Limitations of CAR-T-Cell Therapy in Hematologic Malignancies: Focusing on Antigen Escape and T-Cell Dysfunction
Abstract
1. Introduction
2. CAR-T-Cell Therapy and the Functional Mechanism
3. Targets for CAR-T-Cell Therapy in Hematologic Malignancies
3.1. Targets for B-Cell Neoplasms
3.2. Targets for T-Cell Lymphoblastic Leukemia/Lymphoma
3.3. Targets for Hodgkin Lymphoma (HL)
3.4. Targets for Acute Myeloid Leukemia (AML)
3.5. CAR-T-Cell Therapy in Multiple Myeloma (MM)
4. Limitations of CAR-T-Cell Therapy in Hematologic Tumor Treatment
4.1. Antigen Escape
4.2. T-Cell Dysfunction
5. Therapeutic Strategies by Targeting Antigen Escape and T-Cell Dysfunction
5.1. Multi-Targeted CAR-T Therapy
5.2. Genetic Engineering to Optimize CAR-T-Cell Function
5.3. Enhancing CAR-T In Vivo Persistence and Targeting
6. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Target | Therapeutic Strategies | Disease | Study Phase | Response | Reference |
---|---|---|---|---|---|
CD19 | Anti-CD19 CAR-T | R/R B-ALL | Phase 1 trial, FDA- approved | ORR 81% (61/75), CR 60% (45/75) | [18] |
CD22 | Anti-CD22 CAR-T | R/R B-ALL | Phase 1 trial | CR 73% (11/15) | [49] |
CD38 | Anti-CD38 CAR-T | R/R AML | Phase 1 trial | ORR 66.7% (4/6), CR 16.7% (1/6) | [73] |
BCMA | Anti-BCMA CAR-T | R/R MM | Phase 1 trial | ORR 100% (18/18), CR 72.2% (13/18) | [79] |
GPRC5D | Anti-GPRC5D CAR-T | R/R MM | Phase 1 trial | ORR 71% (12/17), CR 35% (6/17) | [82] |
CD22 + CD19 | Bispecific CAR-T | R/R B-ALL | IIT, Case reports | long-term remission | [142] |
CD19 + CD20 | Bispecific CAR-T | NHL | Phase 1 trial | ORR 90% (9/10), CR 70% (7/10) | [143] |
CD19 + CD123 | Combination, Bispecific CAR-T | B-ALL | Preclinical studies | Prevented antigen-loss relapses | [144] |
CD19 + CD22 | Bispecific CAR-T | B-ALL, LBCL | Phase 1 trial | B-ALL, ORR 100% (15/17), CR 88% (15/17); LBCL, ORR 62% (13/21), CR 29% (6/21); | [9] |
BCMA + CD38 | Bispecific CAR-T | MM | Phase 1 trial | ORR 87% (20/23), CR 52% (12/23) | [145] |
BCMA + CD38 | Bispecific CAR-T | MM | IIT | ORR 87.5% (14/16), CR 81% (13/16) | [146] |
CD19 + CD20 | Bispecific CAR-T | DLBCL, MCL, FL, CLL | Phase 1 trial | DLBCL, ORR 91% (10/11), CR 64% (7/11); FL, ORR 100% (1/1), CR 100% (1/1); MCL, ORR 57% (4/7), CR 57% (4/7); CLL, ORR 100% (3/3), CR 66% (2/3) | [147] |
CD19 + CD22 | Bispecific CAR-T | B-ALL | Phase 1 trial | B-ALL, ORR 86% (13/15) | [11] |
BCMA + GPRC5D | Bispecific CAR-T | R/R MM | Phase 1 trial | ORR 86% (18/21), CR 62% (13/21) | [17] |
BCMA + GPRC5D | Bispecific CAR-T | R/R MM | Phase 1 trial | ORR 100% (9/9), CR 44.4% (4/9) | [148] |
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Lin, Y.; Luo, S.; Wei, J.; Lin, S.; Wang, D.; Zhao, X.; Feng, Z.; Shen, Y.; Chen, Q. Limitations of CAR-T-Cell Therapy in Hematologic Malignancies: Focusing on Antigen Escape and T-Cell Dysfunction. Int. J. Mol. Sci. 2025, 26, 9669. https://doi.org/10.3390/ijms26199669
Lin Y, Luo S, Wei J, Lin S, Wang D, Zhao X, Feng Z, Shen Y, Chen Q. Limitations of CAR-T-Cell Therapy in Hematologic Malignancies: Focusing on Antigen Escape and T-Cell Dysfunction. International Journal of Molecular Sciences. 2025; 26(19):9669. https://doi.org/10.3390/ijms26199669
Chicago/Turabian StyleLin, Yanyu, Shuqi Luo, Jianhui Wei, Shujin Lin, Dawei Wang, Xiangqian Zhao, Zexin Feng, Yangkun Shen, and Qi Chen. 2025. "Limitations of CAR-T-Cell Therapy in Hematologic Malignancies: Focusing on Antigen Escape and T-Cell Dysfunction" International Journal of Molecular Sciences 26, no. 19: 9669. https://doi.org/10.3390/ijms26199669
APA StyleLin, Y., Luo, S., Wei, J., Lin, S., Wang, D., Zhao, X., Feng, Z., Shen, Y., & Chen, Q. (2025). Limitations of CAR-T-Cell Therapy in Hematologic Malignancies: Focusing on Antigen Escape and T-Cell Dysfunction. International Journal of Molecular Sciences, 26(19), 9669. https://doi.org/10.3390/ijms26199669