Abstract 2351: Association of germline genetic variants with CAR T-cell therapy outcomes

Abstract Purpose: CAR T-cell therapy has shown promise in treating B-cell malignancies, but patient responses vary significantly. We hypothesize that germline genetics influence this variability by impacting T-cell programming and consequently CAR T-cell efficacy. This study aims to investigate the association between germline genetics and CAR T-cell therapy outcomes. Materials and Methods: We assembled a retrospective cohort of 108 B-cell lymphoid malignancies patients who were treated with CAR T-cell therapy at the University of Chicago Cell Therapy Biobank from May 2018 to Nov 2023 (IRB approval: IRB23-1114). A comprehensive clinical dataset including demographics, disease characteristics, and post-treatment outcomes was obtained from patients’ electronic health records and clinical notes. DNA samples were extracted from 105 patients’ peripheral blood and underwent low-pass whole-genome sequencing (WGS). Genotype imputation and quality control filtering identified ∼ 11 million genetic variants across the study participants. Polygenic risk scores (PGSs) from the PGS Catalog were calculated to test association of PGSs of major immune diseases with the CAR T-cell treatment response. We used 6-month progression-free survival (PFS) based on clinical evaluation as our primary measure of treatment outcome. Results: Of 98 patients with comprehensive clinical and sequencing data, 55 responded (mean age 61.48 ±12.21 years; 30.91% female) to treatment, while 43 did not respond (mean age 61.60 ±11.28 years; 30.23% female) to treatment. Among clinical covariates, we reproduced a significant association between lactate dehydrogenase (LDH) concentrations and 6-month PFS (adjusted P < .02). We conducted multivariate logistic regression including LDH levels to explore correlations between computed PGSs and CAR T-cell treatment outcomes. PGSs related to type 1 diabetes (T1D) were associated with the CAR T-cell treatment response combining multiple PGSs with Aggregate Cauchy Association Test (ACAT p = 0.016), in contrast to type 2 diabetes (T2D) PGSs that did not show an association. These results suggest the immune component of T1D are specifically associated with CAR T-cell treatment response. Further analysis in larger T1D GWAS is required to substantiate these findings. Conclusion: The association between T1D genetics and the CAR T-cell therapy outcomes suggests germline genetics, particularly autoimmune-related variants, modulate therapy efficacy. These genetic variants may elevate T-cell activation, contributing to autoimmunity but leading to increased CAR T-cell exhaustion and reduced effectiveness. Further research will explore these mechanisms. Integrating genetic insights into patient evaluation and CAR T-cell engineering could improve therapy personalization and clinical outcomes. Citation Format: Salem Werdyani, Xiaotong Sun, Yuanyuan Zha, Peter Riedell, Justin Kline, Xin He, Aly A. Khan. Association of germline genetic variants with CAR T-cell therapy outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2351.