Endogenous CD28 drives the persistent activity of CAR T cells in myeloma and lymphoma models

Abstract Chimeric antigen receptor (CAR) T cell therapy has reshaped the therapeutic landscape for multiple myeloma (MM), 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 MM sensitivity to CAR T cell therapy. Contrary to expectations, blockade of CD28 interaction with CD80/86 accelerated tumor regrowth in preclinical MM and lymphoma CAR T therapy models. Knockout studies revealed that endogenous CD28 on 4-1BB co-stimulated 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. 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.