{"id":"doi:10.1038/s41375-019-0417-9","kind":"article","title":"Constitutively active MyD88/CD40 costimulation enhances expansion and efficacy of chimeric antigen receptor T cells targeting hematological malignancies","authors":["Collinson-Pautz MR","Chang WC","Lu A","Khalil M","Crisostomo JW","Lin PY","Mahendravada A","Shinners NP","Brandt ME","Zhang M","Duong M","Bayle JH","Slawin KM","Spencer DM","Foster AE"],"author_count":15,"year":2019,"published":"2019-02-28","venue":"Leukemia","cited_by":82,"doi":"10.1038/s41375-019-0417-9","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/s41375-019-0417-9","archive_url":"https://space-kitty.com/papers/doi:10.1038/s41375-019-0417-9","updated":null,"pmid":"30816327","pmcid":"PMC6756044","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC6756044/pdf","abstract":"Successful adoptive chimeric antigen receptor (CAR) T-cell therapies against hematological malignancies require CAR-T expansion and durable persistence following infusion. Balancing increased CAR-T potency with safety, including severe cytokine-release syndrome (sCRS) and neurotoxicity, warrants inclusion of safety mechanisms to control in vivo CAR-T activity. Here, we describe a novel CAR-T cell platform that utilizes expression of the toll-like receptor (TLR) adaptor molecule, MyD88, and tumor-necrosis factor family member, CD40 (MC), tethered to the CAR molecule through an intentionally inefficient 2A linker system, providing a constitutive signal that drives CAR-T survival, proliferation, and antitumor activity against CD19 + and CD123 + hematological cancers. Robust activity of MC-enhanced CAR-T cells was associated with cachexia in animal models that corresponded with high levels of human cytokine production. However, toxicity could be successfully resolved by using the inducible caspase-9 (iC9) safety switch to reduce serum cytokines, by administration of a neutralizing antibody against TNF-α, or by selecting \"low\" cytokine-producing CD8 + T cells, without loss of antitumor activity. Interestingly, high basal activity was essential for in vivo CAR-T expansion. This study shows that co-opting novel signaling elements (i.e., MyD88 and CD40) and development of a unique CAR-T architecture can drive T-cell proliferation in vivo to enhance CAR-T therapies.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Constitutively active MyD88/CD40 costimulation enhances expansion and efficacy of chimeric antigen receptor T cells targeting hematological malignancies\" by Collinson-Pautz MR, Chang WC, Lu A et al., https://doi.org/10.1038/s41375-019-0417-9, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.","topics":[{"slug":"gene-cell-therapy","name":"Gene & Cell Therapy","domain_slug":"medicine"}],"cited_in_dossiers":[]}