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Qin H, Luo S, Zuo W, Cao Z, Assaraf YG, Kwok HF. Targeted eradication of glioblastoma via venom decapeptide-conjugated dendrimers: Inducing nuclear translocation and autophagic cell death. J Control Release 2025; 383:113780. [PMID: 40315960 DOI: 10.1016/j.jconrel.2025.113780] [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: 03/10/2025] [Revised: 04/11/2025] [Accepted: 04/24/2025] [Indexed: 05/04/2025]
Abstract
Glioblastoma (GBM) is the most prevalent and aggressive primary central nervous system (CNS) neoplasm. Herein, we developed a nanoparticle (NP) drug delivery system by conjugating a scorpion venom-derived decapeptide Ctir9495 (C9) to a polyamidoamine (PAMAM) dendrimer, where 4-(bromomethyl) phenylboronic acid (PBA) modified PAMAM is used as a drug carrier due to its small size and favorable tumor penetration. This decapeptide-conjugated dendrimer, G5C9, targeted human GBM cells and displayed enhanced cell internalization. The G5C9 complex targeted GBM cells presumably by binding to the overexpressed surface sialic acid, resulting in rapid endocytosis and endolysosome formation. This induced cell cycle arrest, blocked tumor cell proliferation, colony formation and migration, resulting in autophagosome lysosome-based apoptotic GBM cell death. G5C9 suppressed GBM cell proliferation via enhanced nuclear translocation of the transcription factor EB (TFEB), a master regulator of the autophagosome lysosome pathway, by disrupting mTORC1 activity and downregulating the PI3K/AKT/mTOR signaling axis. This G5C9 complex exhibited potent activity against GBM xenografts in vivo. Hence, our delivery strategy not only enhances the uptake of this venom decapeptide-conjugated dendrimers into GBM, but also offers a novel modality to target and eradicate GBM.
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Affiliation(s)
- Haixin Qin
- Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau; Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau; MoE Frontiers Science Centre for Precision Oncology, University of Macau, Avenida da Universidade, Taipa, Macau; Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau
| | - Siyuan Luo
- Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau; Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau
| | - Weimin Zuo
- Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau; Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau
| | - Zhijian Cao
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan 430068, Hubei Province, China
| | - Yehuda G Assaraf
- The Fred Wyszkowski Cancer Research Laboratory, Faculty of Biology, Technion-Israel Institute of Technology, Haifa 3200003, Israel
| | - Hang Fai Kwok
- Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau; Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau; MoE Frontiers Science Centre for Precision Oncology, University of Macau, Avenida da Universidade, Taipa, Macau; Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau.
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2
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Gordon KS, Perez CR, Garmilla A, Lam MSY, Aw JJY, Datta A, Lauffenburger DA, Pavesi A, Birnbaum ME. Pooled screening for CAR function identifies novel IL-13Rα2-targeted CARs for treatment of glioblastoma. J Immunother Cancer 2025; 13:e009574. [PMID: 39933837 PMCID: PMC11815465 DOI: 10.1136/jitc-2024-009574] [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: 05/08/2024] [Accepted: 01/20/2025] [Indexed: 02/13/2025] Open
Abstract
BACKGROUND Chimeric antigen receptor (CAR) therapies have demonstrated potent efficacy in treating B-cell malignancies, but have yet to meaningfully translate to solid tumors. Nonetheless, they are of particular interest for the treatment of glioblastoma, which is an aggressive form of brain cancer with few effective therapeutic options, due to their ability to cross the highly selective blood-brain barrier. METHODS Here, we use our pooled screening platform, CARPOOL, to expedite the discovery of CARs with antitumor functions necessary for solid tumor efficacy. We performed selections in primary human T cells expressing a library of 1.3×106 third generation CARs targeting IL-13Rα2, a cancer testis antigen commonly expressed in glioblastoma. Selections were performed for cytotoxicity, proliferation, memory formation, and persistence on repeated antigen challenge. RESULTS Each enriched CAR robustly produced the phenotype for which it was selected, and one enriched CAR triggered potent cytotoxicity and long-term proliferation on in vitro tumor rechallenge. It also showed significantly improved persistence and comparable tumor control in a microphysiological human in vitro model and a xenograft model of human glioblastoma, but also demonstrated increased off-target recognition of IL-13Rα1. CONCLUSION Taken together, this work demonstrates the utility of extending CARPOOL to diseases beyond hematological malignancies and represents the largest exploration of signaling combinations in human primary cells to date.
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Affiliation(s)
- Khloe S Gordon
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Singapore-MIT Alliance for Research and Technology Centre, Singapore
| | - Caleb R Perez
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Singapore-MIT Alliance for Research and Technology Centre, Singapore
| | - Andrea Garmilla
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Program in Immunology, Harvard Medical School, Boston, Massachusetts, USA
| | - Maxine S Y Lam
- Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Singapore
| | - Joey J Y Aw
- Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Singapore
| | - Anisha Datta
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Douglas A Lauffenburger
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Andrea Pavesi
- Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Singapore
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | - Michael E Birnbaum
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Singapore-MIT Alliance for Research and Technology Centre, Singapore
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3
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Cardle II, Scherer DR, Jensen MC, Pun SH, Sellers DL. In Situ Bioconjugation of Synthetic Peptides onto Universal Chimeric Antigen Receptor T Cells for Targeted Cancer Immunotherapies. ACS NANO 2025; 19:5750-5768. [PMID: 39869930 DOI: 10.1021/acsnano.4c16824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/29/2025]
Abstract
The recent development of modular universal chimeric antigen receptor (CAR) T-cell platforms that use bifunctional adaptor intermediates to redirect engineered T-cell effector function has greatly expanded the capabilities of adoptive T-cell therapy, enabling safer and more comprehensive cancer treatment. However, universal CAR receptor systems rely on unstable transient recognition of tag-coupled intermediates for T-cell activation, and the array of targeting intermediates has been limited to antibodies and small molecules. Addressing these shortcomings, we engineered universal CAR T-cell receptors that can be covalently modified with synthetic biomaterials in vivo by accelerated SpyCatcher003-SpyTag003 chemistry for cancer-cell targeting. SpyCatcher003-modified CARs, nicknamed DB5 CARs, displayed fast, low-nanomolar reaction kinetics with a synthetic αvβ6-binding peptide that incorporates a SpyTag003 peptide via branched peptide synthesis to comprise a bifunctional intermediate. Prearming DB5 CAR T cells or prelabeling target cells with the bifunctional peptide produced selective CD4+ and CD8+ CAR T-cell responses against αvβ6+ cancer cells in vitro. Furthermore, the synthetic targeting intermediate showed robust DB5 CAR T-cell arming in vivo and selectively reduced αvβ6+ tumor progression in a dual flank xenograft model. We demonstrate the versatility and therapeutic potential of "Cyborg" CAR T-cell therapies that utilize synthetic biomaterials to direct CAR T-cell activity via highly selective bioconjugation that occurs in vivo.
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Affiliation(s)
- Ian I Cardle
- Department of Bioengineering, University of Washington, Seattle, Washington 98195-5061, United States
- Seattle Children's Therapeutics, Seattle, Washington 98101, United States
| | - Dylan R Scherer
- Department of Bioengineering, University of Washington, Seattle, Washington 98195-5061, United States
| | - Michael C Jensen
- Seattle Children's Therapeutics, Seattle, Washington 98101, United States
- Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, United States
| | - Suzie H Pun
- Department of Bioengineering, University of Washington, Seattle, Washington 98195-5061, United States
| | - Drew L Sellers
- Department of Bioengineering, University of Washington, Seattle, Washington 98195-5061, United States
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Pinho V, Neves-Petersen MT, Machado R, Castro Gomes A. Light Assisted Covalent Immobilization of Proteins for Biomedical Applications. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2025; 21:e2406561. [PMID: 39887935 DOI: 10.1002/smll.202406561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 01/24/2025] [Indexed: 02/01/2025]
Abstract
The covalent immobilization of proteins attracts considerable interest in the biomedical field due to its potential applications in biosensors, recombinant protein purification, and the development of personalized therapeutic carriers. In response to the demand for more cost-effective, time-efficient, and simpler protocols, photo-immobilization emerges as a technique that circumvents the limitations of conventional methods. This approach offers enhanced precision at the nanoscale level and facilitates device reusability, thereby aligning with current sustainability concerns. Photo-immobilization is versatile, as it can be applied to both 2D and 3D substrates. While some methods involve complex protocols using genetically engineered photosensitive linkers, more straightforward techniques rely on amino acid bonds, such as disulfide bonds, for covalent protein bonding. Photo-immobilization can be achieved with both ultraviolet (UV) and visible light. This systematic review examines literature from Scopus, PubMed, and Web of Science, offering insights into relevant studies and considerations for covalent protein immobilization, and presents photochemical approaches applicable to major protein types.
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Affiliation(s)
- Vanessa Pinho
- Centre of Molecular and Environmental Biology (CBMA)/Aquatic Research Network (ARNET) Associate Laboratory, Universidade do Minho, Campus de Gualtar, Braga, 4710-057, Portugal
- Institute of Science and Innovation for Sustainability (IB-S), Universidade do Minho, Campus de Gualtar, Braga, 4710-057, Portugal
| | | | - Raúl Machado
- Centre of Molecular and Environmental Biology (CBMA)/Aquatic Research Network (ARNET) Associate Laboratory, Universidade do Minho, Campus de Gualtar, Braga, 4710-057, Portugal
- Institute of Science and Innovation for Sustainability (IB-S), Universidade do Minho, Campus de Gualtar, Braga, 4710-057, Portugal
| | - Andreia Castro Gomes
- Centre of Molecular and Environmental Biology (CBMA)/Aquatic Research Network (ARNET) Associate Laboratory, Universidade do Minho, Campus de Gualtar, Braga, 4710-057, Portugal
- Institute of Science and Innovation for Sustainability (IB-S), Universidade do Minho, Campus de Gualtar, Braga, 4710-057, Portugal
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5
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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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de Paula GA, de Paula MC, Dutra JAP, Carvalho SG, Di Filippo LD, Villanova JCO, Chorilli M. Targeted Polymeric Nanoparticles as a Strategy for the Treatment of Glioblastoma: A Review. Curr Drug Deliv 2025; 22:413-430. [PMID: 38013438 DOI: 10.2174/0115672018257713231107060630] [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: 05/26/2023] [Revised: 08/21/2023] [Accepted: 10/04/2023] [Indexed: 11/29/2023]
Abstract
Glioblastoma multiforme is the most common and aggressive malignant tumor that affects the central nervous system, with high mortality and low survival. Glioblastoma multiforme treatment includes resection tumor surgery, followed by radiotherapy and chemotherapy adjuvants. However, the drugs used in chemotherapy present some limitations, such as the difficulty of crossing the bloodbrain barrier and resisting the cellular mechanisms of drug efflux. The use of polymeric nanoparticles has proven to be an effective alternative to circumvent such limitations, as it allows the exploration of a range of polymeric structures that can be modified in order to control the biodistribution and cytotoxic effect of the drug delivery systems. Nanoparticles are nanometric in size and allow the incorporation of targeting ligands on their surface, favoring the transposition of the blood-brain barrier and the delivery of the drug to specific sites, increasing the selectivity and safety of chemotherapy. The present review has described the characteristics of chitosan, poly(vinyl alcohol), poly(lactic-coglycolic acid), poly(ethylene glycol), poly(β-amino ester), and poly(ε-caprolactone), which are some of the most commonly used polymers in the manufacture of nanoparticles for the treatment of glioblastoma multiforme. In addition, some of the main targeting ligands used in these nanosystems are presented, such as transferrin, chlorotoxin, albumin, epidermal growth factor, and epidermal growth factor receptor blockers, explored for the active targeting of antiglioblastoma agents.
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Affiliation(s)
- Geanne Aparecida de Paula
- School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara, São Paulo, Brazil
| | | | | | - Suzana Gonçalves Carvalho
- School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara, São Paulo, Brazil
| | | | | | - Marlus Chorilli
- School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara, São Paulo, Brazil
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7
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Miao L, Zhang J, Xu W, Qian Q, Zhang G, Yuan Q, Lv Y, Zhang H, Shen C, Wang W. Global research trends in CAR-T cell therapy for solid tumors: A comprehensive visualization and bibliometric study (2012-2023). Hum Vaccin Immunother 2024; 20:2338984. [PMID: 38698555 PMCID: PMC11073418 DOI: 10.1080/21645515.2024.2338984] [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: 01/10/2024] [Accepted: 04/02/2024] [Indexed: 05/05/2024] Open
Abstract
CAR-T cell therapy has emerged as a significant approach for the management of hematological malignancies. Over the past few years, the utilization of CAR-T cells in the investigation and treatment of solid tumors has gained momentum, thereby establishing itself as a prominent area of research. This descriptive study involved the retrieval of articles about CAR-T cell therapy for solid tumors from the Web of Science Core Collection (WoSCC) database. Subsequently, bibliometric analysis and knowledge map analysis were conducted on these articles. The field under consideration is currently experiencing a period of swift advancement, as evidenced by the escalating number of publications in this domain each year. The United States holds an indisputable position as the foremost leader in this particular field, with the University of Pennsylvania emerging as the most active institution. The authors with the highest citation frequency and co-citation frequency are Carl H. June and Shannon L. Maude, respectively. The research hotspots in this field mainly focus on five aspects. Additionally, 10 emerging themes were identified. This study undertakes a comprehensive, systematic, and objective analysis and exploration of the field of CAR-T cell treatment for solid tumors, utilizing bibliometric methods. The findings of this study are expected to serve as a valuable reference and enlightenment for future research endeavors in this particular domain.
