Advances in CAR T cell therapy: antigen selection, modifications, and current trials for solid tumors
Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of hematologic malignancies, achieving remarkable clinical success with FDA-approved therapies targeting CD19 and BCMA. However, the extension of these successes to solid tumors remains limited due to several intrinsic c...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2025-01-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1489827/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841558663591886848 |
|---|---|
| author | Safwaan H. Khan Safwaan H. Khan Yeonjoo Choi Mysore Veena Mysore Veena John K. Lee John K. Lee Daniel Sanghoon Shin Daniel Sanghoon Shin |
| author_facet | Safwaan H. Khan Safwaan H. Khan Yeonjoo Choi Mysore Veena Mysore Veena John K. Lee John K. Lee Daniel Sanghoon Shin Daniel Sanghoon Shin |
| author_sort | Safwaan H. Khan |
| collection | DOAJ |
| description | Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of hematologic malignancies, achieving remarkable clinical success with FDA-approved therapies targeting CD19 and BCMA. However, the extension of these successes to solid tumors remains limited due to several intrinsic challenges, including antigen heterogeneity and immunosuppressive tumor microenvironments. In this review, we provide a comprehensive overview of recent advances in CAR T cell therapy aimed at overcoming these obstacles. We discuss the importance of antigen identification by emphasizing the identification of tumor-specific and tumor-associated antigens and the development of CAR T therapies targeting these antigens. Furthermore, we highlight key structural innovations, including cytokine-armored CARs, protease-regulated CARs, and CARs engineered with chemokine receptors, to enhance tumor infiltration and activity within the immunosuppressive microenvironment. Additionally, novel manufacturing approaches, such as the Sleeping Beauty transposon system, mRNA-based CAR transfection, and in vivo CAR T cell production, are discussed as scalable solution to improve the accessibility of CAR T cell therapies. Finally, we address critical therapeutic limitations, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and suboptimal persistence of CAR T cells. An examination of emerging strategies for countering these limitations reveals that CRISPR-Cas9-mediated genetic modifications and combination therapies utilizing checkpoint inhibitors can improve CAR T cell functionality and durability. By integrating insights from preclinical models, clinical trials, and innovative engineering approaches, this review addresses advances in CAR T cell therapies and their performance in solid tumors. |
| format | Article |
| id | doaj-art-000e101d9eb84103b1ab99e935ea34cf |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-000e101d9eb84103b1ab99e935ea34cf2025-01-06T06:59:36ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-01-011510.3389/fimmu.2024.14898271489827Advances in CAR T cell therapy: antigen selection, modifications, and current trials for solid tumorsSafwaan H. Khan0Safwaan H. Khan1Yeonjoo Choi2Mysore Veena3Mysore Veena4John K. Lee5John K. Lee6Daniel Sanghoon Shin7Daniel Sanghoon Shin8Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA, United StatesDepartment of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA, United StatesDivision of Hematology/Oncology, Veterans Affairs (VA) Greater Los Angeles Healthcare System, Los Angeles, CA, United StatesDepartment of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA, United StatesDivision of Hematology/Oncology, Veterans Affairs (VA) Greater Los Angeles Healthcare System, Los Angeles, CA, United StatesDepartment of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA, United StatesDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, United StatesDepartment of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA, United StatesDivision of Hematology/Oncology, Veterans Affairs (VA) Greater Los Angeles Healthcare System, Los Angeles, CA, United StatesChimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of hematologic malignancies, achieving remarkable clinical success with FDA-approved therapies targeting CD19 and BCMA. However, the extension of these successes to solid tumors remains limited due to several intrinsic challenges, including antigen heterogeneity and immunosuppressive tumor microenvironments. In this review, we provide a comprehensive overview of recent advances in CAR T cell therapy aimed at overcoming these obstacles. We discuss the importance of antigen identification by emphasizing the identification of tumor-specific and tumor-associated antigens and the development of CAR T therapies targeting these antigens. Furthermore, we highlight key structural innovations, including cytokine-armored CARs, protease-regulated CARs, and CARs engineered with chemokine receptors, to enhance tumor infiltration and activity within the immunosuppressive microenvironment. Additionally, novel manufacturing approaches, such as the Sleeping Beauty transposon system, mRNA-based CAR transfection, and in vivo CAR T cell production, are discussed as scalable solution to improve the accessibility of CAR T cell therapies. Finally, we address critical therapeutic limitations, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and suboptimal persistence of CAR T cells. An examination of emerging strategies for countering these limitations reveals that CRISPR-Cas9-mediated genetic modifications and combination therapies utilizing checkpoint inhibitors can improve CAR T cell functionality and durability. By integrating insights from preclinical models, clinical trials, and innovative engineering approaches, this review addresses advances in CAR T cell therapies and their performance in solid tumors.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1489827/fullCAR T cellsolid tumorsimmunotherapycancerstructuretargets |
| spellingShingle | Safwaan H. Khan Safwaan H. Khan Yeonjoo Choi Mysore Veena Mysore Veena John K. Lee John K. Lee Daniel Sanghoon Shin Daniel Sanghoon Shin Advances in CAR T cell therapy: antigen selection, modifications, and current trials for solid tumors Frontiers in Immunology CAR T cell solid tumors immunotherapy cancer structure targets |
| title | Advances in CAR T cell therapy: antigen selection, modifications, and current trials for solid tumors |
| title_full | Advances in CAR T cell therapy: antigen selection, modifications, and current trials for solid tumors |
| title_fullStr | Advances in CAR T cell therapy: antigen selection, modifications, and current trials for solid tumors |
| title_full_unstemmed | Advances in CAR T cell therapy: antigen selection, modifications, and current trials for solid tumors |
| title_short | Advances in CAR T cell therapy: antigen selection, modifications, and current trials for solid tumors |
| title_sort | advances in car t cell therapy antigen selection modifications and current trials for solid tumors |
| topic | CAR T cell solid tumors immunotherapy cancer structure targets |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1489827/full |
| work_keys_str_mv | AT safwaanhkhan advancesincartcelltherapyantigenselectionmodificationsandcurrenttrialsforsolidtumors AT safwaanhkhan advancesincartcelltherapyantigenselectionmodificationsandcurrenttrialsforsolidtumors AT yeonjoochoi advancesincartcelltherapyantigenselectionmodificationsandcurrenttrialsforsolidtumors AT mysoreveena advancesincartcelltherapyantigenselectionmodificationsandcurrenttrialsforsolidtumors AT mysoreveena advancesincartcelltherapyantigenselectionmodificationsandcurrenttrialsforsolidtumors AT johnklee advancesincartcelltherapyantigenselectionmodificationsandcurrenttrialsforsolidtumors AT johnklee advancesincartcelltherapyantigenselectionmodificationsandcurrenttrialsforsolidtumors AT danielsanghoonshin advancesincartcelltherapyantigenselectionmodificationsandcurrenttrialsforsolidtumors AT danielsanghoonshin advancesincartcelltherapyantigenselectionmodificationsandcurrenttrialsforsolidtumors |