{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Hammill JA"],"funding":["John Bienenstock Chair in Molecular Medicine","Canadian Cancer Society","Canadian Research Chair in Translational Immunology"],"pagination":["278-292"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC7191649"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["17"],"pubmed_abstract":["Tumor-targeted chimeric antigen receptor (CAR)-engineered T lymphocytes (CAR-T cells) have demonstrated striking clinical success, but their use has been associated with a constellation of toxicities. A better understanding of the pathogenesis of these toxicities is required to improve the safety profile of CAR-T cells. Herein, we describe a xenograft model of off-tumor CAR-T cell-associated toxicity. Human CAR-T cells targeted against HER2 using a small-protein binding domain induced acute, dose-dependent toxicities in mice. The inclusion of a CD28 or 4-1BB co-stimulatory domain in the CAR was required to produce toxicity; however, co-stimulation through CD28 was most toxic on a per-cell basis. CAR-T cell activation in the lungs and heart was associated with a systemic cytokine storm. The"],"journal":["Molecular therapy oncolytics"],"pubmed_title":["A Cross-Reactive Small Protein Binding Domain Provides a Model to Study Off-Tumor CAR-T Cell Toxicity."],"pmcid":["PMC7191649"],"funding_grant_id":["313416","313397"],"pubmed_authors":["Milne K","Bramson JL","Lau VWC","Denisova GF","Dvorkin-Gheva A","Baker C","Hammill JA","Aarts C","Derocher H","Kwiecien JM","Nelson BH","Heslen CW","Wu Y","Bezverbnaya K"],"additional_accession":[]},"is_claimable":false,"name":"A Cross-Reactive Small Protein Binding Domain Provides a Model to Study Off-Tumor CAR-T Cell Toxicity.","description":"Tumor-targeted chimeric antigen receptor (CAR)-engineered T lymphocytes (CAR-T cells) have demonstrated striking clinical success, but their use has been associated with a constellation of toxicities. A better understanding of the pathogenesis of these toxicities is required to improve the safety profile of CAR-T cells. Herein, we describe a xenograft model of off-tumor CAR-T cell-associated toxicity. Human CAR-T cells targeted against HER2 using a small-protein binding domain induced acute, dose-dependent toxicities in mice. The inclusion of a CD28 or 4-1BB co-stimulatory domain in the CAR was required to produce toxicity; however, co-stimulation through CD28 was most toxic on a per-cell basis. CAR-T cell activation in the lungs and heart was associated with a systemic cytokine storm. The","dates":{"release":"2020-01-01T00:00:00Z","publication":"2020 Jun","modification":"2026-05-07T03:16:21.76Z","creation":"2020-05-22T19:18:25Z"},"accession":"S-EPMC7191649","cross_references":{"pubmed":["32368616"],"doi":["10.1016/j.omto.2020.04.001"]}}