在临床前模型中，肥胖会加剧与嵌合抗原受体（CAR）T细胞疗法相关的细胞因子释放综合征（CRS）毒性

Obesity is characterized by a state of meta-inflammation, excess adiposity, and metabolic perturbations. Although generally considered a negative co-morbidity for cancer progression and immune function, our lab has previously shown obesity to exert a beneficial role in the context of immunotherapy, termed the “obesity paradox”, where obese patients derived greater benefit from immune checkpoint inhibition compared to lean counterparts. Chimeric antigen receptor (CAR) T cells have become a transformative immune cellular therapy for hematological malignancies and are being increasingly applied towards solid tumors and autoimmune conditions. Given the pleiotropy of obesity and the widespread usage of CAR therapy, we aimed to assess the role of obesity in CAR T cell function and toxicity using a novel diet-induced obese (DIO) xenograft model. We utilized immunodeficient NOD- scid IL2Rg null (NSG) mice that were fed either a 10% low-fat diet or 60% high-fat diet for four months to generate lean and DIO cohorts, respectively. We observed significant but variable weight gain among the DIO NSG mice compared to lean counterparts. Metabolomic assessment indicated metabolic perturbations in all DIO recipients regardless of adiposity. Interestingly, Raji lymphoma growth was markedly increased in all DIO recipients. We then treated tumor-bearing mice with a tri-specific CD19/CD20/CD22-targeting CAR T cell product on day 9 post-tumor injection, with sub-lethal TBI (135cGy X-ray) conditioning delivered one day prior. Tissues and serum were collected at multiple time-points for flow cytometry immunophenotyping, histopathology, cytokine analysis, and metabolomics as well as imaging for assessment of anti-tumor efficacy. We observed that tumor-bearing DIO mice had comparable anti-tumor effects after CAR therapy and CAR engraftment at various time-points. However, this also coincided with more severe weight loss, increased serum human and mouse pro-inflammatory cytokines (human IL-6, IFNg, TNF; mouse IL-1b, TNF), and mortality in the DIO recipients. This CRS mortality in the DIO recipients precluded ability to assess the CAR recipients long-term for anti-tumor and xenogeneic graft-versus-host disease induction. Overall, we observed negative prognostic effects of obesity on preclinical models of CAR T cells affecting both efficacy and off-target effects. Given the wide application of CAR therapy and high prevalence of obesity, further study of the mechanism driving worse outcomes after treatment and connection to currently available clinical data is warranted.