To prevent relapse in AML patients with an increased risk following successful allogeneic hematopoietic cell transplantation (HCT), 12 patients were infused at least once with healthy donor-derived Epstein-Barr virus (EBV) specific CD8+ T cells transduced with a high-affinity TCR targeting the AML-associated antigen WT1 (TTCR-C4). All 12 patients (100%) remained alive and relapse-free at a median follow-up of 44 months, while a concurrent group of 88 AML patients that only underwent HCT exhibited 60% overall survival and 54% relapse-free survival at 36 months follow-up. TTCR-C4 cells maintained polyfunctionality and persisted long-term.
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 (TCRC4) from HLA-A2(+) normal donor repertoires, inserted TCRC4 into Epstein-Bar virus-specific donor CD8(+) T cells (TTCR-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). TTCR-C4 maintained TCRC4 expression, persisted long-term and were polyfunctional. This strategy appears promising for preventing AML recurrence in individuals at increased risk of post-HCT relapse.
Author Info: (1) Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Universit
Author Info: (1) Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. University of Washington School of Medicine, Seattle, WA, USA. (2) Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. University of Washington School of Medicine, Seattle, WA, USA. (3) Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. University of Washington School of Medicine, Seattle, WA, USA. (4) Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. (5) Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. (6) Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. University of Washington School of Medicine, Seattle, WA, USA. (7) Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. (8) Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. (9) Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Landspitali Haskolasjukrahus, Reykjavik, Iceland. (10) Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. University of Washington School of Medicine, Seattle, WA, USA. (11) Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. University of Washington School of Medicine, Seattle, WA, USA. (12) University of Washington School of Medicine, Seattle, WA, USA. (13) Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Alpine Biotech, Seattle, WA, USA. (14) Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Therapeutic Products Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. (15) Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Therapeutic Products Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. (16) Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. (17) Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. (18) Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. School of Informatics, University of Edinburgh, Edinburgh, UK. (19) Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. (20) Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. (21) Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. University of Washington School of Medicine, Seattle, WA, USA. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. (22) Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. (23) Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. (24) Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. pgreen@u.washington.edu. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. pgreen@u.washington.edu. University of Washington School of Medicine, Seattle, WA, USA. pgreen@u.washington.edu. Departments of Immunology and Medicine, University of Washington, Seattle, WA, USA. pgreen@u.washington.edu.
