Currently, there are two U.S. Food and Drug Administration–approved chimeric antigen receptor (CAR) T-cell therapies targeting the B-cell maturation antigen (BCMA) for adult patients with relapsed or refractory multiple myeloma: idecabtagene vicleucel and citacabtagene autoleucel. However, although CAR T-cell therapy initially leads to high response rates in this cancer, most patients with multiple myeloma will experience recurrent disease.
In a study by Dhodapkar et al published in Blood Cancer Discovery investigating the determinants of durable responses following BCMA CAR T-cell therapy in patients with multiple myeloma, researchers found that longer progression-free survival after BCMA treatment may depend not just on the properties of the CAR T cells, but also on endogenous T-cell status and properties of the tumor microenvironment.
Study Methodology
The researchers analyzed 28 pre- and posttreatment bone marrow specimens from 11 patients with multiple myeloma who had a clinical response to BCMA-targeted CAR T-cell therapy in a previously reported phase I clinical trial. Samples were analyzed by single-cell approaches, including CITE-seq/transcriptome, mass cytometry, and T-cell receptor sequencing.
Changes in the bone marrow microenvironment were compared between patients with short and long progression-free survival, defined as less that 6 months and greater than 6 months, respectively.
Results
The researchers found that a lower diversity of pretherapy T-cell receptor (TCR) repertoire; the presence of hyperexpanded clones with exhaustion phenotype; and BAFF-positive, PD-L1–positive myeloid cells in the marrow correlated with shorter progression-free survival following CAR T-cell therapy. Alternatively, longer progression-free survival was associated with an increased proportion of CLEC9A-positive dendritic cells (DC); CD27-positive, TCF1-positive T cells with diverse T-cell receptors; and emergence of T cells expressing marrow-residence genes.
Residual tumor cells at initial response express stem-like genes, and tumor recurrence was associated with the emergence of new dominant clones.
These data indicate, according to the researchers, a dynamic interplay between endogenous T, CAR T, myeloid/DC, and tumor compartments that affect the durability of response following CAR T-cell therapy in patients with multiple myeloma.
Clinical Significance
“The major finding of this study is that the durability of response may be dependent on characteristics of non–CAR T cells and other immune cells in the tumor microenvironment,” said Madhav V. Dhodapkar, MBBS, Professor at Emory University School of Medicine, Director of the Center for Cancer Immunology at the Winship Cancer Institute of Emory University, and senior author of this study. “This finding has broad implications for the CAR T-cell therapy field, as it emphasizes the importance of the patient’s pre-existing immune microenvironment as a determinant of durable responses.”
Disclosure: Funding for this study was provided by the National Institutes of Health, the Leukemia & Lymphoma Society, and the Paula and Rodger Riney Foundation. For full disclosures of the study authors, visit aacrjournals.org/bloodcancerdiscov.
