biostudies-literatureHammill JAJohn Bienenstock Chair in Molecular MedicineCanadian Cancer SocietyCanadian Research Chair in Translational Immunology278-292https://www.ebi.ac.uk/biostudies/studies/S-EPMC7191649biostudies-literatureUnknown17Tumor-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. TheMolecular therapy oncolyticsA Cross-Reactive Small Protein Binding Domain Provides a Model to Study Off-Tumor CAR-T Cell Toxicity.PMC7191649313416313397Milne KBramson JLLau VWCDenisova GFDvorkin-Gheva ABaker CHammill JAAarts CDerocher HKwiecien JMNelson BHHeslen CWWu YBezverbnaya KfalseA Cross-Reactive Small Protein Binding Domain Provides a Model to Study Off-Tumor CAR-T Cell Toxicity.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. The2020-01-01T00:00:00Z2020 Jun2026-05-07T03:16:21.76Z2020-05-22T19:18:25ZS-EPMC71916493236861610.1016/j.omto.2020.04.001