Department of Medicine III-Hematology/Oncology, University Hospital, LMU Munich, Munich, Germany; German Cancer Consortium (DKTK), Munich Site and German Cancer Research Center, Heidelberg, Germany.
Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, Florida.
Transplant Cell Ther. 2023 Jul;29(7):418-428. doi: 10.1016/j.jtct.2023.04.007. Epub 2023 Apr 17.
Although chimeric antigen receptor (CAR) T cell therapy (CAR-T) has altered the treatment landscape for relapsed/refractory B cell malignancies and multiple myeloma, only a minority of patients attain long-term disease remission. The underlying reasons for CAR-T resistance are multifaceted and can be broadly divided into host-related, tumor-intrinsic, microenvironmental and macroenvironmental, and CAR-T-related factors. Emerging host-related determinants of response to CAR-T relate to gut microbiome composition, intact hematopoietic function, body composition, and physical reserve. Emerging tumor-intrinsic resistance mechanisms include complex genomic alterations and mutations to immunomodulatory genes. Furthermore, the extent of systemic inflammation prior to CAR-T is a potent biomarker of response and reflects a proinflammatory tumor micromilieu characterized by infiltration of myeloid-derived suppressor cells and regulatory T cell populations. The tumor and its surrounding micromilieu also can shape the response of the host to CAR-T infusion and the subsequent expansion and persistence of CAR T cells, a prerequisite for efficient eradication of tumor cells. Here, focusing on both large B cell lymphoma and multiple myeloma, we review resistance mechanisms, explore therapeutic avenues to overcome resistance to CAR-T, and discuss the management of patients who relapse after CAR-T.
尽管嵌合抗原受体 (CAR) T 细胞疗法 (CAR-T) 改变了复发/难治性 B 细胞恶性肿瘤和多发性骨髓瘤的治疗格局，但只有少数患者获得长期疾病缓解。CAR-T 耐药的根本原因是多方面的，可以广泛分为宿主相关、肿瘤内在、微环境和宏观环境以及 CAR-T 相关因素。与 CAR-T 反应相关的新兴宿主相关决定因素与肠道微生物组组成、完整的造血功能、身体成分和体力储备有关。新兴的肿瘤内在耐药机制包括复杂的基因组改变和免疫调节基因的突变。此外，CAR-T 前全身炎症的程度是反应的有力生物标志物，反映了以髓源抑制细胞和调节性 T 细胞群浸润为特征的促炎肿瘤微环境。肿瘤及其周围微环境也可以塑造宿主对 CAR-T 输注的反应以及随后 CAR T 细胞的扩增和持续存在，这是有效清除肿瘤细胞的前提。在这里，我们重点关注大 B 细胞淋巴瘤和多发性骨髓瘤，综述耐药机制，探讨克服 CAR-T 耐药的治疗途径，并讨论 CAR-T 后复发患者的管理。
