Lieberman, Mackenzie M.Tong, Jason H.Odukwe, Nkechi U.Chavel, Colin A.Purdon, Terence J.Burchett, RebeccaGillard, Bryan M.Brackett, Craig M.McGray, A. J. RobertBramson, Jonathan L.Brentjens, Renier J.Lee, Kelvin P.Olejniczak, Scott H.2024-07-112024-07-112024-04-09Lieberman MM, Tong JH, Odukwe NU, et al. Endogenous CD28 drives CAR T cell responses in multiple myeloma. Preprint. bioRxiv. 2024;2024.03.21.586084. Published 2024 Apr 9. doi:10.1101/2024.03.21.586084https://hdl.handle.net/1805/42138Recent FDA approvals of chimeric antigen receptor (CAR) T cell therapy for multiple myeloma (MM) have reshaped the therapeutic landscape for this incurable cancer. In pivotal clinical trials B cell maturation antigen (BCMA) targeted, 4-1BB co-stimulated (BBζ) CAR T cells dramatically outperformed standard-of-care chemotherapy, yet most patients experienced MM relapse within two years of therapy, underscoring the need to improve CAR T cell efficacy in MM. We set out to determine if inhibition of MM bone marrow microenvironment (BME) survival signaling could increase sensitivity to CAR T cells. In contrast to expectations, blocking the CD28 MM survival signal with abatacept (CTLA4-Ig) accelerated disease relapse following CAR T therapy in preclinical models, potentially due to blocking CD28 signaling in CAR T cells. Knockout studies confirmed that endogenous CD28 expressed on BBζ CAR T cells drove in vivo anti-MM activity. Mechanistically, CD28 reprogrammed mitochondrial metabolism to maintain redox balance and CAR T cell proliferation in the MM BME. Transient CD28 inhibition with abatacept restrained rapid BBζ CAR T cell expansion and limited inflammatory cytokines in the MM BME without significantly affecting long-term survival of treated mice. Overall, data directly demonstrate a need for CD28 signaling for sustained in vivo function of CAR T cells and indicate that transient CD28 blockade could reduce cytokine release and associated toxicities.en-USAttribution-NonCommercial-NoDerivatives 4.0 InternationalCD28Co-stimulationCAR T cellsMultiple myelomaTumor microenvironmentMetabolismArticle