1200/jco.23.02019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 12/26/2023] [Accepted: 02/12/2024] [Indexed: 05/23/2024] Open
Abstract
PURPOSE T cells modified with chimeric antigen receptors (CARTs) have demonstrated efficacy for hematologic malignancies; however, benefit for patients with CNS tumors has been limited. To enhance T cell activity against GD2+ CNS malignancies, we modified GD2-directed CART cells (GD2.CARTs) with a constitutively active interleukin (IL)-7 receptor (C7R-GD2.CARTs). METHODS Patients age 1-21 years with H3K27-altered diffuse midline glioma (DMG) or other recurrent GD2-expressing CNS tumors were eligible for this phase I trial (ClinicalTrials.gov identifier: NCT04099797). All subjects received standard-of-care adjuvant radiation therapy or chemotherapy before study enrollment. The first treatment cohort received GD2.CARTs alone (1 × 107 cells/m2), and subsequent cohorts received C7R-GD2.CARTs at two dose levels (1 × 107 cells/m2; 3 × 107 cells/m2). Standard lymphodepletion with cyclophosphamide and fludarabine was included at all dose levels. RESULTS Eleven patients (age 4-18 years) received therapy without dose-limiting toxicity. The GD2.CART cohort did not experience toxicity, but had disease progression after brief improvement of residual neurologic deficits (≤3 weeks). The C7R-GD2.CART cohort developed grade 1 tumor inflammation-associated neurotoxicity in seven of eight (88%) cases, controllable with anakinra. Cytokine release syndrome was observed in six of eight (75%, grade 1 in all but one patient) and associated with increased circulating IL-6 and IP-10 (P < .05). Patients receiving C7R-GD2.CARTs experienced temporary improvement from baseline neurologic deficits (range, 2 to >12 months), and seven of eight (88%) remained eligible for additional treatment cycles (range 2-4 cycles). Partial responses by iRANO criteria were observed in two of seven (29%) patients with DMG treated by C7R-GD2.CARTs. CONCLUSION Intravenous GD2.CARTs with and without C7R were well tolerated. Patients treated with C7R-GD2.CARTs exhibited transient improvement of neurologic deficits and increased circulating cytokines/chemokines. Treatment with C7R-GD2.CARTs represents a novel approach warranting further investigation for children with these incurable CNS cancers.
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Affiliation(s)
- Frank Y. Lin
- Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX
- Dan L Duncan Comprehensive Cancer Center, Houston, TX
| | - Austin Stuckert
- Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX
| | - Candise Tat
- Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX
| | - Mark White
- Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX
| | - Lucia Ruggieri
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX
| | - Huimin Zhang
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX
| | - Birju Mehta
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX
| | - Natalia Lapteva
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX
| | - Zhuyong Mei
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX
| | - Angela Major
- Department of Pathology, Baylor College of Medicine, Houston, TX
| | - Sachin Thakkar
- Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX
| | - Thomas Shum
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX
- Department of Radiology, Brigham and Women's Hospital, Boston, MA
| | - Kathan Parikh
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX
| | - Meng-Fen Wu
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX
- Department of Medicine, Baylor College of Medicine, Houston, TX
| | - Holly B. Lindsay
- Department of Pediatrics Heme-Onc and Bone Marrow Transplantation, Children's Hospital Colorado Center for Cancer and Blood Disorders, University of Colorado Anschutz Medical Campus, Denver, CO
| | - Lauren Scherer
- Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX
| | - Meghan Shekar
- Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX
| | - Patricia Baxter
- Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX
- Dan L Duncan Comprehensive Cancer Center, Houston, TX
| | - Tao Wang
- Dan L Duncan Comprehensive Cancer Center, Houston, TX
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX
- Department of Medicine, Baylor College of Medicine, Houston, TX
| | - Bambi Grilley
- Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX
| | - Karen Moeller
- Department of Radiology, Baylor College of Medicine, Houston, TX
| | - John Hicks
- Department of Pathology, Baylor College of Medicine, Houston, TX
| | - Angshumoy Roy
- Dan L Duncan Comprehensive Cancer Center, Houston, TX
- Department of Pathology, Baylor College of Medicine, Houston, TX
| | - Jamie Anastas
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX
| | - Fatema Malbari
- Department of Neurology, Baylor College of Medicine, Houston, TX
| | - Guillermo Aldave
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX
| | - Murali Chintagumpala
- Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX
- Dan L Duncan Comprehensive Cancer Center, Houston, TX
| | - Susan Blaney
- Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX
- Dan L Duncan Comprehensive Cancer Center, Houston, TX
| | - D. Williams Parsons
- Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX
