CD4⁺ T cells mediate CAR-T cell-associated immune-related adverse events after BCMA CAR-T cell therapy

Area of Science:

• Immunotherapy
• Oncology
• Cellular Therapy

Background:

• B cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T cell therapy offers a revolutionary treatment for multiple myeloma.
• This therapy can lead to unique toxicities, collectively termed CAR T cell therapy-associated immune-related adverse events (CirAEs), including neurological and gastrointestinal complications.

Purpose of the Study:

• To investigate the incidence, risk factors, and underlying mechanisms of CirAEs in patients undergoing BCMA-targeted CAR T cell therapy.
• To identify potential therapeutic targets for managing these adverse events.

Main Methods:

• Retrospective analysis of 198 patients treated with specific BCMA-targeted CAR T cell therapies (ciltacabtagene autoleucel or idecabtagene vicleucel) between June 2021 and December 2024.
• Analysis of clinical data, including adverse event occurrence, lymphocyte counts, apheresis ratios, and tissue infiltration.
• In vitro studies to assess the role of CCR5 inhibition in mitigating CAR T cell expansion.

Main Results:

• Twenty-seven patients (13.6%) developed CirAEs, with one case experiencing three distinct CirAEs linked to extreme CD4+ CAR T cell expansion.
• CirAEs were significantly associated with higher non-relapse mortality (HR=5.2, P=0.006).
• Independent risk factors for CirAEs included specific CAR T cell products, high peak absolute lymphocyte count post-infusion, and a high apheresis CD4:CD8 ratio. Marked CD4+ CAR T cell infiltration was observed in affected tissues.

Conclusions:

• CD4+ CAR T cell expansion and infiltration are key mediators of CirAEs in BCMA-targeted CAR T cell therapy.
• Identifying risk factors and understanding the role of CD4+ T cells are crucial for managing these severe toxicities.
• CCR5 inhibition shows potential for abrogating extreme CAR T cell expansion in vitro.