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Nat Med. 2019 Jul;25(7):1064-1072. doi: 10.1038/s41591-019-0472-9. Epub 2019 Jun 24.

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

Author information

1
Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
2
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
3
University of Washington School of Medicine, Seattle, WA, USA.
4
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
5
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
6
Landspítali Háskólasjúkrahús, Reykjavík, Iceland.
7
Alpine Biotech, Seattle, WA, USA.
8
Therapeutic Products Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
9
School of Informatics, University of Edinburgh, Edinburgh, UK.
10
Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. pgreen@u.washington.edu.
11
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. pgreen@u.washington.edu.
12
University of Washington School of Medicine, Seattle, WA, USA. pgreen@u.washington.edu.
13
Departments of Immunology and Medicine, University of Washington, Seattle, WA, USA. pgreen@u.washington.edu.

Abstract

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 features1-3. 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 cells4. 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 disease5. Thus, AML relapse risk might be more effectively reduced with T cells expressing receptors (TCRs) that target selected AML antigens6. 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 survival7,8, 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.

PMID:
31235963
DOI:
10.1038/s41591-019-0472-9

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