- Dan L Duncan Comprehensive Cancer Center, Houston, TX
| | - Malcolm K. Brenner
- Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX
- Dan L Duncan Comprehensive Cancer Center, Houston, TX
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX
- Department of Medicine, Baylor College of Medicine, Houston, TX
| | - Helen E. Heslop
- Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX
- Dan L Duncan Comprehensive Cancer Center, Houston, TX
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX
- Department of Medicine, Baylor College of Medicine, Houston, TX
| | - Cliona M. Rooney
- Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX
- Dan L Duncan Comprehensive Cancer Center, Houston, TX
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX
| | - Bilal Omer
- Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX
- Dan L Duncan Comprehensive Cancer Center, Houston, TX
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX
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46
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Martins P, D’Souza RCJ, Skarne N, Lekieffre L, Horsefield S, Ranjankumar M, Li X, Le TT, Smith F, Smith C, Burrows J, Day BW, Khanna R. EphA3 CAR T cells are effective against glioblastoma in preclinical models. J Immunother Cancer 2024; 12:e009403. [PMID: 39111832 PMCID: PMC11308892 DOI: 10.1136/jitc-2024-009403] [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] [Accepted: 07/18/2024] [Indexed: 08/10/2024] Open
Abstract
BACKGROUND Adoptive T-cell therapy targeting antigens expressed in glioblastoma has emerged as a potential therapeutic strategy to prevent or delay recurrence and prolong overall survival in this aggressive disease setting. Ephrin receptor A3 (EphA3), which is highly expressed in glioblastoma; in particular, on the tumor vasculature and brain cancer stem cells, is an ideal target for immune-based therapies. METHODS We have designed an EphA3-targeted chimeric antigen receptor (CAR) using the single chain variable fragment of a novel monoclonal antibody, and assessed its therapeutic potential against EphA3-expressing patient-derived glioblastoma neurospheres, organoids and xenografted glioblastoma tumors in immunodeficient mice. RESULTS In vitro expanded EphA3 CAR T cells from healthy individuals efficiently recognize and kill EphA3-positive glioblastoma cells in vitro. Furthermore, these effector cells demonstrated curative efficacy in an orthotopic xenograft model of glioblastoma. EphA3 CAR T cells were equally effective in targeting patient-derived neurospheres and infiltrate, disaggregate, and induce apoptosis in glioblastoma-derived organoids. CONCLUSIONS This study provides compelling evidence supporting the therapeutic potential of EphA3 CAR T-cell therapy against glioblastoma by targeting EphA3 associated with brain cancer stem cells and the tumor vasculature. The ability to target patient-derived glioblastoma underscores the translational significance of this EphA3 CAR T-cell therapy in the pursuit of effective and targeted glioblastoma treatment strategies.
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Affiliation(s)
- Paulo Martins
- QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
- The University of Queensland, Brisbane, Queensland, Australia
| | | | - Niclas Skarne
- QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Lea Lekieffre
- QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Shane Horsefield
- QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
- The University of Queensland, Brisbane, Queensland, Australia
| | | | - Xiang Li
- QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Thuy T Le
- QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Fiona Smith
- QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Corey Smith
- QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Jacqueline Burrows
- QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Bryan W Day
- QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
- Sid Faithfull Brain Cancer Laboratory, Brisbane, Queensland, Australia
| | - Rajiv Khanna
- QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
- The University of Queensland, Brisbane, Queensland, Australia
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Xiong Y, Libby KA, Su X. The physical landscape of CAR-T synapse. Biophys J 2024; 123:2199-2210. [PMID: 37715447 PMCID: PMC11331049 DOI: 10.1016/j.bpj.2023.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/30/2023] [Accepted: 09/12/2023] [Indexed: 09/17/2023] Open
Abstract
Chimeric antigen receptor (CAR)-T cells form dynamic immunological synapses with their cancer cell targets. After a CAR-antigen engagement, the CAR-T synapse forms, matures, and finally disassembles, accompanied by substantial remodeling of cell surface proteins, lipids, and glycans. In this review, we provide perspectives for understanding protein distribution, membrane topology, and force transmission across the CAR-T synapse. We highlight the features of CAR-T synapses that differ from T cell receptor synapses, including the disorganized protein pattern, adjustable synapse width, diverse mechano-responding properties, and resulting signaling consequences. Through a range of examples, we illustrate how revealing the biophysical nature of the CAR-T synapse could guide the design of CAR-Ts with improved anti-tumor function.
