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Short-Lived Responses to Anti-BCMA CAR T-Cell Therapy in Patients With MM Associated With Increased Cytotoxic CD4+ CAR T Cells

June 6, 2024

July 2024

Anna Azvolinsky, PhD

Anna Azvolinsky, PhD, is a freelance medical and science journalist based in New York City.

The persistence of B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T cells is associated with a longer duration of clinical response among patients with relapsed or refractory multiple myeloma (R/R MM) who are treated with idecabtagene vicleucel (ide-cel). Additionally, exhaustion of CD4+ CAR T cells was linked to poorer clinical outcomes among these patients. These results, from a single-cell sequencing study of patient blood and bone marrow samples, were published in Blood Advances.1

“We found that exhaustion of CD4+ CAR T cells, and not CD8+ CAR T cells, was associated with worse clinical outcomes among the patients with MM we studied, and that transforming growth factor-beta (TGF-β) in the tumor niche contributes to exhaustion of these CD4+ CAR T cells in patients treated with anti-BCMA CAR T cells,” said Lawrence Fong, MD, scientific director of the Immunotherapy Integrated Research Center at Fred Hutchinson Cancer Center in Seattle.

Two anti-BCMA CAR T-cell therapies are currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with MM. Ide-cel was initially approved by the FDA in March 2021 for the treatment of patients with R/R MM who have received at least four prior lines of therapy; it was approved in April 2024 for patients with R/R MM after two or more lines of therapy following exposure to three main classes of treatment. In February 2022, the FDA approved ciltacabtagene autoleucel (cilta-cel) for patients with R/R MM after four or more lines of therapy.

While these therapies have exhibited a 75% to 85% response rate among patients with MM, fewer patients achieve long-term remission.2 To begin to understand the factors associated with a long response to anti-BCMA CAR-T cell therapy in patients with R/R MM, Dr. Fong and his colleagues performed single-cell sequencing of T cells, as well as non-T-cell immune cells using 78 longitudinal bone marrow and blood samples, including prior-to-therapy infusion, from 15 patients who had received ide-cel. Patients were grouped into either the transient responder group if they had a response for less than six months, or a durable responder group if they had at least a partial response of six months or longer. T-cell samples from five individuals undergoing hip replacement surgery due to osteoarthritis were analyzed as controls.

“This was an unbiased experimental approach, so this let us see what changes were associated with outcome, rather than us focusing on a specific cell population,” Dr. Fong said.

The analysis showed that for patients in the transient responder group, there was an enrichment of CD4+ cytotoxic CAR T cells with an exhausted phenotype early post-infusion, between days 14 and 30, compared to the durable response patients (p=0.0303). The team also showed that TGF-β contributed to the CD4+ CAR T-cell exhaustion as TGF-β significantly reduced proliferation of these cells. The CAR T cells expressing exhaustion markers were functionally exhausted, with decreased ability to secrete key cytokines including interferon‐gamma and TGF-β. There was no difference in the exhaustion profile of non-CAR CD4+ or CD8+ T cells.

“We usually think about CD8+ T cells as being the cytotoxic cells and most relevant for clinical outcomes. Our findings that, instead, it was the CD4+ CAR T cells that associated with clinical outcome was unexpected,” Dr. Fong said.

Limitations of the study include the relatively small number of patients studied and that only patients treated with one anti-BCMA CAR T-cell therapy, ide-cel, were analyzed. Additional studies are needed to know how applicable these results are for patients treated with other CAR T-cell therapies.

According to Dr. Fong, if the results are validated, blocking CD4+ CAR T-cell exhaustion with a TGF-β blocker or armoring CAR T cells with TGF-β to resist exhaustion are potential ways to extend the effectiveness of CAR T-cell therapy.

Any conflicts of interest declared by the authors can be found in the original article.

References

  1. Lederor G, Fan Z, Wu K, et al. CD4+ CAR-T cell exhaustion associated with early relapse of multiple myeloma after BCMA CAR-T cell therapy [published online ahead of print, 2024 April 4]. Blood Adv. doi: 10.1182/bloodadvances.2023012416.
  2. Dhakal B, Hari PN, Usmani SZ, et al. Chimeric antigen receptor T cell therapy in multiple myeloma: promise and challenges. Bone Marrow Transplant. 2021;56(1):9-19.

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