Chimeric antigen receptor T-cell (CAR-T) therapy is a transformative treatment for relapsed or refractory hematologic cancers. However, outcomes are variable, and predictors of toxicity and mortality remain poorly understood. Emerging evidence suggests that the gut microbiome modulates immune responses to immunotherapy. Proton pump inhibitors (PPIs), commonly used for gastrointestinal protection, are known to disrupt gut microbial composition and have been implicated in worse outcomes in checkpoint inhibitor therapy. This study aims to examine the impact of peri-treatment PPI exposure on all-cause mortality, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and septic shock in CAR-T recipients. Using a large retrospective cohort from linked UK Biobank clinical data, we will identify patients who underwent CAR-T therapy and classify them by PPI exposure within 30 days before and after treatment. Primary outcomes include all-cause mortality at 3, 6, and 12 months; secondary outcomes include CRS, ICANS, septic shock, and ICU admission. Propensity score matching will be applied to balance confounders, and survival analyses will be conducted using Cox regression models. This study will enhance our understanding of modifiable risk factors in CAR-T therapy, supporting microbiome-conscious clinical decisions and future prospective trials.