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Affiliation(s)
- Yiwei Xiong
- Department of Cell Biology, Yale School of Medicine, New Haven, Connecticut
| | - Kendra A Libby
- Department of Cell Biology, Yale School of Medicine, New Haven, Connecticut; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts; Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts
| | - Xiaolei Su
- Department of Cell Biology, Yale School of Medicine, New Haven, Connecticut; Yale Cancer Center, Yale University, New Haven, Connecticut; Yale Stem Cell Center, Yale University, New Haven, Connecticut.
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Mehrab R, Sedighian H, Sotoodehnejadnematalahi F, Halabian R, Imanifooladi AA. Anticancer and bioactivity effect of the AraA-IL13 fusion protein on the glioblastoma cell line. Res Pharm Sci 2024; 19:387-396. [PMID: 39399731 PMCID: PMC11468163 DOI: 10.4103/rps.rps_92_23] [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: 05/25/2023] [Revised: 12/08/2023] [Accepted: 07/21/2024] [Indexed: 10/15/2024] Open
Abstract
Background and purpose Glioblastoma (GBM) is an aggressive and malignant brain cancer with the highest mortality and low survival rates. To discover a more specific and efficient treatment for GBM, we synthesized and examined the cytotoxic effect of arazyme-interleukin-13 (Ara-IL13) fusion protein on GBM cells. Experimental approach At first, the araA-IL13 chimeric gene in the pET28a (+) vector was designed and synthesized. After transformation into Escherichia coli BL21 (DE3), the chimeric gene was verified by colony polymerase chain reaction. Expression optimization and purification of the AraA-IL13 fusion protein was performed and subsequently evaluated by 10% SDS-PAGE. The protein was purified and concentrated using the Amicon® Ultra- 15 centrifugal filter unit. The presence of AraA-IL13 was investigated by the western blotting technique. The enzyme was evaluated for proteolytic activity after purification on skim milk agar. The cytotoxic effect of the AraA-IL13 fusion protein was evaluated by MTT assay on U251 and T98G cell lines in vitro. Findings/Results The chimeric protein had no proteolytic activity on skim milk agar despite high expression. Furthermore, no cytotoxic effect of this fusion protein (up to 400 μg/mL) was observed on the U251 and T98G cell lines. Conclusion and implications The lack of proteolytic activity and cytotoxic effect of AraA-IL13 may be due to the disruption of the three-dimensional structure of the protein or the large structure of the arazyme coupled with the ligand and the lack of proper folding of the arazyme to make the active site of the enzyme inaccessible.
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Affiliation(s)
- Rezvan Mehrab
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Hamid Sedighian
- Applied Microbiology Research Center, Biomedicine Technologies Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | | | - Raheleh Halabian
- Applied Microbiology Research Center, Biomedicine Technologies Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Abbas Ali Imanifooladi
- Applied Microbiology Research Center, Biomedicine Technologies Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
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Vitanza NA, Choe M, Brown C, Beebe A, Kong A, Rogers L, Jacob S, Mano E, Abuan K, Mgebroff S, Lindgren C, Gustafson JA, Wilson AL, Noll A, Ronsley R, Crotty EE, Leary SES, Foster JB, Pinto N, Gust J, Gardner RA, Park JR, Jensen MC. Locoregional CAR T Cells for the Treatment of CNS Tumors in Children: Investigational Drug Service Pharmacy Activities. JOURNAL OF HEMATOLOGY ONCOLOGY PHARMACY 2024; 14:148-154. [PMID: 39238483 PMCID: PMC11375759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 09/07/2024]
Abstract
BACKGROUND A major obstacle in translating the therapeutic potential of chimeric antigen receptor (CAR) T cells to children with central nervous system (CNS) tumors is the blood-brain barrier. To overcome this limitation, preclinical and clinical studies have supported the use of repeated, locoregional intracranial CAR T-cell delivery. However, there is limited literature available describing the process for the involvement of an investigational drug service (IDS) pharmacy, particularly in the setting of a children's hospital with outpatient dosing for CNS tumors. OBJECTIVES To describe Seattle Children's Hospital's experience in clinically producing CAR T cells and the implementation of IDS pharmacy practices used to deliver more than 300 intracranial