3.9 Article

Changes in Bone Marrow Tumor and Immune Cells Correlate with Durability of Remissions Following BCMA CAR T Therapy in Myeloma

Journal

BLOOD CANCER DISCOVERY
Volume 3, Issue 6, Pages -

Publisher

AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2643-3230.BCD-22-0018

Keywords

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Funding

  1. NIH [R35CA197603, 1P01CA214278]
  2. Specialized Center of Research Award from the Leukemia and Lymphoma Society
  3. Paula and Roger Rinney Foundation
  4. LLS Scholar in Clinical Research Award
  5. Novartis
  6. University of Pennsylvania
  7. [CA238471]
  8. [AR077926]
  9. [P30CA138292]

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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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