Endogenous CD28 Drives the Persistent Activity of CAR T Cells in Myeloma and Lymphoma Models

作者：M Lieberman, Jason H. Tong, Nkechi U. Odukwe, Colin Chavel, Gina Bishara, Kimberly M. Crasti, Megan Herr, Payal Goala, Terence J. Purdon, Rebecca Burchett, Bryan M. Gillard, Craig M. Brackett, Joseph D. Tario, Spencer R. Rosario, AJ Robert McGray, Jonathan L. Bramson, Marco L. Davila, Renier J. Brentjens, Ehsan Malek, Kelvin P. Lee, Scott H. Olejniczak · 发表于：Blood Cancer Discovery · 年份：2026 · DOI：10.1158/2643-3230.bcd-25-0092 · 被引用次数：1 · 研究领域：CAR-T cell therapy research、Multiple Myeloma Research and Treatments、Immunotherapy and Immune Responses

Chimeric antigen receptor (CAR) T-cell therapy has reshaped the therapeutic landscape for multiple myeloma, yet most patients treated with BCMA-targeted CAR T cells experience disease relapse. Consequently, we sought to determine if inhibition of CD28 survival signaling could increase multiple myeloma sensitivity to CAR T-cell therapy. Contrary to expectations, blockade of CD28 interaction with CD80/86 accelerated tumor regrowth in preclinical multiple myeloma and lymphoma CAR T-cell therapy models. Knockout studies revealed that endogenous CD28 on 4-1BB costimulated CAR T cells prolonged in vivo activity, reprogrammed mitochondrial metabolism to maintain redox balance, and stimulated proliferation and release of tumor model-specific inflammatory cytokines in the tumor microenvironment (TME). Intriguingly, transient CD28 blockade decreased levels of certain TME cytokines without significantly affecting survival of CAR T cell-treated mice. Collectively, these data provide direct evidence that endogenous CD28 signaling modulates CAR T-cell responses in multiple myeloma and lymphoma models. SIGNIFICANCE: This study provides direct evidence that endogenous CD28 on 4-1BB costimulated CAR T cells promotes cytotoxic activity and the production of inflammatory cytokines in the TME. These findings have important implications for ongoing efforts to improve CAR T-cell therapy for the treatment of hematologic malignancies. See related commentary by Hamieh and Sadelain, p. 343.