CAR T-cell doses to children, as well as to share how we refined the processing techniques from CAR T-cell generation to the thawing of fractionated doses for intracranial delivery. METHODS Autologous CD4+ and CD8+ T cells were collected and transduced to express HER2, EGFR, or B7-H3-specific CAR T cells. Cryopreserved CAR T cells were thawed by the IDS pharmacy before intracranial delivery to patients with recurrent/refractory CNS tumors or with diffuse intrinsic pontine glioma/diffuse midline glioma. RESULTS The use of a thaw-and-dilute procedure for cryopreserved individual CAR T-cell doses provides reliable viability and is more efficient than typical thaw-and-wash protocols. Cell viability with the thaw-and-dilute protocol was approximately 75% and was always within 10% of the viability assessed at cryopreservation. Cell viability was preserved through 6 hours after thawing, which exceeded the 1-hour time frame from thawing to infusion. CONCLUSION As the field of adoptive immunotherapy grows and continues to bring hope to patients with fatal CNS malignancies, it is critical to focus on improving the preparatory steps for CAR T-cell delivery.
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Affiliation(s)
- Nicholas A Vitanza
- University of Washington (UW), a Laboratory Principal Investigator (PI) at the Ben Towne Center for Childhood Cancer Research at Seattle Children's Research Institute (SCRI), and a Neuro-Oncologist at Seattle Children's Hospital (SCH)
| | - Michelle Choe
- Fred Hutch Cancer Center and an Assistant Professor of Pediatrics at UW
| | | | | | - Ada Kong
- Clinical Research Support Cores, SCH
| | | | | | | | | | | | | | | | | | | | | | | | | | - Jessica B Foster
- Children's Hospital of Philadelphia and Pediatric Neuro-Oncologist at the University of Pennsylvania
| | | | - Juliane Gust
- Pediatrics at UW, a Laboratory PI at the Center for Integrated Brain Health at SCRI, and a Neurologist at SCH
| | - Rebecca A Gardner
- Pediatrics at UW, an Oncologist at SCH, and the Associate Medical Director of SCTx
| | - Julie R Park
- Pediatrics at UW, an Oncologist at SCH, and the Medical Director of SCTx
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Gu X, Zhang Y, Zhou W, Wang F, Yan F, Gao H, Wang W. Infusion and delivery strategies to maximize the efficacy of CAR-T cell immunotherapy for cancers. Exp Hematol Oncol 2024; 13:70. [PMID: 39061100 PMCID: PMC11282638 DOI: 10.1186/s40164-024-00542-2] [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: 05/22/2024] [Accepted: 07/19/2024] [Indexed: 07/28/2024] Open
Abstract
Chimeric antigen receptor (CAR) T-cell therapy has achieved substantial clinical outcomes for tumors, especially for hematological malignancies. However, extending the duration of remission, reduction of relapse for hematological malignancies and improvement of the anti-tumor efficacy for solid tumors are challenges for CAR-T cells immunotherapy. Besides the endeavors to enhance the functionality of CAR-T cell per se, optimization of the infusion and delivery strategies facilitates the breakthrough of the hurdles that limited the efficacy of this cancer immunotherapy. Here, we summarized the infusion and delivery strategies of CAR-T cell therapies under pre-clinical study, clinical trials and on-market status, through which the improvements of safety and efficacy for hematological and solid tumors were analyzed. Of note, novel infusion and delivery strategies, including local-regional infusion, biomaterials bearing the CAR-T cells and multiple infusion technique, overcome many limitations of CAR-T cell therapy. This review provides hints to determine infusion and delivery strategies of CAR-T cell cancer immunotherapy to maximize clinical benefits.
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Affiliation(s)
- Xinyu Gu
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, People's Republic of China
| | - Yalan Zhang
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, People's Republic of China
| | - Weilin Zhou
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, People's Republic of China
| | - Fengling Wang
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, People's Republic of China
| | - Feiyang Yan
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, People's Republic of China
| | - Haozhan Gao
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, People's Republic of China
| | - Wei Wang
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, People's Republic of China.
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