{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T14:17:05Z","timestamp":1781878625123,"version":"3.54.5"},"posted":{"date-parts":[[2024,3,24]]},"group-title":"Cancer Biology","reference-count":91,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,4,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Recent 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 (BB\u03b6) 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 BB\u03b6 CAR T cells drove\n                  <jats:italic>in vivo<\/jats:italic>\n                  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 BB\u03b6 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\n                  <jats:italic>in vivo<\/jats:italic>\n                  function of CAR T cells and indicate that transient CD28 blockade could reduce cytokine release and associated toxicities.\n                <\/jats:p>","DOI":"10.1101\/2024.03.21.586084","type":"posted-content","created":{"date-parts":[[2024,3,24]],"date-time":"2024-03-24T19:24:40Z","timestamp":1711308280000},"source":"Crossref","is-referenced-by-count":5,"title":["Endogenous CD28 drives CAR T cell responses in multiple myeloma"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9480-3589","authenticated-orcid":false,"given":"Mackenzie M.","family":"Lieberman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1795-9480","authenticated-orcid":false,"given":"Jason H.","family":"Tong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nkechi U.","family":"Odukwe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin A.","family":"Chavel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7824-7760","authenticated-orcid":false,"given":"Terence J.","family":"Purdon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0328-2336","authenticated-orcid":false,"given":"Rebecca","family":"Burchett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1403-6456","authenticated-orcid":false,"given":"Bryan M.","family":"Gillard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig M.","family":"Brackett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7145-8444","authenticated-orcid":false,"given":"A. 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