期刊
BLOOD CANCER DISCOVERY
卷 3, 期 6, 页码 -出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2643-3230.BCD-22-0018
关键词
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资金
- NIH [R35CA197603, 1P01CA214278]
- Specialized Center of Research Award from the Leukemia and Lymphoma Society
- Paula and Roger Rinney Foundation
- LLS Scholar in Clinical Research Award
- Novartis
- University of Pennsylvania
- [CA238471]
- [AR077926]
- [P30CA138292]
This study combined multiple approaches to study the tumor/immune cells in the tumor microenvironment of myeloma patients before and after BCMA CAR T therapy. The findings suggest that lower diversity of T-cell receptor repertoire, presence of hyperexpanded clones and exhausted phenotype, as well as the presence of specific cells in the bone marrow are associated with shorter progression-free survival following therapy. Conversely, longer progression-free survival is associated with an increased proportion of certain cells and the emergence of cells expressing marrow-residence genes. Tumor recurrence is associated with the emergence of new dominant clones.
Chimeric antigen-receptor (CAR) T cells lead to high response rates in myeloma, but most patients experience recurrent disease. We combined several high-dimensional approaches to study tumor/immune cells in the tumor microenvironment (TME) of myeloma patients pre- and post-B-cell maturation antigen (BCMA)-specific CAR T therapy. Lower diversity of pretherapy T-cell receptor (TCR) repertoire, presence of hyperexpanded clones with exhaustion phenotype, and BAFF(+)PD-L1(+) myeloid cells in the marrow correlated with shorter progression-free survival (PFS) following CAR T therapy. In contrast, longer PFS was associated with an increased proportion of CLEC9A(+) dendritic cells (DC), CD27(+)TCF1(+) T cells with diverse T-cell receptors, and emergence of T cells expressing marrow-residence genes. Residual tumor cells at initial response express stemlike genes, and tumor recurrence was associated with the emergence of new dominant clones. These data illustrate a dynamic interplay between endogenous T, CAR T, myeloid/DC, and tumor compartments that affects the durability of response following CAR T therapy in myeloma. SIGNIFICANCE: There is an unmet need to identify determinants of durable responses following BCMA CAR T therapy of myeloma. High-dimensional analysis of the TME was performed to identify features of immune and tumor cells that correlate with survival and suggest several strategies to improve outcomes following CAR T therapy.
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