Cellular and Molecular Mechanisms Determining Allogeneic CAR T-cell Rejection and Expansion
Menée à l'aide de séquençages longitudinaux du récepteur TCR-bêta, de profilages moléculaires à l'échelle cellulaire (single-cell) et d'essais de réaction lymphocytaire mixte (MLR) à partir d'échantillons issus de 11 patients atteints d'un lymphome à grandes cellules B traité par cémacabtagène anségédleucel (lymphocytes CAR-T allogéniques anti-CD19), cette étude met en évidence des mécanismes cellulaires et moléculaires favorisant le rejet ou l'expansion des lymphocytes CAR-T allogéniques
Allogeneic chimeric antigen receptor (CAR) T cells could overcome limitations of autologous therapies but are limited by immune rejection. We evaluated 11 patients with large B-cell lymphoma treated with a single lot of cemacabtagene ansegedleucel (cema-cel), an allogeneic anti-CD19 CAR T product. Despite receiving identical infusion products (IP), patients exhibited heterogeneous cema-cel expansion and clinical outcomes. Our integrated analyses using longitudinal T-cell receptor (TCR)
β sequencing, single-cell molecular profiling, and mixed lymphocyte reaction assays revealed that high frequencies of preexisting, recipient-derived alloreactive CD8+ T cells-mediated rapid CAR T rejection in nonexpanders. Furthermore, effector-like features, rather than stem/central memory programs, drove robust clonal CAR T expansion consistently across expanders. We confirmed similar expansion patterns in two independent cohorts treated with a separate lot of cema-cel or an allogeneic anti
–B-cell maturation antigen (BCMA) CAR T product. These findings highlight distinct cell-extrinsic and cell-intrinsic mechanisms that influence allogeneic CAR T performance and provide insights to optimize donor selection, manufacturing, and product design.
Cancer Discovery , résumé, 2026