{"doi":"10.1101/2024.03.21.586084","title":"Endogenous CD28 drives CAR T cell responses in multiple myeloma","abstract":"Abstract 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 (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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":485475,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9425,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1058800,"name":"Jason H. Tong","orcid":"0000-0003-1795-9480","position":1,"is_corresponding":false},{"id":1328951,"name":"Nkechi U. Odukwe","orcid":null,"position":2,"is_corresponding":false},{"id":351776,"name":"Colin Chavel","orcid":"0000-0003-1458-8979","position":3,"is_corresponding":false},{"id":1253441,"name":"Terence J. Purdon","orcid":"0009-0009-7824-7760","position":4,"is_corresponding":false},{"id":1328490,"name":"Rebecca Burchett","orcid":"0000-0002-0328-2336","position":5,"is_corresponding":false},{"id":29343,"name":"Bryan M. Gillard","orcid":"0000-0002-1403-6456","position":6,"is_corresponding":false},{"id":397564,"name":"Craig M. Brackett","orcid":"0000-0001-9897-5276","position":7,"is_corresponding":false},{"id":563459,"name":"AJ Robert McGray","orcid":"0000-0002-7145-8444","position":8,"is_corresponding":false},{"id":1328491,"name":"Jonathan L. Bramson","orcid":"0000-0003-2874-6886","position":9,"is_corresponding":false},{"id":243186,"name":"Renier J. Brentjens","orcid":"0000-0002-3364-5388","position":10,"is_corresponding":false},{"id":351783,"name":"Kelvin P. Lee","orcid":"0000-0003-2587-0734","position":11,"is_corresponding":false},{"id":351782,"name":"Scott H. Olejniczak","orcid":"0000-0001-6857-5554","position":12,"is_corresponding":false},{"id":1328950,"name":"M Lieberman","orcid":null,"position":0,"is_corresponding":true}],"reference_count":93,"raw_metadata":null,"created_at":"2026-07-19T02:07:52.536246Z","pmid":"38562904","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}