CT-018: Germline Immune Genetics Influencing CAR-T Therapy Response in Patients With Aggressive B-Cell Lymphoma

Anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy has shifted the paradigm for patients with relapsed/refractory non-Hodgkin lymphoma (R/R NHL). However, major challenges remain, including early progression in approximately 40% of cases. Developing predictive tools to anticipate progression would be highly beneficial, and immune system gene polymorphisms are promising candidates. To identify polymorphisms within immune system genes and clinical characteristics that allow for the prediction of early progression in NHL patients treated with CAR T cells. The study included 102 samples from patients with NHL treated with CAR T cells (axicabtagene ciloleucel and tisagenlecleucel). Clinical information was collected for all subjects. Samples were sequenced using a custom panel of 6,000 variants on the MiSeq platform. Data preprocessing was performed following Genome Analysis Toolkit (GATK) best practices. Quality control and filtering were conducted according to the standards established for population association studies using PLINK and R. Variant annotation was carried out with Variant Effect Predictor (VEP). Finally, enrichment analyses were performed using Cytoscape and stringApp. The association of genetic variants and early progression (defined as progression within the first 3 months) was analyzed using logistic regression. For clinical characteristics, Mann Whitney U and chi-square tests were used for numerical and categorical variables, respectively. Results with a P < 0.05 were considered significant. Early progression was significantly associated with the absence of prior autologous transplantation and with disease progression occurring before apheresis or infusion. Regarding genetic variants, early progression was associated with 267 variants located in 67 distinct genes. Among them, 16 genes were identified as involved in the dysregulation of the Hippo-Merlin pathway, with these genes harboring the highest number of variants (38%). This study identifies clinical and germline genetic factors associated with early progression in B-cell lymphoma patients treated with CAR-T therapy, with nearly 40% of variants linked to the Hippo-Merlin pathway. Dysregulation of this pathway may contribute to CAR-T therapy resistance by promoting the recruitment of tumor-associated macrophages and their polarization into M2 macrophages, creating an anti-inflammatory microenvironment that hinders immunotherapy efficacy. Carlos III Health Research Projects (Proyectos de I+D+I en Salud), co-funded by the European Regional Development Fund (ERDF) FIS20/00521 ISCIII.