Relapse remains a leading cause of death after allogeneic hematopoietic cell transplantation (HCT) for patients with high-risk leukemias. The potentially beneficial donor T-cell-mediated graft-versus-leukemia (GVL) effect is often mitigated by concurrent graft versus host disease (GVHD). Providing T-cells that can selectively target Wilms’ Tumor Antigen 1 (WT1), a transcription factor over-expressed in leukemias that contributes to the malignant phenotype, represents a potential opportunity to promote anti-leukemic activity without inducing GVHD. HLA A*0201-restricted WT1-specific donor-derived CD8+ cytotoxic T-cell (CTL) clones were administered post-HCT to 11 relapsed or high-risk leukemia patients without any evidence of on-target toxicity. The last four treated patients received CTL clones generated with exposure to IL-21 as a means to prolong in vivo CTL survival, as IL-21 can limit terminal differentiation of antigen-specific T-cells generated in vitro. Transferred cells exhibited direct evidence of anti-leukemic activity in 2 patients: a transient response in one patient with advanced progressive disease and the induction of a prolonged remission in a patient with minimal residual disease (MRD). Additionally, three treated patients at high risk for relapse post-HCT survive without leukemia relapse, GVHD or additional anti-leukemic treatment. CTL generated in the presence of IL-21, which were transferred in these latter three patients and the patient with MRD, all remained detectable long-term and maintained/acquired in vivo phenotypic and functional characteristics associated with long-lived memory CD8+ T-cells. This study supports expanding efforts to immunologically target WT1, and provides insights into the requirements necessary to establish potent persistent T-cell responses in patients.

No abstract

Relapse after allogeneic hematopoietic cell transplantation (HCT) is the leading cause of death in acute myeloid leukemia (AML) patients entering HCT with poor-risk features. 1-3 When HCT does produce prolonged relapse-free survival (RFS), it commonly reflects graft-versus-leukemia (GVL) 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, GVL is often accompanied by morbidity and mortality from graft-versus-host disease (GVHD). 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

T cell-based adoptive immunotherapy has been shown to be a promising treatment for various types of cancer. However, adoptive T cell therapy currently requires the custom isolation and characterization of tumor-specific T cells from each patient-a process that can be not only difficult and time-consuming but also often fails to yield high-avidity T cells, which together have limited the broad application of this approach as a clinical treatment. Employing T cell receptor (TCR) gene therapy as a component of adoptive T cell therapy strategies can overcome many of these obstacles, allowing autologous T cells with a defined specificity to be generated in a much shorter time period. Initial studies using this approach have been hampered by a number of technical difficulties resulting in low TCR expression and acquisition of potentially problematic specificities due to mispairing of introduced TCR chains with endogenous TCR chains. The last several years have seen substantial progress in our understanding of the multiple facets of TCR gene therapy that will have to be properly orchestrated for this strategy to succeed. Here we outline the challenges of TCR gene therapy and the advances that have been made toward realizing the promise of this approach.