Cellular and molecular mechanisms determining allogeneic CAR T cell rejection and expansion
Andrew P. Jallouk, Zhongqi Ge, Vivek Kaimal, Kristen Zhang, Elvin J. Lauron, Paul B. Robbins, Zachary J. Roberts, Emerie Danson, Matthew D. Richard, Pragya Devashish, Sattva S. Neelapu, Pavan BachireddyAbstract
Allogeneic 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, patients exhibited heterogeneous cema-cel expansion and clinical outcomes. Our integrated analyses using longitudinal TCRβ sequencing, single‑cell molecular profiling, and mixed lymphocyte reaction assays revealed that high frequencies of pre‑existing, recipient-derived alloreactive CD8+ T cells mediated rapid CAR T rejection in non-expanders. 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-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.