Posted: Thursday, October 30, 2025
An investigation published in Leukemia found that anti-BCMA CAR T-cell therapy for patients with relapsed/refractory multiple myeloma may reduce immune responses over time, diminishing CAR T-cell therapy’s effectiveness. Julia Frede, PhD, of the Dana Farber Cancer Institute in Boston, and colleagues looked at how endogenous CD8+ T cells are remodeled following anti-BCMA CAR-T cell therapy.
The study enrolled 24 patients from the KarMMa‑2 and KarMMa‑3 trials. Samples were obtained prior to treatment, 1 month post-infusion (M2D1), and 6 months post-infusion (M7D1). They were stratified based on patient median progression-free survival into short-term responders (STR) versus long-term responders (LTR) and processed for single-cell RNA sequencing.
At M2D1, STR patients had higher expression of cytolytic and exhaustion markers in endogenous CD8+ T cells, whereas LTR patients displayed stronger memory-like signatures and higher diversity of endogenous T-cell clonotypes. Naïve-like T cells declined at M2D1 and failed to fully recover by M7D1. A transitional CD8+ subset was also identified whose higher abundance correlated with poorer outcomes and lower CAR-T persistence, suggesting it may serve as a predictive biomarker.
“Overall, CAR-T treatment, consisting of lymphodepletion followed by CAR-T cell infusion, appears to induce short-term activation and longer-term changes in the differentiation state of endogenous T cells, marked by a reduction in naïve T cells,” said the study authors. They also advocated for future studies to understand the long-term effects of CAR-T therapy, along with further research into the timing and sequencing of immunotherapies.
Disclosures: The authors reported no conflicts of interest.
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