Ancestry-restricted expression of P2RX5 defines a CAR T-cell target across diverse blood cancers

Purinergic receptor P2RX5 can serve as an HLA-restricted graft-versus-leukemia antigen. Yet, its direct targeting with chimeric antigen receptor (CAR) T cells remains unexplored, due to the prevailing view that protein-truncating mutations have rendered human P2RX5 a pseudogene. Here, leveraging transcriptomic datasets and newly-developed monoclonal antibodies, we show that up to 75% of individuals with African ancestry express the full-length variant of P2RX5 (P2RX5-FL). While in healthy tissues P2RX5 is transcribed only in B cells and prenatal thymocytes, it is upregulated across multiple hematologic cancers including B-cell lymphomas (BCL), multiple myelomas (MM), and T-cell acute lymphoblastic leukemias (T-ALL). Crucially, unlike its truncated counterparts, P2RX5-FL protein is stable and plasma membrane-bound. We reformatted one monoclonal antibody as a P2RX5-directed CAR and expressed it in donor T cells. These CART-X5 cells were not prone to fratricide and were effective in reducing disease burden and extending survival in xenograft mouse models of T-ALL and MM. Together, these findings nominate P2RX5-FL as an immunotherapy target for BCL and MM patients that have relapsed after CD19 or BCMA-directed therapies with antigen-negative disease. P2RX5-FL could also be targeted in chemoresistant T-ALL, where new immunotherapies avoiding CAR T-cell fratricide and T-cell aplasia are urgently needed.