Pathology associated with human CAR T cell administration in NOD.Cg- <i>Prkdc</i> ^<i>scid</i> <i>Il2rg</i> ^{<i>tm1Wjl</i>} /SzJ (NSG) mice: A retrospective analysis

Chimeric antigen receptor (CAR) T-cell therapy is a promising treatment for neoplasia and autoimmune diseases. Immunocompromised mice are a common model to test the efficacy and safety of CAR T cells of human origin. Preclinical toxicity associated with human CAR T-cell products encompasses a spectrum of morphologic changes, with currently limited documentation in the scientific literature. The purpose of this retrospective study was to characterize the histopathologic features associated with human CAR T-cell administration in immunodeficient NOD.Cg-<i>Prkdc</i>^<i>scid</i> <i>Il2rg</i>^{<i>tm1Wjl</i>}/SzJ (NSG) mice (<i>n</i> = 392) submitted to 3 different academic institutions in the United States between 2017 and 2024. Lesions were categorized into xenogeneic graft-versus-host disease (xGvHD) (<i>n</i> = 287), aberrant proliferation of human T cells (<i>n</i> = 188), vascular pathologies (<i>n</i> = 66), on-target/off-tumor (OTOT) toxicity (<i>n</i> = 44), immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) in mice previously humanized with human CD34+ hematopoietic stem cells (HSCs) (<i>n</i> = 21), and acute lysis syndrome (ALS) (<i>n</i> = 5). This study provides veterinary pathologists with descriptive guidance on the pathology associated with human CAR T-cell therapy in immunodeficient mice. Additional molecular data and detailed information related to each construct are necessary to further investigate the translatability of such liabilities to the clinical setting.