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Affiliation(s)
- Lele Miao
- Department of Thyroid and Breast Surgery, Jining NO.1 People’s Hospital, Jining, China
| | - Juan Zhang
- Department of Hematology, Jining NO.1 People’s Hospital, Jining, China
| | - Wei Xu
- Department of Thyroid and Breast Surgery, Jining NO.1 People’s Hospital, Jining, China
| | - Qian Qian
- Department of Thyroid and Breast Surgery, Jining NO.1 People’s Hospital, Jining, China
| | - Guochao Zhang
- Department of Thyroid and Breast Surgery, Jining NO.1 People’s Hospital, Jining, China
| | - Quan Yuan
- Department of Thyroid and Breast Surgery, Jining NO.1 People’s Hospital, Jining, China
| | - Yuetao Lv
- Department of Thyroid and Breast Surgery, Jining NO.1 People’s Hospital, Jining, China
| | - Haiguo Zhang
- Department of Hematology, Jining NO.1 People’s Hospital, Jining, China
| | - Chaoyan Shen
- Department of Ultrasound, Jining NO.1 People’s Hospital, Jining, China
| | - Wei Wang
- Department of Thyroid and Breast Surgery, Jining NO.1 People’s Hospital, Jining, China
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8
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Firuzpour F, Saleki K, Aram C, Rezaei N. Nanocarriers in glioblastoma treatment: a neuroimmunological perspective. Rev Neurosci 2024:revneuro-2024-0097. [PMID: 39733347 DOI: 10.1515/revneuro-2024-0097] [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: 07/19/2024] [Accepted: 12/08/2024] [Indexed: 12/31/2024]
Abstract
Glioblastoma multiforme (GBM) is the most fatal brain tumor with a poor prognosis with current treatments, mainly because of intrinsic resistance processes. GBM is also referred to as grade 4 astrocytoma, that makes up about 15.4 % of brain cancers globally as well as 60-75 % of astrocytoma. The most prevalent therapeutic choices for GBM comprise surgery in combination with radiotherapy and chemotherapy, providing patients with an average survival of 6-14 months. Nanocarriers provide various benefits such as enhanced drug solubility, biocompatibility, targeted activity, as well as minimized side effects. In addition, GBM treatment comes with several challenges such as the presence of the blood-brain barrier (BBB), blood-brain tumor barrier (BBTB), overexpressed efflux pumps, infiltration, invasion, drug resistance, as well as immune escape due to tumor microenvironment (TME) and cancer stem cells (CSC). Recent research has focused on nanocarriers due to their ability to self-assemble, improve bioavailability, provide controlled release, and penetrate the BBB. These nano-based components could potentially enhance drug accumulation in brain tumor tissues and reduce systemic toxicity, making them a compelling solution for GBM therapy. This review captures the complexities associated with multi-functional nano drug delivery systems (NDDS) in crossing the blood-brain barrier (BBB) and targeting cancer cells. In addition, it presents a succinct overview of various types of targeted multi-functional nano drug delivery system (NDDS) which has exhibited promising value for improving drug delivery to the brain.
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Affiliation(s)
- Faezeh Firuzpour
- USERN Office, Babol University of Medical Sciences, 47176-41367, Babol, Iran
- Student Research Committee, Babol University of Medical Sciences, 47176-41367, Babol, Iran
| | - Kiarash Saleki
- USERN Office, Babol University of Medical Sciences, 47176-41367, Babol, Iran
- Student Research Committee, Babol University of Medical Sciences, 47176-41367, Babol, Iran
- Research Center for Immunodeficiencies, Children's Medical Center, 48439 Tehran University of Medical Sciences , Tehran, 1416634793, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, 1416634793, Iran
| | - Cena Aram
- Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, 15719-14911, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, 48439 Tehran University of Medical Sciences , Tehran, 1416634793, Iran
- Department of Immunology, School of Medicine, 48439 Tehran University of Medical Sciences , Tehran, 1416634793, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, 1416634793, Iran
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9
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You H, Geng S, Li S, Imani M, Brambilla D, Sun T, Jiang C. Recent advances in biomimetic strategies for the immunotherapy of glioblastoma. Biomaterials 2024; 311:122694. [PMID: 38959533 DOI: 10.1016/j.biomaterials.2024.122694] [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: 04/08/2024] [Revised: 06/22/2024] [Accepted: 06/26/2024] [Indexed: 07/05/2024]
Abstract
Immunotherapy is regarded as one of the most promising approaches for treating tumors, with a multitude of immunotherapeutic thoughts currently under consideration for the lethal glioblastoma (GBM). However, issues with immunotherapeutic agents, such as limited in vivo stability, poor blood-brain barrier (BBB) penetration, insufficient GBM targeting, and represented monotherapy, have hindered the success of immunotherapeutic interventions. Moreover, even with the aid of conventional drug delivery systems, outcomes remain suboptimal. Biomimetic strategies seek to overcome these formidable drug delivery challenges by emulating nature's intelligent structures and functions. Leveraging the variety of biological structures and functions, biomimetic drug delivery systems afford a versatile platform with enhanced biocompatibility for the co-delivery of diverse immunotherapeutic agents. Moreover, their inherent capacity to traverse the BBB and home in on GBM holds promise for augmenting the efficacy of GBM immunotherapy. Thus, this review begins by revisiting the various thoughts and agents on immunotherapy for GBM. Then, the barriers to successful GBM immunotherapy are analyzed, and the corresponding biomimetic strategies are explored from the perspective of function and structure. Finally, the clinical translation's current state and prospects of biomimetic strategy are addressed. This review aspires to provide fresh perspectives on the advancement of immunotherapy for GBM.
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Affiliation(s)
- Haoyu You
- Key Laboratory of Smart Drug Delivery/Innovative Center for New Drug Development of Immune Inflammatory Diseases (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Shuo Geng
- Key Laboratory of Smart Drug Delivery/Innovative Center for New Drug Development of Immune Inflammatory Diseases (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Shangkuo Li
- Key Laboratory of Smart Drug Delivery/Innovative Center for New Drug Development of Immune Inflammatory Diseases (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Mohammad Imani
- Department of Science, Iran Polymer and Petrochemical Institute, Tehran 14977-13115, Iran; Center for Nanoscience and Nanotechnology, Institute for Convergence Science & Technology, Tehran 14588-89694, Iran
| | - Davide Brambilla
- Faculty of Pharmacy, University of Montreal, Montreal Quebec H3T 1J4, Canada
| | - Tao Sun
- Key Laboratory of Smart Drug Delivery/Innovative Center for New Drug Development of Immune Inflammatory Diseases (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China.
| | - Chen Jiang
- Key Laboratory of Smart Drug Delivery/Innovative Center for New Drug Development of Immune Inflammatory Diseases (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China
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10
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Khan M, Nasim M, Feizy M, Parveen R, Gull A, Khan S, Ali J. Contemporary strategies in glioblastoma therapy: Recent developments and innovations. Neuroscience 2024; 560:211-237. [PMID: 39368608 DOI: 10.1016/j.neuroscience.2024.09.022] [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: 07/11/2024] [Revised: 08/30/2024] [Accepted: 09/12/2024] [Indexed: 10/07/2024]
Abstract
Glioblastoma multiforme (GBM) represents one of the most prevailing and aggressive primary brain tumors among adults. Despite advances in therapeutic approaches, the complex microenvironment of GBM poses significant challenges in its optimal therapy, which are attributed to immune evasion, tumor repopulation by stem cells, and limited drug penetration across the blood-brain barrier (BBB). Nanotechnology has emerged as a promising avenue for GBM treatment, offering biosafety, sustained drug release, enhanced solubility, and improved BBB penetrability. In this review, a comprehensive overview of recent advancements in nanocarrier-based drug delivery systems for GBM therapy is emphasized. The conventional and novel treatment modalities for GBM and the potential of nanocarriers to overcome existing limitations are comprehensively covered. Furthermore, the updates in the clinical landscape of GBM therapeutics are presented in addition to the current status of drugs and patents in the same context. Through a critical evaluation of existing literature, the therapeutic prospect and limitations of nanocarrier-based drug delivery strategies are highlighted offering insights into future research directions and clinical translation.
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Affiliation(s)
- Mariya Khan
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, Delhi, India
| | - Modassir Nasim
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, Delhi, India
| | - Mohammadamin Feizy
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, Delhi, India
| | - Rabea Parveen
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, Delhi, India
| | - Azka Gull
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, Delhi, India
| | - Saba Khan
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, Delhi, India.
| | - Javed Ali
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, Delhi, India.
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11
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Zhang H, Grippin A, Sun M, Ma Y, Kim BYS, Teng L, Jiang W, Yang Z. New avenues for cancer immunotherapy: Cell-mediated drug delivery systems. J Control Release 2024; 375:712-732. [PMID: 39326499 DOI: 10.1016/j.jconrel.2024.09.037] [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: 07/01/2024] [Revised: 09/15/2024] [Accepted: 09/22/2024] [Indexed: 09/28/2024]
Abstract
Cancer research has become increasingly complex over the past few decades as knowledge of the heterogeneity of cancer cells, their proliferative ability, and their tumor microenvironments has become available. Although conventional therapies remain the most compelling option for cancer treatment to date, immunotherapy is a promising way to harness natural immune defenses to target and kill cancer cells. Cell-mediated drug delivery systems (CDDSs) have been an active line of research for enhancing the therapeutic efficacy and specificity of cancer immunotherapy. These systems can be tailored to different types of immune cells, allowing immune evasion and accumulation in the tumor microenvironment. By enabling the targeted delivery of therapeutic agents such as immune stimulants, cytokines, antibodies, and antigens, CDDSs have improved the survival of some patients with cancer. This review summarizes the research status of CDDSs, with a focus on their underlying mechanisms of action, biology, and clinical applications. We also discuss opportunities and challenges for implementation of CDDSs into mainstream cancer immunotherapy.
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Affiliation(s)
- Huan Zhang
- School of Life Sciences, Jilin University, Changchun 130012, China
| | - Adam Grippin
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Man Sun
- School of Life Sciences, Jilin University, Changchun 130012, China
| | - Yifan Ma
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Betty Y S Kim
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Lesheng Teng
- School of Life Sciences, Jilin University, Changchun 130012, China
| | - Wen Jiang
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
| | - Zhaogang Yang
- School of Life Sciences, Jilin University, Changchun 130012, China.
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12
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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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13
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Hou AJ, Shih RM, Uy BR, Shafer A, Chang ZL, Comin-Anduix B, Guemes M, Galic Z, Phyu S, Okada H, Grausam KB, Breunig JJ, Brown CE, Nathanson DA, Prins RM, Chen YY. IL-13Rα2/TGF-β bispecific CAR-T cells counter TGF-β-mediated immune suppression and potentiate anti-tumor responses in glioblastoma. Neuro Oncol 2024; 26:1850-1866. [PMID: 38982561 PMCID: PMC11449012 DOI: 10.1093/neuonc/noae126] [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: 06/30/2023] [Indexed: 07/11/2024] Open
Abstract
BACKGROUND Chimeric antigen receptor (CAR)-T cell therapies targeting glioblastoma (GBM)-associated antigens such as interleukin-13 receptor subunit alpha-2 (IL-13Rα2) have achieved limited clinical efficacy to date, in part due to an immunosuppressive tumor microenvironment (TME) characterized by inhibitory molecules such as transforming growth factor-beta (TGF-β). The aim of this study was to engineer more potent GBM-targeting CAR-T cells by countering TGF-β-mediated immune suppression in the TME. METHODS We engineered a single-chain, bispecific CAR targeting IL-13Rα2 and TGF-β, which programs tumor-specific T cells to convert TGF-β from an immunosuppressant to an immunostimulant. Bispecific IL-13Rα2/TGF-β CAR-T cells were evaluated for efficacy and safety against both patient-derived GBM xenografts and syngeneic models of murine glioma. RESULTS Treatment with IL-13Rα2/TGF-β CAR-T cells leads to greater T-cell infiltration and reduced suppressive myeloid cell presence in the tumor-bearing brain compared to treatment with conventional IL-13Rα2 CAR-T cells, resulting in improved survival in both patient-derived GBM xenografts and syngeneic models of murine glioma. CONCLUSIONS Our findings demonstrate that by reprogramming tumor-specific T-cell responses to TGF-β, bispecific IL-13Rα2/TGF-β CAR-T cells resist and remodel the immunosuppressive TME to drive potent anti-tumor responses in GBM.
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Affiliation(s)
- Andrew J Hou
- Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, California, USA
| | - Ryan M Shih
- Department of Molecular Biology, University of California, Los Angeles, California, USA
| | - Benjamin R Uy
- Department of Neurosurgery, University of California, Los Angeles, California, USA
| | - Amanda Shafer
- Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California, USA
| | - ZeNan L Chang
- Department of Molecular Biology, University of California, Los Angeles, California, USA
| | - Begonya Comin-Anduix
- Department of Surgery, University of California, Los Angeles, California, USA
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, USA
| | - Miriam Guemes
- Department of Medicine, Division of Hematology/Oncology, University of California, Los Angeles, California, USA
| | - Zoran Galic
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, USA
- Department of Medicine, Division of Hematology/Oncology, University of California, Los Angeles, California, USA
| | - Su Phyu
- Department of Neurosurgery, University of California, San Francisco, California, USA
| | - Hideho Okada
- Department of Neurosurgery, University of California, San Francisco, California, USA
- Parker Institute for Cancer Immunotherapy Center at UCSF, San Francisco, California, USA
| | - Katie B Grausam
- Board of Governor’s Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Joshua J Breunig
- Board of Governor’s Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Christine E Brown
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center and Beckman Research Institute, Duarte, California, USA
| | - David A Nathanson
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, USA
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, California, USA
| | - Robert M Prins
- Department of Neurosurgery, University of California, Los Angeles, California, USA
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, USA
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, California, USA
| | - Yvonne Y Chen
- Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, California, USA
- Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California, USA
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, USA
- Parker Institute for Cancer Immunotherapy Center at UCLA, Los Angeles, California, USA
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14
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Liu C, Wang Q, Li L, Gao F, Zhang Y, Zhu Y. The peptide-based bispecific CAR T cells target EGFR and tumor stroma for effective cancer therapy. Int J Pharm 2024; 663:124558. [PMID: 39111352 DOI: 10.1016/j.ijpharm.2024.124558] [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: 05/20/2024] [Revised: 07/23/2024] [Accepted: 08/04/2024] [Indexed: 08/12/2024]
Abstract
BACKGROUND AND PURPOSE The efficacy of chimeric antigen receptor (CAR)-T cell for solid tumors is limited partially because of the lack of tumor-specific antigens and off-target effects. Low molecular weight peptides allowed CAR T cell to display several antigen receptors to reduce off-target effects. Here, we develop a peptide-based bispecific CAR for EGFR and tumor stroma, which are expressed in a variety of tumor types. EXPERIMENTAL APPROACH AND KEY RESULTS The peptide-based CAR T cells show excellent proliferation, cytotoxicity activity and are only activated by tumor cells overexpressing EGFR instead of normal cells with low EGFR expressing. In mouse xenograft models, the peptide bispecific CAR T cells can be delivered into the inner of tumor masses and thus are effective in inhibiting tumor growth. Meanwhile, they show strong expansion capacity and the property of maintaining long-term function in vivo. During treatment, no off-tumor toxicity is observed on healthy organs expressing lower levels of EGFR. CONCLUSIONS & IMPLICATIONS Our findings demonstrate that peptide-based bispecific CAR T holds great potential in solid tumor therapy due to an excellent targeting ability towards tumors and tumor microenvironment.
