Phase 1 CART-45 anti-CD45 CAR T + CD45 base-edited HSPC epitope shield

University of Pennsylvania’s Phase 1 open-label, dose-finding study evaluates a two-step, autologous cell-therapy strategy: infusion of CD45 base-edited hematopoietic stem and progenitor cells (CD45BE-HSPC) followed by autologous anti-CD45 CAR T cells (CART-45). The CAR T mechanism is CD45 (PTPRC) targeting to kill malignant hematologic cells that broadly express CD45 across lineages; the HSPC intervention uses base editing of the CD45 epitope to “shield” reconstituting normal hematopoiesis from on-target/off-tumor CD45 CAR T toxicity after transplant-like reconstitution. Eligible cohorts include heavily pretreated relapsed/refractory Richter’s transformation and multiple B-cell NHL subtypes (including mantle cell and follicular lymphoma), plus relapsed/refractory T-cell NHL and CD45-positive Hodgkin lymphoma, among other specified entities. The key scientific angle is the coupling of base editing with a “universal” hematologic antigen target (CD45), aiming to widen CAR T applicability beyond single-lineage targets like CD19 while addressing predictable marrow toxicity with an engineered graft. Today’s care for these relapsed/refractory lymphomas is sequential systemic therapy and/or commercial lineage-restricted CAR T or bispecific antibodies when eligible, with some patients proceeding to autologous or allogeneic transplant; this trial tests whether CD45-directed cellular immunotherapy can be made feasible by protecting normal blood-forming cells.