淋巴瘤
医学
多发性骨髓瘤
免疫学
癌症研究
T细胞
促炎细胞因子
生物
炎症
免疫系统
嵌合抗原受体
作者
Kai Rejeski,Michael D. Jain,Eric L. Smith
标识
DOI:10.1016/j.jtct.2023.04.007
摘要
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.
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