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Affiliation(s)
- Cuijuan Liu
- School of Nano Technology and Nano Bionics, University of Science and Technology of China, Hefei 230026, China; CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China; The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, China
| | - Qianqian Wang
- School of Nano Technology and Nano Bionics, University of Science and Technology of China, Hefei 230026, China; CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China
| | - Lin Li
- CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China
| | - Fan Gao
- School of Nano Technology and Nano Bionics, University of Science and Technology of China, Hefei 230026, China; CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China
| | - Yuanyue Zhang
- Department of Oncology, Suzhou BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Suzhou, China
| | - Yimin Zhu
- CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China.
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15
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Duan M, Cao R, Yang Y, Chen X, Liu L, Ren B, Wang L, Goh BC. Blood-Brain Barrier Conquest in Glioblastoma Nanomedicine: Strategies, Clinical Advances, and Emerging Challenges. Cancers (Basel) 2024; 16:3300. [PMID: 39409919 PMCID: PMC11475686 DOI: 10.3390/cancers16193300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 09/24/2024] [Accepted: 09/24/2024] [Indexed: 10/20/2024] Open
Abstract
Glioblastoma (GBM) is a prevalent type of malignancy within the central nervous system (CNS) that is associated with a poor prognosis. The standard treatment for GBM includes the surgical resection of the tumor, followed by radiotherapy and chemotherapy; yet, despite these interventions, overall treatment outcomes remain suboptimal. The blood-brain barrier (BBB), which plays a crucial role in maintaining the stability of brain tissue under normal physiological conditions of the CNS, also poses a significant obstacle to the effective delivery of therapeutic agents to GBMs. Recent preclinical studies have demonstrated that nanomedicine delivery systems (NDDSs) offer promising results, demonstrating both effective GBM targeting and safety, thereby presenting a potential solution for targeted drug delivery. In this review, we first explore the various strategies employed in preclinical studies to overcome the BBB for drug delivery. Subsequently, the results of the clinical translation of NDDSs are summarized, highlighting the progress made. Finally, we discuss potential strategies for advancing the development of NDDSs and accelerating their translational research through well-designed clinical trials in GBM therapy.
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Affiliation(s)
- Mengyun Duan
- Department of Medical Imaging, Health Science Center, Yangtze University, Jingzhou 434023, China; (M.D.); (X.C.)
| | - Ruina Cao
- Department of Anesthesiology, Maternal and Child Health Hospital of Hubei Province, Wuhan 430070, China;
| | - Yuan Yang
- Department of Radiology, Renmin Hospital of Wuhan University, Wuhan 430060, China;
| | - Xiaoguang Chen
- Department of Medical Imaging, Health Science Center, Yangtze University, Jingzhou 434023, China; (M.D.); (X.C.)
| | - Lian Liu
- Department of Pharmacology, Health Science Center, Yangtze University, Jingzhou 434023, China;
| | - Boxu Ren
- Department of Medical Imaging, Health Science Center, Yangtze University, Jingzhou 434023, China; (M.D.); (X.C.)
| | - Lingzhi Wang
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore;
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore
| | - Boon-Cher Goh
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore;
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore
- Department of Haematology-Oncology, National University Cancer Institute, Singapore 119228, Singapore
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16
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Nader NE, Frederico SC, Miller T, Huq S, Zhang X, Kohanbash G, Hadjipanayis CG. Barriers to T Cell Functionality in the Glioblastoma Microenvironment. Cancers (Basel) 2024; 16:3273. [PMID: 39409893 PMCID: PMC11476085 DOI: 10.3390/cancers16193273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 09/17/2024] [Accepted: 09/19/2024] [Indexed: 10/20/2024] Open
Abstract
Glioblastoma (GBM) is an aggressive primary brain tumor depicted by a cold tumor microenvironment, low immunogenicity, and limited effective therapeutic interventions. Its location in the brain, a highly immune-selective organ, acts as a barrier, limiting immune access and promoting GBM dissemination, despite therapeutic interventions. Currently, chemotherapy and radiation combined with surgical resection are the standard of care for GBM treatment. Although immune checkpoint blockade has revolutionized the treatment of solid tumors, its observed success in extracranial tumors has not translated into a significant survival benefit for GBM patients. To develop effective immunotherapies for GBM, it is vital to tailor treatments to overcome the numerous immunosuppressive barriers that inhibit T cell responses to these tumors. In this review, we address the unique physical and immunological barriers that make GBM challenging to treat. Additionally, we explore potential therapeutic mechanisms, studied in central nervous system (CNS) and non-CNS cancers, that may overcome these barriers. Furthermore, we examine current and promising immunotherapy clinical trials and immunotherapeutic interventions for GBM. By highlighting the array of challenges T cell-based therapies face in GBM, we hope this review can guide investigators as they develop future immunotherapies for this highly aggressive malignancy.
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Affiliation(s)
- Noor E. Nader
- School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA; (N.E.N.); (S.C.F.); (T.M.)
| | - Stephen C. Frederico
- School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA; (N.E.N.); (S.C.F.); (T.M.)
- Harvard Medical School, Boston, MA 02115, USA
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA;
| | - Tracy Miller
- School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA; (N.E.N.); (S.C.F.); (T.M.)
| | - Sakibul Huq
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA;
| | - Xiaoran Zhang
- Sloan Kettering Memorial Cancer Center, New York, NY 10065, USA;
| | - Gary Kohanbash
- Sloan Kettering Memorial Cancer Center, New York, NY 10065, USA;
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17
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Saleh HA, Mitwasi N, R Loureiro L, Kegler A, Soto KEG, Hoffmann L, Crespo E, Arndt C, Bergmann R, Bachmann M, Feldmann A. RevCAR-expressing immune effector cells for targeting of Fn14-positive glioblastoma. Cancer Gene Ther 2024; 31:1323-1334. [PMID: 38582787 PMCID: PMC11405279 DOI: 10.1038/s41417-024-00766-8] [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: 10/10/2023] [Revised: 03/18/2024] [Accepted: 03/21/2024] [Indexed: 04/08/2024]
Abstract
In recent studies, we have established the unique adapter chimeric antigen receptor (CAR) platform RevCAR which uses, as an extracellular CAR domain, a peptide epitope instead of an antibody domain. RevCAR adapters (termed RevCAR target modules, RevTMs) are bispecific antibodies that enable the reversible ON/OFF switch of the RevCAR system, improving the safety compared to conventional CARs. Here, we describe for the first time its use for retargeting of both T and NK-92 cells. In addition, we describe the development and preclinical validation of a novel RevTM for targeting of the fibroblast growth factor-inducible 14 (Fn14) surface receptor which is overexpressed on Glioblastoma (GBM) cells, and therefore serves as a promising target for the treatment of GBM. The novel RevTM efficiently redirects RevCAR modified T and NK-92 cells and leads to the killing of GBM cells both in vitro and in vivo. Tumor cell killing is associated with increased IL-2, TNF-α and/or IFN-γ secretion. Hence, these findings give an insight into the complementary potential of both RevCAR T and NK-92 systems as a safe and specific immunotherapeutic approach against GBM.
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Affiliation(s)
- Haidy A Saleh
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Radioimmunology, Bautzner Landstraße 400, D-01328, Dresden, Germany
| | - Nicola Mitwasi
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Radioimmunology, Bautzner Landstraße 400, D-01328, Dresden, Germany
| | - Liliana R Loureiro
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Radioimmunology, Bautzner Landstraße 400, D-01328, Dresden, Germany
| | - Alexandra Kegler
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Radioimmunology, Bautzner Landstraße 400, D-01328, Dresden, Germany
| | - Karla Elizabeth González Soto
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Radioimmunology, Bautzner Landstraße 400, D-01328, Dresden, Germany
| | - Lydia Hoffmann
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Radioimmunology, Bautzner Landstraße 400, D-01328, Dresden, Germany
| | - Eugenia Crespo
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Radioimmunology, Bautzner Landstraße 400, D-01328, Dresden, Germany
| | - Claudia Arndt
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Radioimmunology, Bautzner Landstraße 400, D-01328, Dresden, Germany
- Mildred Scheel Early Career Center, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, D-01307, Dresden, Germany
| | - Ralf Bergmann
- Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary
| | - Michael Bachmann
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Radioimmunology, Bautzner Landstraße 400, D-01328, Dresden, Germany.
- National Center for Tumor Diseases Dresden (NCT/UCC), Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany.
- German Cancer Research Center (DKFZ), Heidelberg, Germany.
- German Cancer Consortium (DKTK), Partner Site Dresden, Dresden, Germany.
| | - Anja Feldmann
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Radioimmunology, Bautzner Landstraße 400, D-01328, Dresden, Germany.
- National Center for Tumor Diseases Dresden (NCT/UCC), Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany.
- German Cancer Research Center (DKFZ), Heidelberg, Germany.
- German Cancer Consortium (DKTK), Partner Site Dresden, Dresden, Germany.
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18
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Wang M, Jia L, Dai X, Zhang X. Advanced strategies in improving the immunotherapeutic effect of CAR-T cell therapy. Mol Oncol 2024; 18:1821-1848. [PMID: 38456710 PMCID: PMC11306536 DOI: 10.1002/1878-0261.13621] [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: 08/12/2023] [Revised: 12/23/2023] [Accepted: 02/20/2024] [Indexed: 03/09/2024] Open
Abstract
Chimeric antigen receptor (CAR-T) cell therapy is a newly developed immunotherapy strategy and has achieved satisfactory outcomes in the treatment of hematological malignancies. However, some adverse effects related to CAR-T cell therapy have to be resolved before it is widely used in clinics as a cancer treatment. Furthermore, the application of CAR-T cell therapy in the treatment of solid tumors has been hampered by numerous limitations. Therefore, it is essential to explore novel strategies to improve the therapeutic effect of CAR-T cell therapy. In this review, we summarized the recently developed strategies aimed at optimizing the generation of CAR-T cells and improving the anti-tumor efficiency of CAR-T cell therapy. Furthermore, the discovery of new targets for CAR-T cell therapy and the combined treatment strategies of CAR-T cell therapy with chemotherapy, radiotherapy, cancer vaccines and nanomaterials are highlighted.
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Affiliation(s)
- Minmin Wang
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of EducationFirst Hospital of Jilin UniversityChangchunChina
- National‐Local Joint Engineering Laboratory of Animal Models for Human DiseaseFirst Hospital of Jilin UniversityChangchunChina
| | - Linzi Jia
- Department of General MedicineShanxi Province Cancer HospitalTaiyuanChina
| | - Xiangpeng Dai
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of EducationFirst Hospital of Jilin UniversityChangchunChina
- National‐Local Joint Engineering Laboratory of Animal Models for Human DiseaseFirst Hospital of Jilin UniversityChangchunChina
| | - Xiaoling Zhang
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of EducationFirst Hospital of Jilin UniversityChangchunChina
- National‐Local Joint Engineering Laboratory of Animal Models for Human DiseaseFirst Hospital of Jilin UniversityChangchunChina
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19
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Mog BJ, Marcou N, DiNapoli SR, Pearlman AH, Nichakawade TD, Hwang MS, Douglass J, Hsiue EHC, Glavaris S, Wright KM, Konig MF, Paul S, Wyhs N, Ge J, Miller MS, Azurmendi P, Watson E, Pardoll DM, Gabelli SB, Bettegowda C, Papadopoulos N, Kinzler KW, Vogelstein B, Zhou S. Preclinical studies show that Co-STARs combine the advantages of chimeric antigen and T cell receptors for the treatment of tumors with low antigen densities. Sci Transl Med 2024; 16:eadg7123. [PMID: 38985855 DOI: 10.1126/scitranslmed.adg7123] [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: 01/16/2023] [Revised: 04/01/2024] [Accepted: 06/13/2024] [Indexed: 07/12/2024]
Abstract
Two types of engineered T cells have been successfully used to treat patients with cancer, one with an antigen recognition domain derived from antibodies [chimeric antigen receptors (CARs)] and the other derived from T cell receptors (TCRs). CARs use high-affinity antigen-binding domains and costimulatory domains to induce T cell activation but can only react against target cells with relatively high amounts of antigen. TCRs have a much lower affinity for their antigens but can react against target cells displaying only a few antigen molecules. Here, we describe a new type of receptor, called a Co-STAR (for costimulatory synthetic TCR and antigen receptor), that combines aspects of both CARs and TCRs. In Co-STARs, the antigen-recognizing components of TCRs are replaced by high-affinity antibody fragments, and costimulation is provided by two modules that drive NF-κB signaling (MyD88 and CD40). Using a TCR-mimic antibody fragment that targets a recurrent p53 neoantigen presented in a common human leukocyte antigen (HLA) allele, we demonstrate that T cells equipped with Co-STARs can kill cancer cells bearing low densities of antigen better than T cells engineered with conventional CARs and patient-derived TCRs in vitro. In mouse models, we show that Co-STARs mediate more robust T cell expansion and more durable tumor regressions than TCRs similarly modified with MyD88 and CD40 costimulation. Our data suggest that Co-STARs may have utility for other peptide-HLA antigens in cancer and other targets where antigen density may limit the efficacy of engineered T cells.
