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

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.

SUBMITTER: Chapuis AG

PROVIDER: S-EPMC6982533 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

Chapuis Aude G AG Egan Daniel N DN Bar Merav M Schmitt Thomas M TM McAfee Megan S MS Paulson Kelly G KG Voillet Valentin V Gottardo Raphael R Ragnarsson Gunnar B GB Bleakley Marie M Yeung Cecilia C CC Muhlhauser Petri P Nguyen Hieu N HN Kropp Lara A LA Castelli Luca L Wagener Felecia F Hunter Daniel D Lindberg Marcus M Cohen Kristen K Seese Aaron A McElrath M Juliana MJ Duerkopp Natalie N Gooley Ted A TA Greenberg Philip D PD

Nature medicine 20190624 7

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<sup>1-3</sup>. 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<sup>4</sup>. As graft T cells have not been selected for leukemia specificity and frequently recognize proteins expressed by many nor ...[more]

PMID: 31235963

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Project description:BackgroundOverexpression of Wilms' tumor-1 (WT1) transcription factor facilitates proliferation in acute myeloid leukemia (AML). However, whether WT1 is enriched in the leukemia-initiating cells (LICs) and leukemia stem cells (LSCs) and facilitates the self-renewal of LSCs remains poorly understood.MethodsMLL-AF9-induced murine leukemia model was used to evaluate the effect of knockdown of wt1 on the self-renewal ability of LSC. RNA sequencing was performed on WT1-overexpressing cells to select WT1 targets. Apoptosis and colony formation assays were used to assess the anti-leukemic potential of a deubiquitinase inhibitor WP1130. Furthermore, NOD/SCID-IL2R? (NSG) AML xenotransplantation and MLL-AF9-induced murine leukemia models were used to evaluate the anti-leukemogenic potential of WP1130 in vivo.ResultsWe found that wt1 is highly expressed in LICs and LSCs and facilitates the maintenance of leukemia in a murine MLL-AF9-induced model of AML. WT1 enhanced the self-renewal of LSC by increasing the expression of BCL2L2, a member of B cell lymphoma 2 (BCL2) family, by direct binding to its promoter region. Loss of WT1 impaired self-renewal ability in LSC and delayed the progression of leukemia. WP1130 was found to modify the WT1-BCL2L2 axis, and WP1130-induced anti-leukemic activity was mediated by ubiquitin proteasome-mediated destruction of WT1 protein. WP1130 induced apoptosis and decreased colony formation abilities of leukemia cells and prolonged the overall survival in the THP1-based xenograft NSG mouse model. WP1130 also decreased the frequency of LSC and prolonged the overall survival in MLL-AF9-induced murine leukemia model. Mechanistically, WP1130 induced the degradation of WT1 by positively affecting the ubiquitination of WT1 protein.ConclusionsOur results indicate that WT1 is required for the development of AML. WP1130 exhibits anti-leukemic activity by inhibiting the WT1-BCL2L2 axis, which may represent a new acute myeloid leukemia therapy target.

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

Publications

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

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