T cell receptor gene therapy targeting WT1 prevents acute myeloid leukemia relapse post-transplant

Relapse after allogeneic hematopoietic cell transplantation (HCT) is the leading cause of death in patients with acute myeloid leukemia (AML) entering HCT with poor-risk features 1 – 3 . When HCT does produce prolonged relapse-free survival, it commonly reflects graft-versus-leukemia effects mediated by donor T cells reactive with antigens on leukemic cells 4 . As graft T cells have not been selected for leukemia specificity and frequently recognize proteins expressed by many normal host tissues, graft-versus-leukemia effects are often accompanied by morbidity and mortality from graft-versus-host disease 5 . Thus, AML relapse risk might be more effectively reduced with T cells expressing receptors (TCRs) that target selected AML antigens 6 . We therefore isolated a high-affinity Wilms’ Tumor Antigen 1-specific TCR (TCR C4 ) from HLA-A2 + normal donor repertoires, inserted TCR C4 into Epstein–Bar virus-specific donor CD8 + T cells (T TCR-C4 ) to minimize graft-versus-host disease risk and enhance transferred T cell survival 7 , 8 , and infused these cells prophylactically post-HCT into 12 patients ( NCT01640301 ). Relapse-free survival was 100% at a median of 44 months following infusion, while a concurrent comparative group of 88 patients with similar risk AML had 54% relapse-free survival ( P = 0.002). T TCR-C4 maintained TCR C4 expression, persisted long-term and were polyfunctional. This strategy appears promising for preventing AML recurrence in individuals at increased risk of post-HCT relapse.