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Affiliation(s)
- Brian J Mog
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
- Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Nikita Marcou
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
- Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Sarah R DiNapoli
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
- Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Alexander H Pearlman
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
- Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Tushar D Nichakawade
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
- Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
- Institute for NanoBioTechnology, Johns Hopkins University, 3400 N. Charles St., Baltimore, MD 21218, USA
| | - Michael S Hwang
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
- Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Jacqueline Douglass
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
- Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Emily Han-Chung Hsiue
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
- Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Stephanie Glavaris
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
- Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Katharine M Wright
- Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
- Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA
| | - Maximilian F Konig
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
- Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA
| | - Suman Paul
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Nicolas Wyhs
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Jiaxin Ge
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
- Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Michelle S Miller
- Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
- Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA
| | - P Azurmendi
- Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
- Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA
| | - Evangeline Watson
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
- Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Drew M Pardoll
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA
| | - Sandra B Gabelli
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Chetan Bettegowda
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Nickolas Papadopoulos
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Kenneth W Kinzler
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA
| | - Bert Vogelstein
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
- Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Shibin Zhou
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA
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20
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Nix MA, Wiita AP. Alternative target recognition elements for chimeric antigen receptor (CAR) T cells: beyond standard antibody fragments. Cytotherapy 2024; 26:729-738. [PMID: 38466264 DOI: 10.1016/j.jcyt.2024.02.024] [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: 10/16/2023] [Revised: 01/31/2024] [Accepted: 02/26/2024] [Indexed: 03/12/2024]
Abstract
BACKGROUND AIMS Chimeric antigen receptor T (CAR-T) cells are a remarkably efficacious, highly promising and rapidly evolving strategy in the field of immuno-oncology. The precision of these targeted cellular therapies is driven by the specificity of the antigen recognition element (the "binder") encoded in the CAR. This binder redirects these immune effector cells precisely toward a defined antigen on the surface of cancer cells, leading to T-cell receptor-independent tumor lysis. Currently, for tumor targeting most CAR-T cells are designed using single-chain variable fragments (scFvs) derived from murine or human immunoglobulins. However, there are several emerging alternative binder modalities that are finding increasing utility for improved CAR function beyond scFvs. METHODS Here we review the most recent developments in the use of non-canonical protein binding domains in CAR design, including nanobodies, DARPins, natural ligands, and de novo-designed protein elements. RESULTS Overall, we describe how new protein binder formats, with their unique structural properties and mechanisms of action, may possess key advantages over traditional scFv CAR designs. CONCLUSIONS These alternative binder designs may contribute to enhanced CAR-T therapeutic options and, ultimately, improved outcomes for cancer patients.
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Affiliation(s)
- Matthew A Nix
- Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA; Cartography Biosciences, South San Francisco, California, USA
| | - Arun P Wiita
- Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA; Chan Zuckerberg Biohub San Francisco, San Francisco, California, USA; Parker Institute for Cancer Immunotherapy, San Francisco, California, USA.
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21
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Aleksandrovic E, Zhang S, Yu D. From pre-clinical to translational brain metastasis research: current challenges and emerging opportunities. Clin Exp Metastasis 2024; 41:187-198. [PMID: 38430319 PMCID: PMC11456321 DOI: 10.1007/s10585-024-10271-9] [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: 10/27/2023] [Accepted: 01/18/2024] [Indexed: 03/03/2024]
Abstract
Brain metastasis, characterized by poor clinical outcomes, is a devastating disease. Despite significant mechanistic and therapeutic advances in recent years, pivotal improvements in clinical interventions have remained elusive. The heterogeneous nature of the primary tumor of origin, complications in drug delivery across the blood-brain barrier, and the distinct microenvironment collectively pose formidable clinical challenges in developing new treatments for patients with brain metastasis. Although current preclinical models have deepened our basic understanding of the disease, much of the existing research on brain metastasis has employed a reductionist approach. This approach, which often relies on either in vitro systems or in vivo injection models in young and treatment-naive mouse models, does not give sufficient consideration to the clinical context. Given the translational importance of brain metastasis research, we advocate for the design of preclinical experimental models that take into account these unique clinical challenges and align more closely with current clinical practices. We anticipate that aligning and simulating real-world patient conditions will facilitate the development of more translatable treatment regimens. This brief review outlines the most pressing clinical challenges, the current state of research in addressing them, and offers perspectives on innovative metastasis models and tools aimed at identifying novel strategies for more effective management of clinical brain metastasis.
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Affiliation(s)
- Emilija Aleksandrovic
- Department of Pathology, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, 6001 Forest Park Rd, Dallas, TX, 75235, USA
| | - Siyuan Zhang
- Department of Pathology, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, 6001 Forest Park Rd, Dallas, TX, 75235, USA.
| | - Dihua Yu
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA.
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22
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Gordon KS, Perez CR, Garmilla A, Lam MSY, Aw JJ, Datta A, Lauffenburger DA, Pavesi A, Birnbaum ME. Pooled screening for CAR function identifies novel IL13Rα2-targeted CARs for treatment of glioblastoma. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.04.586240. [PMID: 38766252 PMCID: PMC11100612 DOI: 10.1101/2024.04.04.586240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
Chimeric antigen receptor therapies have demonstrated potent efficacy in treating B cell malignancies, but have yet to meaningfully translate to solid tumors. Here, we utilize our pooled screening platform, CARPOOL, to expedite the discovery of CARs with anti-tumor functions necessary for solid tumor efficacy. We performed selections in primary human T cells expressing a library of 1.3×10 6 3 rd generation CARs targeting IL13Rα2, a cancer testis antigen commonly expressed in glioblastoma. Selections were performed for cytotoxicity, proliferation, memory formation, and persistence upon repeated antigen challenge. Each enriched CAR robustly produced the phenotype for which it was selected, and one enriched CAR triggered potent cytotoxicity and long-term proliferation upon in vitro tumor rechallenge. It also showed significantly improved persistence and comparable antigen-specific tumor control in a microphysiological human in vitro model and a xenograft model of human glioblastoma. Taken together, this work demonstrates the utility of extending CARPOOL to diseases beyond hematological malignancies and represents the largest exploration of signaling combinations in human primary cells to date.
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23
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Valerius AR, Webb LM, Sener U. Novel Clinical Trials and Approaches in the Management of Glioblastoma. Curr Oncol Rep 2024; 26:439-465. [PMID: 38546941 DOI: 10.1007/s11912-024-01519-4] [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] [Accepted: 03/14/2024] [Indexed: 05/02/2024]
Abstract
PURPOSE OF REVIEW The purpose of this review is to discuss a wide variety of novel therapies recently studied or actively undergoing study in patients with glioblastoma. This review also discusses current and future strategies for improving clinical trial design in patients with glioblastoma to maximize efficacy in discovering effective treatments. RECENT FINDINGS Over the years, there has been significant expansion in therapy modalities studied in patients with glioblastoma. These therapies include, but are not limited to, targeted molecular therapies, DNA repair pathway targeted therapies, immunotherapies, vaccine therapies, and surgically targeted radiotherapies. Glioblastoma is the most common malignant primary brain tumor in adults and unfortunately remains with poor overall survival following the current standard of care. Given the dismal prognosis, significant clinical and research efforts are ongoing with the goal of improving patient outcomes and enhancing quality and quantity of life utilizing a wide variety of novel therapies.
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Affiliation(s)
| | - Lauren M Webb
- Department of Neurology, Mayo Clinic, Rochester, MN, USA
| | - Ugur Sener
- Department of Neurology, Mayo Clinic, Rochester, MN, USA
- Department of Oncology, Mayo Clinic, Rochester, MN, USA
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24
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Chen X, Cui Y, Zou L. Treatment advances in high-grade gliomas. Front Oncol 2024; 14:1287725. [PMID: 38660136 PMCID: PMC11039916 DOI: 10.3389/fonc.2024.1287725] [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: 09/02/2023] [Accepted: 03/25/2024] [Indexed: 04/26/2024] Open
Abstract
High-grade gliomas (HGG) pose significant challenges in modern tumour therapy due to the distinct biological properties and limitations of the blood-brain barrier. This review discusses recent advancements in HGG treatment, particularly in the context of immunotherapy and cellular therapy. Initially, treatment strategies focus on targeting tumour cells guided by the molecular characteristics of various gliomas, encompassing chemotherapy, radiotherapy and targeted therapy for enhanced precision. Additionally, technological enhancements are augmenting traditional treatment modalities. Furthermore, immunotherapy, emphasising comprehensive tumour management, has gained widespread attention. Immune checkpoint inhibitors, vaccines and CAR-T cells exhibit promising efficacy against recurrent HGG. Moreover, emerging therapies such as tumour treating fields (TTFields) offer additional treatment avenues for patients with HGG. The combination of diverse treatments holds promise for improving the prognosis of HGG, particularly in cases of recurrence.
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Affiliation(s)
- Xi Chen
- Department of Radiotherapy, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Yi Cui
- State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Liqun Zou
- Department of Medical Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
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25
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Deng D, Hao T, Lu L, Yang M, Zeng Z, Lovell JF, Liu Y, Jin H. Applications of Intravital Imaging in Cancer Immunotherapy. Bioengineering (Basel) 2024; 11:264. [PMID: 38534538 DOI: 10.3390/bioengineering11030264] [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: 12/20/2023] [Revised: 02/20/2024] [Accepted: 03/06/2024] [Indexed: 03/28/2024] Open
Abstract
Currently, immunotherapy is one of the most effective treatment strategies for cancer. However, the efficacy of any specific anti-tumor immunotherapy can vary based on the dynamic characteristics of immune cells, such as their rate of migration and cell-to-cell interactions. Therefore, understanding the dynamics among cells involved in the immune response can inform the optimization and improvement of existing immunotherapy strategies. In vivo imaging technologies use optical microscopy techniques to visualize the movement and behavior of cells in vivo, including cells involved in the immune response, thereby showing great potential for application in the field of cancer immunotherapy. In this review, we briefly introduce the technical aspects required for in vivo imaging, such as fluorescent protein labeling, the construction of transgenic mice, and various window chamber models. Then, we discuss the elucidation of new phenomena and mechanisms relating to tumor immunotherapy that has been made possible by the application of in vivo imaging technology. Specifically, in vivo imaging has supported the characterization of the movement of T cells during immune checkpoint inhibitor therapy and the kinetic analysis of dendritic cell migration in tumor vaccine therapy. Finally, we provide a perspective on the challenges and future research directions for the use of in vivo imaging technology in cancer immunotherapy.
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Affiliation(s)
- Deqiang Deng
- College of Biomedicine and Health and College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Tianli Hao
- College of Biomedicine and Health and College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Lisen Lu
- College of Biomedicine and Health and College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Muyang Yang
- College of Biomedicine and Health and College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Zhen Zeng
- College of Biomedicine and Health and College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Jonathan F Lovell
- Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, NY 14260, USA
| | - Yushuai Liu
- Department of Ophthalmology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Honglin Jin
- College of Biomedicine and Health and College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
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26
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Gutova M, Hibbard JC, Ma E, Natri HM, Adhikarla V, Chimge NO, Qiu R, Nguyen C, Melendez E, Aguilar B, Starr R, Yin H, Rockne RC, Ono M, Banovich NE, Yuan YC, Brown CE, Kahn M. Targeting Wnt signaling for improved glioma immunotherapy. Front Immunol 2024; 15:1342625. [PMID: 38449858 PMCID: PMC10915090 DOI: 10.3389/fimmu.2024.1342625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 01/29/2024] [Indexed: 03/08/2024] Open
Abstract
Introduction Despite aggressive standard-of-care therapy, including surgery, radiation, and chemotherapy, glioblastoma recurrence is almost inevitable and uniformly lethal. Activation of glioma-intrinsic Wnt/β-catenin signaling is associated with a poor prognosis and the proliferation of glioma stem-like cells, leading to malignant transformation and tumor progression. Impressive results in a subset of cancers have been obtained using immunotherapies including anti-CTLA4, anti-PD-1, and anti-PD-L1 or chimeric antigen receptor (CAR) T cell therapies. However, the heterogeneity of tumors, low mutational burden, single antigen targeting, and associated antigen escape contribute to non-responsiveness and potential tumor recurrence despite these therapeutic efforts. In the current study, we determined the effects of the small molecule, highly specific Wnt/CBP (CREB Binding Protein)/β-catenin antagonist ICG-001, on glioma tumor cells and the tumor microenvironment (TME)-including its effect on immune cell infiltration, blood vessel decompression, and metabolic changes. Methods Using multiple glioma patient-derived xenografts cell lines and murine tumors (GL261, K-Luc), we demonstrated in vitro cytostatic effects and a switch from proliferation to differentiation after treatment with ICG-001. Results In these glioma cell lines, we further demonstrated that ICG-001 downregulated the CBP/β-catenin target gene Survivin/BIRC5-a hallmark of Wnt/CBP/β-catenin inhibition. We found that in a syngeneic mouse model of glioma (K-luc), ICG-001 treatment enhanced tumor infiltration by CD3+ and CD8+ cells with increased expression of the vascular endothelial marker CD31 (PECAM-1). We also observed differential gene expression and induced immune cell infiltration in tumors pretreated with ICG-001 and then treated with CAR T cells as compared with single treatment groups or when ICG-001 treatment was administered after CAR T cell therapy. Discussion We conclude that specific Wnt/CBP/β-catenin antagonism results in pleotropic changes in the glioma TME, including glioma stem cell differentiation, modulation of the stroma, and immune cell activation and recruitment, thereby suggesting a possible role for enhancing immunotherapy in glioma patients.
