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

Abstract

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. See related commentary by Graham and Maus, p. 478. This article is highlighted in the In This Issue feature, p. 476.

• Authors: Kavita M Dhodapkar, Adam D Cohen, Akhilesh Kaushal, Alfred L Garfall, Renee Julia Manalo, Allison R Carr, Samuel S McCachren, Edward A Stadtmauer, Simon F Lacey, J Joseph Melenhorst, Carl H June, Michael C Milone, Madhav V Dhodapkar
• Journal: Blood cancer discovery (Blood Cancer Discov) Vol. 3 Issue 6 Pg. 490-501 (11 02 2022) ISSN: 2643-3249 [Electronic] United States
• PMID: 36026513 (Publication Type: Editorial, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural, Comment)
• Copyright: ©2022 American Association for Cancer Research.

Chemical References

• B-Cell Maturation Antigen
• Receptors, Chimeric Antigen

Topics

• Humans
• B-Cell Maturation Antigen (genetics)
• Receptors, Chimeric Antigen (genetics)
• Multiple Myeloma (immunology)
• Bone Marrow (pathology)
• Neoplasm Recurrence, Local
• T-Lymphocytes (immunology)
• Bone Marrow Neoplasms
• Tumor Microenvironment