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

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.