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Affiliation(s)
- Margarita Gutova
- Department of Stem Cell Biology and Regenerative Medicine, City of Hope Beckman Research Institute, Duarte, CA, United States
| | - Jonathan C. Hibbard
- Department of Hematology & Hematopoietic Cell transplantation (T cell Therapeutic Research Laboratories), City of Hope Beckman Research Institute, Duarte, CA, United States
| | - Eric Ma
- Department of Hematology & Hematopoietic Cell transplantation (T cell Therapeutic Research Laboratories), City of Hope Beckman Research Institute, Duarte, CA, United States
| | - Heini M. Natri
- Translational Genomics Research Institute (TGen), Phoenix, AZ, United States
| | - Vikram Adhikarla
- Division of Mathematical Oncology, Department of Computational and Quantitative Medicine, City of Hope Beckman Research Institute, Duarte, CA, United States
| | - Nyam-Osor Chimge
- Cancer Biology and Molecular Medicine, City of Hope Beckman Research Institute, Duarte, CA, United States
| | - Runxiang Qiu
- Department of Stem Cell Biology and Regenerative Medicine, City of Hope Beckman Research Institute, Duarte, CA, United States
| | - Cu Nguyen
- Cancer Biology and Molecular Medicine, City of Hope Beckman Research Institute, Duarte, CA, United States
| | - Elizabeth Melendez
- Cancer Biology and Molecular Medicine, City of Hope Beckman Research Institute, Duarte, CA, United States
| | - Brenda Aguilar
- Department of Hematology & Hematopoietic Cell transplantation (T cell Therapeutic Research Laboratories), City of Hope Beckman Research Institute, Duarte, CA, United States
| | - Renate Starr
- Department of Hematology & Hematopoietic Cell transplantation (T cell Therapeutic Research Laboratories), City of Hope Beckman Research Institute, Duarte, CA, United States
| | - Holly Yin
- Cancer Biology and Molecular Medicine, City of Hope Beckman Research Institute, Duarte, CA, United States
| | - Russel C. Rockne
- Division of Mathematical Oncology, Department of Computational and Quantitative Medicine, City of Hope Beckman Research Institute, Duarte, CA, United States
| | | | | | - Yate-Ching Yuan
- Department of Computational and Quantitative Medicine, City of Hope Beckman Research Institute, Duarte, CA, United States
| | - Christine E. Brown
- Department of Hematology & Hematopoietic Cell transplantation (T cell Therapeutic Research Laboratories), City of Hope Beckman Research Institute, Duarte, CA, United States
| | - Michael Kahn
- Cancer Biology and Molecular Medicine, City of Hope Beckman Research Institute, Duarte, CA, United States
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27
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Kudruk S, Forsyth CM, Dion MZ, Hedlund Orbeck JK, Luo J, Klein RS, Kim AH, Heimberger AB, Mirkin CA, Stegh AH, Artzi N. Multimodal neuro-nanotechnology: Challenging the existing paradigm in glioblastoma therapy. Proc Natl Acad Sci U S A 2024; 121:e2306973121. [PMID: 38346200 PMCID: PMC10895370 DOI: 10.1073/pnas.2306973121] [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: 02/15/2024] Open
Abstract
Integrating multimodal neuro- and nanotechnology-enabled precision immunotherapies with extant systemic immunotherapies may finally provide a significant breakthrough for combatting glioblastoma (GBM). The potency of this approach lies in its ability to train the immune system to efficiently identify and eradicate cancer cells, thereby creating anti-tumor immune memory while minimizing multi-mechanistic immune suppression. A critical aspect of these therapies is the controlled, spatiotemporal delivery of structurally defined nanotherapeutics into the GBM tumor microenvironment (TME). Architectures such as spherical nucleic acids or poly(beta-amino ester)/dendrimer-based nanoparticles have shown promising results in preclinical models due to their multivalency and abilities to activate antigen-presenting cells and prime antigen-specific T cells. These nanostructures also permit systematic variation to optimize their distribution, TME accumulation, cellular uptake, and overall immunostimulatory effects. Delving deeper into the relationships between nanotherapeutic structures and their performance will accelerate nano-drug development and pave the way for the rapid clinical translation of advanced nanomedicines. In addition, the efficacy of nanotechnology-based immunotherapies may be enhanced when integrated with emerging precision surgical techniques, such as laser interstitial thermal therapy, and when combined with systemic immunotherapies, particularly inhibitors of immune-mediated checkpoints and immunosuppressive adenosine signaling. In this perspective, we highlight the potential of emerging treatment modalities, combining advances in biomedical engineering and neurotechnology development with existing immunotherapies to overcome treatment resistance and transform the management of GBM. We conclude with a call to action for researchers to leverage these technologies and accelerate their translation into the clinic.
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Affiliation(s)
- Sergej Kudruk
- Department of Chemistry, Northwestern University, Evanston, IL60208
- International Institute for Nanotechnology, Northwestern University, Evanston, IL60208
| | - Connor M. Forsyth
- Department of Chemistry, Northwestern University, Evanston, IL60208
- International Institute for Nanotechnology, Northwestern University, Evanston, IL60208
| | - Michelle Z. Dion
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA02115
- Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA02139
| | - Jenny K. Hedlund Orbeck
- Department of Chemistry, Northwestern University, Evanston, IL60208
- International Institute for Nanotechnology, Northwestern University, Evanston, IL60208
| | - Jingqin Luo
- The Brain Tumor Center, Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, St. Louis, MO63110
- Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO63110
| | - Robyn S. Klein
- Department of Medicine, Washington University School of Medicine, St. Louis, MO
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO63110
- Department of Neuroscience, Washington University School of Medicine, St. Louis, MO63110
- Center for Neuroimmunology and Neuroinfectious Diseases, Washington University School of Medicine, St. Louis, MO63110
| | - Albert H. Kim
- The Brain Tumor Center, Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, St. Louis, MO63110
- Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO63110
| | - Amy B. Heimberger
- Department of Neurological Surgery, Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL60611
| | - Chad A. Mirkin
- Department of Chemistry, Northwestern University, Evanston, IL60208
- International Institute for Nanotechnology, Northwestern University, Evanston, IL60208
| | - Alexander H. Stegh
- The Brain Tumor Center, Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, St. Louis, MO63110
- Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO63110
| | - Natalie Artzi
- Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA02139
- Department of Medicine, Engineering in Medicine Division, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA02115
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28
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Matkivska R, Samborska I, Maievskyi O. Effect of animal venom toxins on the main links of the homeostasis of mammals (Review). Biomed Rep 2024; 20:16. [PMID: 38144889 PMCID: PMC10739175 DOI: 10.3892/br.2023.1704] [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: 05/31/2023] [Accepted: 11/15/2023] [Indexed: 12/26/2023] Open
Abstract
The human body is affected by environmental factors. The dynamic balance between the organism and its environment results from the influence of natural, anthropogenic and social aspects. The factors of exogenous origin determine development of adaptive changes. The present article summarises the mechanisms of animal venom toxins and homeostasis disruption in the body of mammals. The mechanisms underlying pathological changes are associated with shifts in biochemical reactions. Components of the immune, nervous and endocrine systems are key in the host defense and adaptation processes in response to venom by triggering signalling pathways (PI3kinase pathway, arachidonic acid cascade). Animal venom toxins initiate the development of inflammatory processes, the synthesis of pro-inflammatory mediators (cytokines), ROS, proteolytic enzymes, activate the migration of leukocytes and macrophages. Keratinocytes and endothelial cells act as protective barriers under the action of animal venom toxins on the body of mammals. In addition, the formation of pores in cell membranes, structural changes in cell ion channels are characteristic of the action of animal venom toxins.
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Affiliation(s)
- Ruzhena Matkivska
- Department of Descriptive and Clinical Anatomy, Bogomolets National Medical University, Kyiv 03680, Ukraine
| | - Inha Samborska
- Department of Biological and General Chemistry, National Pirogov Memorial Medical University, Vinnytsya 21018, Ukraine
| | - Oleksandr Maievskyi
- Department of Clinical Medicine, Educational and Scientific Center ‘Institute of Biology and Medicine’ of Taras Shevchenko National University of Kyiv, Kyiv 03127, Ukraine
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Kosianova А, Pak O, Bryukhovetskiy I. Regulation of cancer stem cells and immunotherapy of glioblastoma (Review). Biomed Rep 2024; 20:24. [PMID: 38170016 PMCID: PMC10758921 DOI: 10.3892/br.2023.1712] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 11/24/2023] [Indexed: 01/05/2024] Open
Abstract
Glioblastoma (GB) is one of the most adverse diagnoses in oncology. Complex current treatment results in a median survival of 15 months. Resistance to treatment is associated with the presence of cancer stem cells (CSCs). The present review aimed to analyze the mechanisms of CSC plasticity, showing the particular role of β-catenin in regulating vital functions of CSCs, and to describe the molecular mechanisms of Wnt-independent increase of β-catenin levels, which is influenced by the local microenvironment of CSCs. The present review also analyzed the reasons for the low effectiveness of using medication in the regulation of CSCs, and proposed the development of immunotherapy scenarios with tumor cell vaccines, containing heterogenous cancer cells able of producing a multidirectional antineoplastic immune response. Additionally, the possibility of managing lymphopenia by transplanting hematopoietic stem cells from a healthy sibling and using clofazimine or other repurposed drugs that reduce β-catenin concentration in CSCs was discussed in the present study.
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Affiliation(s)
- Аleksandra Kosianova
- Medical Center, School of Medicine and Life Science, Far Eastern Federal University, Vladivostok 690091, Russian Federation
| | - Oleg Pak
- Medical Center, School of Medicine and Life Science, Far Eastern Federal University, Vladivostok 690091, Russian Federation
| | - Igor Bryukhovetskiy
- Medical Center, School of Medicine and Life Science, Far Eastern Federal University, Vladivostok 690091, Russian Federation
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30
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Mishchenko TA, Turubanova VD, Gorshkova EN, Krysko O, Vedunova MV, Krysko DV. Glioma: bridging the tumor microenvironment, patient immune profiles and novel personalized immunotherapy. Front Immunol 2024; 14:1299064. [PMID: 38274827 PMCID: PMC10809268 DOI: 10.3389/fimmu.2023.1299064] [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: 09/22/2023] [Accepted: 12/11/2023] [Indexed: 01/27/2024] Open
Abstract
Glioma is the most common primary brain tumor, characterized by a consistently high patient mortality rate and a dismal prognosis affecting both survival and quality of life. Substantial evidence underscores the vital role of the immune system in eradicating tumors effectively and preventing metastasis, underscoring the importance of cancer immunotherapy which could potentially address the challenges in glioma therapy. Although glioma immunotherapies have shown promise in preclinical and early-phase clinical trials, they face specific limitations and challenges that have hindered their success in further phase III trials. Resistance to therapy has been a major challenge across many experimental approaches, and as of now, no immunotherapies have been approved. In addition, there are several other limitations facing glioma immunotherapy in clinical trials, such as high intra- and inter-tumoral heterogeneity, an inherently immunosuppressive microenvironment, the unique tissue-specific interactions between the central nervous system and the peripheral immune system, the existence of the blood-brain barrier, which is a physical barrier to drug delivery, and the immunosuppressive effects of standard therapy. Therefore, in this review, we delve into several challenges that need to be addressed to achieve boosted immunotherapy against gliomas. First, we discuss the hurdles posed by the glioma microenvironment, particularly its primary cellular inhabitants, in particular tumor-associated microglia and macrophages (TAMs), and myeloid cells, which represent a significant barrier to effective immunotherapy. Here we emphasize the impact of inducing immunogenic cell death (ICD) on the migration of Th17 cells into the tumor microenvironment, converting it into an immunologically "hot" environment and enhancing the effectiveness of ongoing immunotherapy. Next, we address the challenge associated with the accurate identification and characterization of the primary immune profiles of gliomas, and their implications for patient prognosis, which can facilitate the selection of personalized treatment regimens and predict the patient's response to immunotherapy. Finally, we explore a prospective approach to developing highly personalized vaccination strategies against gliomas, based on the search for patient-specific neoantigens. All the pertinent challenges discussed in this review will serve as a compass for future developments in immunotherapeutic strategies against gliomas, paving the way for upcoming preclinical and clinical research endeavors.
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Affiliation(s)
- Tatiana A. Mishchenko
- Institute of Biology and Biomedicine, National Research Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia
| | - Victoria D. Turubanova
- Institute of Biology and Biomedicine, National Research Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia
- Neuroscience Research Institute, National Research Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia
| | - Ekaterina N. Gorshkova
- Institute of Biology and Biomedicine, National Research Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia
| | - Olga Krysko
- Cell Death Investigation and Therapy Laboratory, Anatomy and Embryology Unit, Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Maria V. Vedunova
- Institute of Biology and Biomedicine, National Research Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia
- Faculty of Biology and Biotechnologies, National Research University Higher School of Economics, Moscow, Russia
| | - Dmitri V. Krysko
- Institute of Biology and Biomedicine, National Research Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia
- Cell Death Investigation and Therapy Laboratory, Anatomy and Embryology Unit, Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
- Department of Pathophysiology, Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
- Cancer Research Institute Ghent, Ghent, Belgium
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31
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Teng F, Cui T, Zhou L, Gao Q, Zhou Q, Li W. Programmable synthetic receptors: the next-generation of cell and gene therapies. Signal Transduct Target Ther 2024; 9:7. [PMID: 38167329 PMCID: PMC10761793 DOI: 10.1038/s41392-023-01680-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 09/22/2023] [Accepted: 10/11/2023] [Indexed: 01/05/2024] Open
Abstract
Cell and gene therapies hold tremendous promise for treating a range of difficult-to-treat diseases. However, concerns over the safety and efficacy require to be further addressed in order to realize their full potential. Synthetic receptors, a synthetic biology tool that can precisely control the function of therapeutic cells and genetic modules, have been rapidly developed and applied as a powerful solution. Delicately designed and engineered, they can be applied to finetune the therapeutic activities, i.e., to regulate production of dosed, bioactive payloads by sensing and processing user-defined signals or biomarkers. This review provides an overview of diverse synthetic receptor systems being used to reprogram therapeutic cells and their wide applications in biomedical research. With a special focus on four synthetic receptor systems at the forefront, including chimeric antigen receptors (CARs) and synthetic Notch (synNotch) receptors, we address the generalized strategies to design, construct and improve synthetic receptors. Meanwhile, we also highlight the expanding landscape of therapeutic applications of the synthetic receptor systems as well as current challenges in their clinical translation.
