Factors Unrelated to CAR-T Cells May Influence BCMA Therapy Response in Patients With Myeloma

By Cameron Kelsall, MD /alert Contributor
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Changes in the tumor immune microenvironment of patients with multiple myeloma may indicate which patients will achieve durable progression-free survival after treatment with B-cell maturation antigen (BCMA) targeted CAR T-cell therapy, according to study results published in Blood Cancer Discovery.

Factors associated with longer PFS included a diverse T-cell repertoire at baselines, less evidence of immune cell exhaustion and changes to the immune cell population, suggesting that cellular activity beyond CAR T cells influences response to therapy.

“Two CAR T-cell therapies targeting the BCMA are now approved for the treatment of myeloma, but the challenge is that many of the responses to this therapy are not durable, and patients remain at risk for recurrence,” said Madhav V. Dhodapkar, MBBS, director of the Center for Cancer Immunology at the Winship Cancer Institute of Emory University, in a press release. “A key goal in the field is to identify the factors that influence the durability of response so that we can improve treatment accordingly.”

Dhodapkar and colleagues had access to 28 bone marrow samples collected from 11 patients treated with BCMA–targeted therapy in a previous phase 1 study. The specimens were collected prior to and following treatment, and all patients achieved an initial response to therapy.

The researchers sought to determine whether differences in the bone marrow microenvironment were present in patients with short-term PFS, which they defined as an interval lasting less than 6 months (n = 7; median length, 125 days; range, 57-150); and long-term PFS, which was defined as an interval greater than 6 months (n = 4; median length, 752 days; range, 190-1053).

In total, 23 samples underwent cellular indexing of transcriptomes and epitomes by sequencing and single-cell transcriptomics, and 24 cells underwent mass cytometry. Dhodapkar and colleagues compared sequencing results with the length of PFS to determine a connection with treatment durability.

The researchers did not observe a significant difference in peripheral blood CAR T-cell vector copy number at peak expansion or at 28 days post-infusion, and all patients achieved a significant decline in tumor cells at day 28 in comparison to baseline samples (P = .03).

The proportion of T-cells at day 28, however, was higher in patients with long-term PFS when compared to patients with short-term PFS (62% vs. 21%). Patients with long-term PFS also had declining levels of myeloid cells over time, which was not observed in patients with short-term PFS. These findings suggest that the continued proliferation of myeloid cells could drive early recurrence following initial response to therapy.

Factors present in the baseline samples also correlated with longer PFS. These factors, which existed outside of CAR T cells, included greater diversity of T-cell receptors, increased tumor expression of interferon response and mature plasma genes, and decreased expression of genes related to the epithelial-to-mesenchymal transition.

“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 Dhodapkar. “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.” 

Study limitations included the small sample size and the external examination of immune cells, which did not allow for observation within the tumor microenvironment.

“As a field, we need to pursue similar analyses of bone marrow cells from patients receiving commercially available BCMA–targeted CAR T-cell therapies to allow us to home in on those factors that remain most important for determining response durability,” said Adam D. Cohen, MD, director of myeloma immunotherapy and associate professor of medicine at the Hospital of the University of Pennsylvania.

Disclosures: Dhodapkar declared no financial ties to drugmakers. Cohen declared financial ties to drugmakers. See full study for details. 



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