Journal
NATURE MEDICINE
Volume 25, Issue 7, Pages 1064-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41591-019-0472-9
Keywords
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Funding
- Juno Therapeutics
- Immunotherapy Integrated Research Center at the Fred Hutchinson Cancer Research Center
- Damon Runyon
- Guillot Family ZachAttacksLeukemia Foundation
- [P01CA18029-41]
- [NIH-5K08CA169485]
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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-versushost 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 graftversus-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.
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