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Affiliation(s)
- Fei Teng
- University of Chinese Academy of Sciences, Beijing, 101408, China.
| | - Tongtong Cui
- State Key Laboratory of Stem Cell and Regenerative Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
| | - Li Zhou
- University of Chinese Academy of Sciences, Beijing, 101408, China
- State Key Laboratory of Stem Cell and Regenerative Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
| | - Qingqin Gao
- University of Chinese Academy of Sciences, Beijing, 101408, China
- State Key Laboratory of Stem Cell and Regenerative Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
| | - Qi Zhou
- University of Chinese Academy of Sciences, Beijing, 101408, China.
- State Key Laboratory of Stem Cell and Regenerative Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
| | - Wei Li
- University of Chinese Academy of Sciences, Beijing, 101408, China.
- State Key Laboratory of Stem Cell and Regenerative Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
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Goutnik M, Iakovidis A, Still MEH, Moor RSF, Melnick K, Yan S, Abbas M, Huang J, Ghiaseddin AP. Advancements in chimeric antigen receptor-expressing T-cell therapy for glioblastoma multiforme: Literature review and future directions. Neurooncol Adv 2024; 6:vdae025. [PMID: 38486856 PMCID: PMC10939440 DOI: 10.1093/noajnl/vdae025] [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] [Indexed: 03/17/2024] Open
Abstract
Glioblastoma multiforme (GBM) is an aggressive cancer that has been difficult to treat and often requires multimodal therapy consisting of surgery, radiotherapy, and chemotherapy. Chimeric antigen receptor-expressing (CAR-T) cells have been efficacious in treating hematological malignancies, resulting in several FDA-approved therapies. CAR-T cells have been more recently studied for the treatment of GBM, with some promising preclinical and clinical results. The purpose of this literature review is to highlight the commonly targeted antigens, results of clinical trials, novel modifications, and potential solutions for challenges that exist for CAR-T cells to become more widely implemented and effective in eradicating GBM.
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Affiliation(s)
- Michael Goutnik
- Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Alexandria Iakovidis
- Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Megan E H Still
- Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Rachel S F Moor
- Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Kaitlyn Melnick
- Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Sandra Yan
- Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Muhammad Abbas
- Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Jianping Huang
- Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Ashley P Ghiaseddin
- Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, Florida, USA
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33
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Wala JA, Hanna GJ. Chimeric Antigen Receptor T-Cell Therapy for Solid Tumors. Hematol Oncol Clin North Am 2023; 37:1149-1168. [PMID: 37353377 DOI: 10.1016/j.hoc.2023.05.009] [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: 06/25/2023]
Abstract
We review chimeric antigen receptor (CAR) T-cell therapy for solid tumors. We discuss patient selection factors and aspects of clinical management. We describe challenges including physical and molecular barriers to trafficking CAR-Ts, an immunosuppressive tumor microenvironment, and difficulty finding cell surface target antigens. The application of new approaches in synthetic biology and cellular engineering toward solid tumor CAR-Ts is described. Finally, we summarize reported and ongoing clinical trials of CAR-T therapies for select disease sites such as head and neck (including thyroid cancer), lung, central nervous system (glioblastoma, neuroblastoma, glioma), sarcoma, genitourinary (prostate, renal, bladder, kidney), breast and ovarian cancer.
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Affiliation(s)
- Jeremiah A Wala
- Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana Building 2nd Floor, Room 2-140, Boston, MA 02215, USA
| | - Glenn J Hanna
- Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana Building 2nd Floor, Room 2-140, Boston, MA 02215, USA.
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Jin G, Chang Y, Bao X. Generation of chimeric antigen receptor macrophages from human pluripotent stem cells to target glioblastoma. IMMUNO-ONCOLOGY TECHNOLOGY 2023; 20:100409. [PMID: 38192614 PMCID: PMC10772262 DOI: 10.1016/j.iotech.2023.100409] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/10/2024]
Abstract
Background Glioblastoma (GBM) is an aggressive brain tumor giving a poor prognosis with the current treatment options. The advent of chimeric antigen receptor (CAR) T-cell therapy revolutionized the field of immunotherapy and has provided a new set of therapeutic options for refractory blood cancers. In an effort to apply this therapeutic approach to solid tumors, various immune cell types and CAR constructs are being studied. Notably, macrophages have recently emerged as potential candidates for targeting solid tumors, attributed to their inherent tumor-infiltrating capacity and abundant presence in the tumor microenvironment. Materials and methods In this study, we developed a chemically defined differentiation protocol to generate macrophages from human pluripotent stem cells (hPSCs). A GBM-specific CAR was genetically incorporated into hPSCs to generate CAR hPSC-derived macrophages. Results The CAR hPSC-derived macrophages exhibited potent anticancer activity against GBM cells in vitro. Conclusion Our findings demonstrate the feasibility of generating functional CAR-macrophages from hPSCs for adoptive immunotherapy, thereby opening new avenues for the treatment of solid tumors, particularly GBM.
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Affiliation(s)
- G. Jin
- Davidson School of Chemical Engineering, Purdue University, West Lafayette
- Purdue University Center for Cancer Research, West Lafayette, USA
| | - Y. Chang
- Davidson School of Chemical Engineering, Purdue University, West Lafayette
- Purdue University Center for Cancer Research, West Lafayette, USA
| | - X. Bao
- Davidson School of Chemical Engineering, Purdue University, West Lafayette
- Purdue University Center for Cancer Research, West Lafayette, USA
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35
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Liang Y, Xu Q, Gao Q. Advancing CAR-based immunotherapies in solid tumors: CAR- macrophages and neutrophils. Front Immunol 2023; 14:1291619. [PMID: 38090576 PMCID: PMC10715261 DOI: 10.3389/fimmu.2023.1291619] [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: 09/09/2023] [Accepted: 11/13/2023] [Indexed: 12/18/2023] Open
Abstract
Macrophages and neutrophils are the main components of the innate immune system and play important roles in promoting angiogenesis, extracellular matrix remodeling, cancer cell proliferation, and metastasis in the tumor microenvironment (TME). They can also be harnessed to mediate cytotoxic tumor killing effects and orchestrate effective anti-tumor immune responses with proper stimulation and modification. Therefore, macrophages and neutrophils have strong potential in cancer immunotherapy. In this review, we briefly outlined the applications of macrophages or neutrophils in adoptive cell therapies, and focused on chimeric antigen receptor (CAR)-engineered macrophages (CAR-Ms) and neutrophils (CAR-Ns). We summarized the construction strategies, the preclinical and clinical studies of CAR-Ms and CAR-Ns. In the end, we briefly discussed the limitations and challenges of CAR-Ms and CAR-Ns, as well as future research directions to extend their applications in treating solid tumors.
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Affiliation(s)
- Yanling Liang
- Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, China
- Human Phenome Institute, Zhangjiang Fudan International Innovation Center, Fudan University, Shanghai, China
| | - Qumiao Xu
- BGI Research, Hangzhou, China
- BGI Research, Shenzhen, China
| | - Qianqian Gao
- Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, China
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36
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Temple WC, Nix MA, Naik A, Izgutdina A, Huang BJ, Wicaksono G, Phojanakong P, Serrano JAC, Young EP, Ramos E, Salangsang F, Steri V, Xirenayi S, Hermiston M, Logan AC, Stieglitz E, Wiita AP. Framework humanization optimizes potency of anti-CD72 nanobody CAR-T cells for B-cell malignancies. J Immunother Cancer 2023; 11:e006985. [PMID: 38007238 PMCID: PMC10680002 DOI: 10.1136/jitc-2023-006985] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/17/2023] [Indexed: 11/27/2023] Open
Abstract
BACKGROUND Approximately 50% of patients who receive anti-CD19 CAR-T cells relapse, and new immunotherapeutic targets are urgently needed. We recently described CD72 as a promising target in B-cell malignancies and developed nanobody-based CAR-T cells (nanoCARs) against it. This cellular therapy design is understudied compared with scFv-based CAR-T cells, but has recently become of significant interest given the first regulatory approval of a nanoCAR in multiple myeloma. METHODS We humanized our previous nanobody framework regions, derived from llama, to generate a series of humanized anti-CD72 nanobodies. These nanobody binders were inserted into second-generation CD72 CAR-T cells and were evaluated against preclinical models of B cell acute lymphoblastic leukemia and B cell non-Hodgkin's lymphoma in vitro and in vivo. Humanized CD72 nanoCARs were compared with parental ("NbD4") CD72 nanoCARs and the clinically approved CD19-directed CAR-T construct tisangenlecleucel. RNA-sequencing, flow cytometry, and cytokine secretion profiling were used to determine differences between the different CAR constructs. We then used affinity maturation on the parental NbD4 construct to generate high affinity binders against CD72 to test if higher affinity to CD72 improved antitumor potency. RESULTS Toward clinical translation, here we humanize our previous nanobody framework regions, derived from llama, and surprisingly discover a clone ("H24") with enhanced potency against B-cell tumors, including patient-derived samples after CD19 CAR-T relapse. Potentially underpinning improved potency, H24 has moderately higher binding affinity to CD72 compared with a fully llama framework. However, further affinity maturation (KD<1 nM) did not lead to improvement in cytotoxicity. After treatment with H24 nanoCARs, in vivo relapse was accompanied by CD72 antigen downregulation which was partially reversible. The H24 nanobody clone was found to have no off-target binding and is therefore designated as a true clinical candidate. CONCLUSION This work supports translation of H24 CD72 nanoCARs for refractory B-cell malignancies, reveals potential mechanisms of resistance, and unexpectedly demonstrates that nanoCAR potency can be improved by framework alterations alone. These findings may have implications for future engineering of nanobody-based cellular therapies.
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Affiliation(s)
- William C Temple
- Department of Pediatrics, Division of Hematology/Oncology, University of California, UCSF Benioff Children's Hospital, San Francisco, California, USA
- Department of Pediatrics, Division of Allergy, Immunology, and Bone Marrow Transplantation, University of California, UCSF Benioff Children's Hospital, San Francisco, California, USA
- Department of Laboratory Medicine, University of California, San Francisco, California, USA
| | - Matthew A Nix
- Department of Laboratory Medicine, University of California, San Francisco, California, USA
| | - Akul Naik
- Department of Laboratory Medicine, University of California, San Francisco, California, USA
| | - Adila Izgutdina
- Department of Laboratory Medicine, University of California, San Francisco, California, USA
| | - Benjamin J Huang
- Department of Pediatrics, Division of Hematology/Oncology, University of California, UCSF Benioff Children's Hospital, San Francisco, California, USA
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA
| | - Gianina Wicaksono
- Department of Laboratory Medicine, University of California, San Francisco, California, USA
| | - Paul Phojanakong
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA
| | | | - Elizabeth P Young
- Department of Pediatrics, Division of Hematology/Oncology, University of California, UCSF Benioff Children's Hospital, San Francisco, California, USA
| | - Emilio Ramos
- Department of Laboratory Medicine, University of California, San Francisco, California, USA
| | - Fernando Salangsang
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA
| | - Veronica Steri
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA
| | - Simayijiang Xirenayi
- Department of Pediatrics, Division of Hematology/Oncology, University of California, UCSF Benioff Children's Hospital, San Francisco, California, USA
| | - Michelle Hermiston
- Department of Pediatrics, Division of Hematology/Oncology, University of California, UCSF Benioff Children's Hospital, San Francisco, California, USA
- Department of Pediatrics, Division of Allergy, Immunology, and Bone Marrow Transplantation, University of California, UCSF Benioff Children's Hospital, San Francisco, California, USA
| | - Aaron C Logan
- Department of Medicine, Division of Hematology and Blood and Marrow Transplantation, University of California, San Francisco, California, USA
| | - Elliot Stieglitz
- Department of Pediatrics, Division of Hematology/Oncology, University of California, UCSF Benioff Children's Hospital, San Francisco, California, USA
| | - Arun P Wiita
- Department of Laboratory Medicine, University of California, San Francisco, California, USA
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, USA
- Chan Zuckerberg Biohub, San Francisco, California, USA
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37
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Hänsch L, Peipp M, Mastall M, Villars D, Myburgh R, Silginer M, Weiss T, Gramatzki D, Vasella F, Manz MG, Weller M, Roth P. Chimeric antigen receptor T cell-based targeting of CD317 as a novel immunotherapeutic strategy against glioblastoma. Neuro Oncol 2023; 25:2001-2014. [PMID: 37335916 PMCID: PMC10628943 DOI: 10.1093/neuonc/noad108] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Indexed: 06/21/2023] Open
Abstract
BACKGROUND Chimeric antigen receptor (CAR) T cell therapy has proven to be successful against hematological malignancies. However, exploiting CAR T cells to treat solid tumors is more challenging for various reasons including the lack of suitable target antigens. Here, we identify the transmembrane protein CD317 as a novel target antigen for CAR T cell therapy against glioblastoma, one of the most aggressive solid tumors. METHODS CD317-targeting CAR T cells were generated by lentivirally transducing human T cells from healthy donors. The anti-glioma activity of CD317-CAR T cells toward various glioma cells was assessed in vitro in cell lysis assays. Subsequently, we determined the efficacy of CD317-CAR T cells to control tumor growth in vivo in clinically relevant mouse glioma models. RESULTS We generated CD317-specific CAR T cells and demonstrate strong anti-tumor activity against several glioma cell lines as well as primary patient-derived cells with varying CD317 expression levels in vitro. A CRISPR/Cas9-mediated knockout of CD317 protected glioma cells from CAR T cell lysis, demonstrating the target specificity of the approach. Silencing of CD317 expression in T cells by RNA interference reduced fratricide of engineered T cells and further improved their effector function. Using orthotopic glioma mouse models, we demonstrate the antigen-specific anti-tumor activity of CD317-CAR T cells, which resulted in prolonged survival and cure of a fraction of CAR T cell-treated animals. CONCLUSIONS These data reveal a promising role of CD317-CAR T cell therapy against glioblastoma, which warrants further evaluation to translate this immunotherapeutic strategy into clinical neuro-oncology.
