Mediterranean CD19 genetic variations and potential influence on CAR T-cell therapy efficacy: Implications for population-tailored immunotherapy.

Abstract

7008 Background: CAR T-cell therapy has transformed the treatment of B-cell malignancies. However, relapse due to CD19 antigen escape remain a major challenge, often driven by genetic variants affecting CD19 structure, leading to CAR-T resistance. Mediterranean populations including Arabs, remain underrepresented in genomic studies. The Arabian prevalence and functional impact of CD19 variants is unknown. Methods: We analyzed and annotated CD19 NGS data from a Mediterranean cohort comprised of 1,305 Arabian individuals. The overall allele frequencies were compared to global databases. Clinically reported resistance mutations were prioritized based on published CAR T-cell studies. Hardy-Weinberg Equilibrium (HWE) was also assessed. Results: This study characterizes functionally significant CD19 polymorphisms in a Mediterranean population, with particular focus on the clinically relevant L174V (rs2904880) variant known to associate with CAR-T therapy resistance. 174V was seen in this cohort with a Minor Allele Frequency (MAF) of 76.3%., and a variant allele homozygosity (V/V) of 65.2%. Conclusions: Our cohort displayed elevated V174 homozygosity compared to other populations, including Europeans, Americans, and South Asians, potentially predisposing to diminished CAR-T efficacy. These findings indorse population-adjusted CAR-T product development, and implementation of pre-therapy CD19 genotyping protocols to identify at-risk patients. Development of CARs targeting conserved CD19-epitopes, or combinatorial antigen approaches is warranted to mitigate resistance.