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Affiliation(s)
- Lena Hänsch
- Department of Neurology and Brain Tumor Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Matthias Peipp
- Division of Antibody-Based Immunotherapy, Department of Internal Medicine II, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
- Division of Antibody-based Immunotherapy, Christian-Albrechts-University, Kiel, Germany
| | - Maximilian Mastall
- Department of Neurology and Brain Tumor Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Danielle Villars
- Department of Neurology and Brain Tumor Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Renier Myburgh
- Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Manuela Silginer
- Department of Neurology and Brain Tumor Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Tobias Weiss
- Department of Neurology and Brain Tumor Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Dorothee Gramatzki
- Department of Neurology and Brain Tumor Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Flavio Vasella
- Department of Neurology and Brain Tumor Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland
- Department of Neurosurgery, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Markus G Manz
- Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Michael Weller
- Department of Neurology and Brain Tumor Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Patrick Roth
- Department of Neurology and Brain Tumor Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland
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Roth P. Chimeric antigen receptors in the brain: Can we tackle glioblastoma with engineered NK cells? Neuro Oncol 2023; 25:2072-2073. [PMID: 37522296 PMCID: PMC10628930 DOI: 10.1093/neuonc/noad131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Indexed: 08/01/2023] Open
Affiliation(s)
- Patrick Roth
- University Hospital Zurich and University of Zurich, Department of Neurology and Brain Tumor Center, Zurich, Switzerland
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39
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Xia Z, He D, Wu Y, Kwok HF, Cao Z. Scorpion venom peptides: Molecular diversity, structural characteristics, and therapeutic use from channelopathies to viral infections and cancers. Pharmacol Res 2023; 197:106978. [PMID: 37923027 DOI: 10.1016/j.phrs.2023.106978] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 10/23/2023] [Accepted: 10/27/2023] [Indexed: 11/07/2023]
Abstract
Animal venom is an important evolutionary innovation in nature. As one of the most representative animal venoms, scorpion venom contains an extremely diverse set of bioactive peptides. Scorpion venom peptides not only are 'poisons' that immobilize, paralyze, kill, or dissolve preys but also become important candidates for drug development and design. Here, the review focuses on the molecular diversity of scorpion venom peptides, their typical structural characteristics, and their multiple therapeutic or pharmaceutical applications in channelopathies, viral infections and cancers. Especially, the group of scorpion toxin TRPTx targeting transient receptor potential (TRP) channels is systematically summarized and worthy of attention because TRP channels play a crucial role in the regulation of homeostasis and the occurrence of diseases in human. We also further establish the potential relationship between the molecular characteristics and functional applications of scorpion venom peptides to provide a research basis for modern drug development and clinical utilization of scorpion venom resources.
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Affiliation(s)
- Zhiqiang Xia
- School of Biological and Food Processing Engineering, Huanghuai University, Zhumadian, China
| | - Dangui He
- State Key Laboratory of Virology, College of Life Sciences, Shenzhen Research Institute, Wuhan University, Wuhan, China; Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macao; Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macao
| | - Yingliang Wu
- State Key Laboratory of Virology, College of Life Sciences, Shenzhen Research Institute, Wuhan University, Wuhan, China
| | - Hang Fai Kwok
- Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macao; Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macao; MoE Frontiers Science Center for Precision Oncology, University of Macau, Avenida de Universidade, Taipa, Macao.
| | - Zhijian Cao
- State Key Laboratory of Virology, College of Life Sciences, Shenzhen Research Institute, Wuhan University, Wuhan, China; Bio-drug Research Center, Wuhan University, Wuhan, China.
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Tang OY, Binder ZA, O'Rourke DM, Bagley SJ. Optimizing CAR-T Therapy for Glioblastoma. Mol Diagn Ther 2023; 27:643-660. [PMID: 37700186 DOI: 10.1007/s40291-023-00671-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/14/2023] [Indexed: 09/14/2023]
Abstract
Chimeric antigen receptor T-cell therapies have transformed the management of hematologic malignancies but have not yet demonstrated consistent efficacy in solid tumors. Glioblastoma is the most common primary malignant brain tumor in adults and remains a major unmet medical need. Attempts at harnessing the potential of chimeric antigen receptor T-cell therapy for glioblastoma have resulted in glimpses of promise but have been met with substantial challenges. In this focused review, we discuss current and future strategies being developed to optimize chimeric antigen receptor T cells for efficacy in patients with glioblastoma, including the identification and characterization of new target antigens, reversal of T-cell dysfunction with novel chimeric antigen receptor constructs, regulatable platforms, and gene knockout strategies, and the use of combination therapies to overcome the immune-hostile microenvironment.
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Affiliation(s)
- Oliver Y Tang
- Warren Alpert Medical School, Brown University, Providence, RI, 02903, USA
| | - Zev A Binder
- Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Donald M O'Rourke
- Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Stephen J Bagley
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA, 19104, USA.
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Wang Q, Xin X, Dai Q, Sun M, Chen J, Mostafavi E, Shen Y, Li X. Medulloblastoma targeted therapy: From signaling pathways heterogeneity and current treatment dilemma to the recent advances in development of therapeutic strategies. Pharmacol Ther 2023; 250:108527. [PMID: 37703952 DOI: 10.1016/j.pharmthera.2023.108527] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 08/27/2023] [Accepted: 09/05/2023] [Indexed: 09/15/2023]
Abstract
Medulloblastoma (MB) is a major pediatric malignant brain tumor that arises in the cerebellum. MB tumors exhibit highly heterogeneous driven by diverse genetic alterations and could be divided into four major subgroups based on their different biological drivers and molecular features (Wnt, Sonic hedgehog (Shh), group 3, and group 4 MB). Even though the therapeutic strategies for each MB subtype integrate their pathogenesis and were developed to focus on their specific target sites, the unexpected drug non-selective cytotoxicity, low drug accumulation in the brain, and complexed MB tumor microenvironment still be huge obstacles to achieving satisfied MB therapeutic efficiency. This review discussed the current advances in modern MB therapeutic strategy development. Through the recent advances in knowledge of the origin, molecular pathogenesis of MB subtypes and their current therapeutic barriers, we particularly reviewed the current development in advanced MB therapeutic strategy committed to overcome MB treatment obstacles, focusing on novel signaling pathway targeted therapeutic agents and their combination discovery, advanced drug delivery systems design, and MB immunotherapy strategy development.
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Affiliation(s)
- Qiyue Wang
- School of Pharmaceutical Science, Nanjing Tech University, Nanjing 211816, China
| | - Xiaofei Xin
- Center for Research Development and Evaluation of Pharmaceutical Excipients and Generic Drugs, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Qihao Dai
- School of Pharmaceutical Science, Nanjing Tech University, Nanjing 211816, China
| | - Mengjuan Sun
- Center for Research Development and Evaluation of Pharmaceutical Excipients and Generic Drugs, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Jinhua Chen
- Center for Research Development and Evaluation of Pharmaceutical Excipients and Generic Drugs, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Ebrahim Mostafavi
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
| | - Yan Shen
- Center for Research Development and Evaluation of Pharmaceutical Excipients and Generic Drugs, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China.
| | - Xueming Li
- School of Pharmaceutical Science, Nanjing Tech University, Nanjing 211816, China.
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Alsajjan R, Mason WP. Bispecific T-Cell Engagers and Chimeric Antigen Receptor T-Cell Therapies in Glioblastoma: An Update. Curr Oncol 2023; 30:8501-8549. [PMID: 37754534 PMCID: PMC10529026 DOI: 10.3390/curroncol30090619] [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: 05/21/2023] [Revised: 09/04/2023] [Accepted: 09/08/2023] [Indexed: 09/28/2023] Open
Abstract
Glioblastoma is the most common malignant primary brain tumor in adults. The prognosis is extremely poor even with standard treatment of maximal safe resection, radiotherapy, and chemotherapy. Recurrence is inevitable within months, and treatment options are very limited. Chimeric antigen receptor T-cell therapy (CART) and bispecific T-cell engagers (TCEs) are two emerging immunotherapies that can redirect T-cells for tumor-specific killing and have shown remarkable success in hematological malignancies and been under extensive study for application in glioblastoma. While there have been multiple clinical trials showing preliminary evidence of safety and efficacy for CART, bispecific TCEs are still in the early stages of clinical testing, with preclinical studies showing very promising results. However, there are multiple shared challenges that need to be addressed in the future, including the route of delivery, antigen escape, the immunosuppressive tumor microenvironment, and toxicity resulting from the limited choice of tumor-specific antigens. Efforts are underway to optimize the design of both these treatments and find the ideal combination therapy to overcome these challenges. In this review, we describe the work that has been performed as well as novel approaches in glioblastoma and in other solid tumors that may be applicable in the future.
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Affiliation(s)
- Roa Alsajjan
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON M5G 2C1, Canada
- Division of Neurology, Department of Medicine, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia
| | - Warren P. Mason
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON M5G 2C1, Canada
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43
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Liang T, Song Y, Gu L, Wang Y, Ma W. Insight into the Progress in CAR-T Cell Therapy and Combination with Other Therapies for Glioblastoma. Int J Gen Med 2023; 16:4121-4141. [PMID: 37720174 PMCID: PMC10503554 DOI: 10.2147/ijgm.s418837] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 08/02/2023] [Indexed: 09/19/2023] Open
Abstract
Glioblastoma (GBM) is the most common malignant primary brain cancer in adults. It is always resistant to existing treatments, including surgical resection, postoperative radiotherapy, and chemotherapy, which leads to a dismal prognosis and a high relapse rate. Therefore, novel curative therapies are urgently needed for GBM. Chimeric antigen receptor T (CAR-T) cell therapy has significantly improved life expectancy for hematological malignancies patients, and thus it increases the interest in applying CAR-T cell therapy for solid tumors. In the recently published research, it is indicated that there are numerous obstacles to achieve clinical benefits for solid tumors, especially for GBM, because of GBM anatomical characteristics (the blood-brain barrier and suppressive tumor microenvironment) and the tumor heterogeneity. CAR-T cells are difficult to penetrate blood-brain barrier, and immunosuppressive tumor microenvironment (TME), which induces CAR-T cell exhaustion, impairs CAR-T cell therapy response. Moreover, under the pressure of CAR-T cell therapy, the tumor heterogeneity and tumor plasticity drive tumor evolution and therapy resistance, such as antigen escape. Nonetheless, scientists strive for strategies to overcome these hurdles, including novel CAR-T cell designs and regional delivery. For instance, the structure of multi-antigen-targeted CAR-T cells can enrich CAR-T accumulation in tumor TME and eliminate abundant tumor cells to avoid tumor antigen heterogeneity. Additionally, paired with an immune modifier and one or more stimulating domains, different generation of innovations in the structure and manufacturing of CAR-T cells have improved efficacy and persistence. While single CAR-T cell therapy receives limited clinical survival benefit. Compared with single CAR-T cell therapy, the combination therapies have supplemented the treatment paradigm. Combinatorial treatment methods consolidate the CAR-T cells efficacy by regulating the tumor microenvironment, optimizing the CAR structure, targeting the CAR-T cells to the tumor cells, reversing the tumor-immune escape mechanisms, and represent a promising avenue against GBM, based on multiple impressive research. Moreover, exciting results are also reported to be realized through combining effective therapies with CAR-T cells in preclinical and clinical trials samples, have aroused inspiration to explore the antitumor function of combination therapies. In summary, this study aims to summarize the limitation of CAR-T cell therapies and introduces novel strategies to enhance CAR-T cell function as well as prospect the potential of the therapeutic combination.
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Affiliation(s)
- Tingyu Liang
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
| | - Yixuan Song
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
| | - Lingui Gu
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
| | - Yu Wang
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
| | - Wenbin Ma
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
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Nehama D, Woodell AS, Maingi SM, Hingtgen SD, Dotti G. Cell-based therapies for glioblastoma: Promising tools against tumor heterogeneity. Neuro Oncol 2023; 25:1551-1562. [PMID: 37179459 PMCID: PMC10484163 DOI: 10.1093/neuonc/noad092] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Indexed: 05/15/2023] Open
Abstract
Glioblastoma (GBM) is a highly aggressive tumor with a devastating impact on quality-of-life and abysmal survivorship. Patients have very limited effective treatment options. The successes of targeted small molecule drugs and immune checkpoint inhibitors seen in various solid tumors have not translated to GBM, despite significant advances in our understanding of its molecular, immune, and microenvironment landscapes. These discoveries, however, have unveiled GBM's incredible heterogeneity and its role in treatment failure and survival. Novel cellular therapy technologies are finding successes in oncology and harbor characteristics that make them uniquely suited to overcome challenges posed by GBM, such as increased resistance to tumor heterogeneity, modularity, localized delivery, and safety. Considering these advantages, we compiled this review article on cellular therapies for GBM, focusing on cellular immunotherapies and stem cell-based therapies, to evaluate their utility. We categorize them based on their specificity, review their preclinical and clinical data, and extract valuable insights to help guide future cellular therapy development.
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Affiliation(s)
- Dean Nehama
- Department of Internal Medicine, Montefiore Medical Center, New York, New York, USA
| | - Alex S Woodell
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - Spencer M Maingi
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - Shawn D Hingtgen
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - Gianpietro Dotti
- Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
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Farkas S, Cioca D, Murányi J, Hornyák P, Brunyánszki A, Szekér P, Boros E, Horváth P, Hujber Z, Rácz GZ, Nagy N, Tóth R, Nyitray L, Péterfi Z. Chlorotoxin binds to both matrix metalloproteinase 2 and neuropilin 1. J Biol Chem 2023; 299:104998. [PMID: 37394009 PMCID: PMC10477481 DOI: 10.1016/j.jbc.2023.104998] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 06/03/2023] [Accepted: 06/28/2023] [Indexed: 07/04/2023] Open
Abstract
Chlorotoxin (CTX), a scorpion venom-derived 36-residue miniprotein, binds to and is taken up selectively by glioblastoma cells. Previous studies provided controversial results concerning target protein(s) of CTX. These included CLC3 chloride channel, matrix metalloproteinase 2 (MMP-2), regulators of MMP-2, annexin A2, and neuropilin 1 (NRP1). The present study aimed at clarifying which of the proposed binding partners can really interact with CTX using biochemical methods and recombinant proteins. For this purpose, we established two new binding assays based on anchoring the tested proteins to microbeads and quantifying the binding of CTX by flow cytometry. Screening of His-tagged proteins anchored to cobalt-coated beads indicated strong interaction of CTX with MMP-2 and NRP1, whereas binding to annexin A2 was not confirmed. Similar results were obtained with fluorophore-labeled CTX and CTX-displaying phages. Affinity of CTX to MMP-2 and NRP1 was assessed by the "immunoglobulin-coated bead" test, in which the proteins were anchored to beads by specific antibodies. This assay yielded highly reproducible data using both direct titration and displacement approach. The affinities of labeled and unlabeled CTX appeared to be similar for both MMP-2 and NRP1 with estimated KD values of 0.5 to 0.7 μM. Contrary to previous reports, we found that CTX does not inhibit the activity of MMP-2 and that CTX not only with free carboxyl end but also with carboxamide terminal end binds to NRP1. We conclude that the presented robust assays could also be applied for affinity-improving studies of CTX to its genuine targets using phage display libraries.
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Affiliation(s)
| | | | | | | | | | | | - Eszter Boros
- Department of Biochemistry, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Patrik Horváth
- Department of Biochemistry, ELTE Eötvös Loránd University, Budapest, Hungary
| | | | | | | | | | - László Nyitray
- Department of Biochemistry, ELTE Eötvös Loránd University, Budapest, Hungary
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Ji F, Xu L, Long K, Zhang F, Zhang M, Lu X, Xia M, Chen J, Du Y, Tang Y, Wu H, Shi Y, Ma R, Li J, Chen Z, Xu B, Zhang Q, Liang J, Jia S, Hu Z, Guo Z. Rabies virus glycoprotein 29 (RVG29) promotes CAR-T immunotherapy for glioma. Transl Res 2023; 259:1-12. [PMID: 36977441 DOI: 10.1016/j.trsl.2023.03.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 01/28/2023] [Accepted: 03/22/2023] [Indexed: 03/30/2023]
Abstract
Chimeric antigen receptor T cell (CAR-T) therapy has limited efficacy for treating glioma because of the infiltrative nature of the blood-brain barrier (BBB) and T cell exhaustion. Conjugation with rabies virus glycoprotein (RVG) 29 enhances the brain-related efficacy of various agents. Here we assess whether RVG enhances the ability of CAR-T cells to cross the BBB and improves their immunotherapy. We generated 70R CAR-T cells (anti-CD70 CAR-T modified with RVG29) and validated their tumor-killing efficacy in vitro and in vivo. We validated their effects on tumor regression in a human glioma mouse orthotopic xenograft model as well as in patient-derived orthotopic xenograft (PDOX) models. The signaling pathways activated in 70R CAR-T cells were revealed by RNA sequencing. The 70R CAR-T cells we generated showed effective antitumor function against CD70+ glioma cells both in vitro and in vivo. 70R CAR-T cells were better able to cross the BBB into the brain than CD70 CAR-T cells under the same treatment conditions. Moreover, 70R CAR-T cells significantly promote the regression of glioma xenografts and improve the physical characteristics of mice without causing overt adverse effects. RVG modification enables CAR-T cells to cross the BBB, and stimulation with glioma cells induces 70R CAR-T cells to expand in a resting state. The modification of RVG29 has a positive impact on CAR-T therapy for brain tumors and may have potential in CAR-T therapy for glioma.
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Affiliation(s)
- Feng Ji
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China; Zhongda Hospital, Southeast University, Nanjing, China.
| | - Luxia Xu
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China
| | - Kaili Long
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China
| | - Fan Zhang
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China
| | - Miaomiao Zhang
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China
| | - Xiao Lu
- Xiamen University, Xiamen, China
| | - Mingyue Xia
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China
| | - Jiannan Chen
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China
| | - Yu Du
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China
| | - Yong Tang
- Nanjing First Hospital, Nanjing, China
| | - Heming Wu
- Nanjing First Hospital, Nanjing, China
| | - Yan Shi
- Nanjing First Hospital, Nanjing, China
| | - Ruiting Ma
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China
| | - Jun Li
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China
| | - Zhengliang Chen
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China
| | - Bin Xu
- Zhongda Hospital, Southeast University, Nanjing, China
| | - Qi Zhang
- Zhongda Hospital, Southeast University, Nanjing, China
| | - Junqing Liang
- The Affiliated People's Hospital of Inner Mongolia Medical University, Inner Mongolia, China
| | - Shaochang Jia
- Jinling Hospital of Nanjing University, Nanjing, China
| | - Zhigang Hu
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China.
| | - Zhigang Guo
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China.
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Tang F, Wang Y, Zeng Y, Xiao A, Tong A, Xu J. Tumor-associated macrophage-related strategies for glioma immunotherapy. NPJ Precis Oncol 2023; 7:78. [PMID: 37598273 PMCID: PMC10439959 DOI: 10.1038/s41698-023-00431-7] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 07/31/2023] [Indexed: 08/21/2023] Open
Abstract
High-grade glioma is one of the deadliest primary tumors of the central nervous system. Despite the many novel immunotherapies currently in development, it has been difficult to achieve breakthrough results in clinical studies. The reason may be due to the suppressive tumor microenvironment of gliomas that limits the function of specific immune cells (e.g., T cells) which are currently the primary targets of immunotherapy. However, tumor-associated macrophage, which are enriched in tumors, plays an important role in the development of GBM and is becoming a research hotspot for immunotherapy. This review focuses on current research advances in the use of macrophages as therapeutic targets or therapeutic tools for gliomas, and provides some potential research directions.
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Affiliation(s)
- Fansong Tang
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Yuelong Wang
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
| | - Yunhui Zeng
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Anqi Xiao
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Aiping Tong
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, Sichuan, China
| | - Jianguo Xu
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
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Guo C, Yu C, Gao W, Ren D, Zhang Y, Zheng P. A novel classifier combining G protein-coupled receptors and the tumor microenvironment is associated with survival status in glioblastoma. Front Pharmacol 2023; 14:1093263. [PMID: 37560473 PMCID: PMC10407249 DOI: 10.3389/fphar.2023.1093263] [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: 11/08/2022] [Accepted: 07/11/2023] [Indexed: 08/11/2023] Open
Abstract
Background: Numerous studies have highlighted the crucial role of G protein-coupled receptors (GPCRs) in tumor microenvironment (TME) remodeling and their correlation with tumor progression. However, the association between GPCRs and the TME in glioblastoma (GBM) remains largely unexplored. Methods: In this study, we investigated the expression profile of GPCRs in GBM using integrated data from single-cell RNA sequencing and bulk sequencing. Surgical samples obtained from meningioma and GBM patients underwent single-cell RNA sequencing to examine GPCR levels and cell-cell interactions. Tumor microenvironment (TME) score is calculated by the infiltrated immune cells with CIBERSORT. Results: Our findings revealed a predominantly increased expression of GPCRs in GBM, and demonstrated that the classification of GPCRs and TME is an independent risk factor in GBM. Patients with high GPCR expression in the tumor tissue and low TME score exhibited the worst outcomes, suggesting a potentially aggressive tumor phenotype. On the other hand, patients with low GPCR expression in the tumor tissue and high TME score showed significantly better outcomes, indicating a potentially more favorable tumor microenvironment. Furthermore, the study found that T cells with high GPCR levels displayed extensive cell-cell connections with other tumor and immune cells in the single cell RNA analysis, indicating their potential involvement in immune escape. Conclusion: In conclusion, GPCRs in combination with TME classification can serve as prognostic markers for GBM. GPCRs play an essential role in tumor progression and the TME in GBM.
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Affiliation(s)
- Chunyu Guo
- Department of Neurosurgery, Shanghai Pudong New area People’s Hospital, Shanghai, China
| | - Cong Yu
- Department of Neurosurgery, Shanghai Pudong New area People’s Hospital, Shanghai, China
| | - Weizhen Gao
- Department of Neurosurgery, Renji Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Dabin Ren
- Department of Neurosurgery, Shanghai Pudong New area People’s Hospital, Shanghai, China
| | - Yisong Zhang
- Department of Neurosurgery, Shanghai Pudong New area People’s Hospital, Shanghai, China
| | - Ping Zheng
- Department of Neurosurgery, Shanghai Pudong New area People’s Hospital, Shanghai, China
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Wang S, Wei W, Yuan Y, Sun B, Yang D, Liu N, Zhao X. Chimeric antigen receptor T cells targeting cell surface GRP78 efficiently kill glioblastoma and cancer stem cells. J Transl Med 2023; 21:493. [PMID: 37481592 PMCID: PMC10362566 DOI: 10.1186/s12967-023-04330-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 07/07/2023] [Indexed: 07/24/2023] Open
Abstract
BACKGROUND Glioblastoma (GBM) is recognized as among the most aggressive forms of brain tumor. Patients typically present with a five-year survival rate of less than 6% with traditional surgery and chemoradiotherapy, which calls for novel immunotherapies like chimeric antigen receptor T (CAR-T) cells therapy. In response to endoplasmic reticulum (ER) stress in multiple tumor cells including GBM, the glucose-regulated protein 78 (GRP78) expression increases and the protein is partially translocated to the cell surface, while it is restricted to the cytoplasm and the nucleus in normal cells. METHODS In this study, to target the cell surface GRP78 (csGRP78), CAR-T cells based on its binding peptide were generated. In vitro two GBM cell lines and glioma stem cells (GSCs) were used to confirm the localization of csGRP78 and the cytotoxicity of the CAR-T cells. In vivo a GBM xenograft model was used to assess the killing activity and the safety of the CAR-T cells. RESULTS We confirmed the localization of csGRP78 at the cell surface of two GBM cell lines (U-251MG and U-87MG) and in GSCs. Co-culture experiments revealed that the CAR-T cells could specifically kill the GBM tumor cells and GSCs with specific IFN-γ release. Furthermore, in the tumor xenograft model, the CAR-T cells could decrease the number of GSCs and significantly suppress tumor cell growth. Importantly, we found no obvious off-target effects or T cell infiltration in major organs following systemic administration of these cells. CONCLUSIONS The csGRP78 targeted CAR-T cells efficiently kill GBM tumor cells and GSCs both in vitro and in vivo, and ultimately suppress the xenograft tumors growth without obvious tissue injuries. Therefore, our study demonstrates that csGRP78 represents a valuable target and the csGRP78-targeted CAR-T cells strategy is an effective immunotherapy against GBM.
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Affiliation(s)
- Shijie Wang
- Department of Targeting Therapy and Immunology and Laboratory of Animal Tumor Models, Cancer Center and National Clinical Research Center for Geriatrics and Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Wenwen Wei
- Department of Targeting Therapy and Immunology and Laboratory of Animal Tumor Models, Cancer Center and National Clinical Research Center for Geriatrics and Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yuncang Yuan
- Department of Targeting Therapy and Immunology and Laboratory of Animal Tumor Models, Cancer Center and National Clinical Research Center for Geriatrics and Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Bin Sun
- Department of Targeting Therapy and Immunology and Laboratory of Animal Tumor Models, Cancer Center and National Clinical Research Center for Geriatrics and Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Dong Yang
- Department of Targeting Therapy and Immunology and Laboratory of Animal Tumor Models, Cancer Center and National Clinical Research Center for Geriatrics and Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Nan Liu
- Department of Targeting Therapy and Immunology and Laboratory of Animal Tumor Models, Cancer Center and National Clinical Research Center for Geriatrics and Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xudong Zhao
- Department of Targeting Therapy and Immunology and Laboratory of Animal Tumor Models, Cancer Center and National Clinical Research Center for Geriatrics and Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Martin NT, Crupi MJF, Taha Z, Poutou J, Whelan JT, Vallati S, Petryk J, Marius R, Austin B, Azad T, Boulanger M, Burgess T, Sanders I, Victoor C, Dickinson BC, Diallo JS, Ilkow CS, Bell JC. Engineering Rapalog-Inducible Genetic Switches Based on Split-T7 Polymerase to Regulate Oncolytic Virus-Driven Production of Tumour-Localized IL-12 for Anti-Cancer Immunotherapy. Pharmaceuticals (Basel) 2023; 16:ph16050709. [PMID: 37242495 DOI: 10.3390/ph16050709] [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: 03/20/2023] [Revised: 04/15/2023] [Accepted: 05/02/2023] [Indexed: 05/28/2023] Open
Abstract
The approval of different cytokines as anti-neoplastic agents has been challenged by dose-limiting toxicities. Although reducing dose levels affords improved tolerability, efficacy is precluded at these suboptimal doses. Strategies combining cytokines with oncolytic viruses have proven to elicit potent survival benefits in vivo, despite promoting rapid clearance of the oncolytic virus itself. Herein, we developed an inducible expression system based on a Split-T7 RNA polymerase for oncolytic poxviruses to regulate the spatial and temporal expression of a beneficial transgene. This expression system utilizes approved anti-neoplastic rapamycin analogues for transgene induction. This treatment regimen thus offers a triple anti-tumour effect through the oncolytic virus, the induced transgene, and the pharmacologic inducer itself. More specifically, we designed our therapeutic transgene by fusing a tumour-targeting chlorotoxin (CLTX) peptide to interleukin-12 (IL-12), and demonstrated that the constructs were functional and cancer-selective. We next encoded this construct into the oncolytic vaccinia virus strain Copenhagen (VV-iIL-12mCLTX), and were able to demonstrate significantly improved survival in multiple syngeneic murine tumour models through both localized and systemic virus administration, in combination with rapalogs. In summary, our findings demonstrate that rapalog-inducible genetic switches based on Split-T7 polymerase allow for regulation of the oncolytic virus-driven production of tumour-localized IL-12 for improved anti-cancer immunotherapy.
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Affiliation(s)
- Nikolas T Martin
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Mathieu J F Crupi
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Zaid Taha
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Joanna Poutou
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Jack T Whelan
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Sydney Vallati
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Julia Petryk
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
| | - Ricardo Marius
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
| | - Bradley Austin
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
| | - Taha Azad
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Mason Boulanger
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
| | - Tamara Burgess
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
| | - Ilson Sanders
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
| | - Camille Victoor
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
| | - Bryan C Dickinson
- Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA
| | - Jean-Simon Diallo
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Carolina S Ilkow
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - John C Bell
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada
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