In this issue of Blood, Tawara et al report the first results of a novel treatment approach with T-cell receptor transduced autologous T cells targeting a restricted Wilms’ tumor 1 (WT1)-derived epitope in patients with refractory acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS).1
The WT1 protein is a zinc finger transcription factor that has been implicated in cell proliferation, differentiation, apoptosis, and organ development.2 It was initially described as a tumor suppressor gene but later identified as a true oncogene,3 and a modulator of tumor angiogenesis and progression.4 WT1 is a tumor-associated antigen that has been used as a target for immunotherapy by adoptive transfer of antigen-specific T lymphocytes and/or vaccination.5,6 These studies demonstrate the possibility of specific WT1-directed immune responses, particularly in hematologic malignancies.7-9
T-cell receptor (TCR) transduced T cells recognize malignant cells in the context of an HLA-restricted, epitope-specific manner. In this study, Tawara and coworkers administered 2 doses of autologous HLA*2402-restricted WT1235-243-specific TCR-redirected T cells to patients with refractory AML or high-risk MDS in a dose-escalation phase 1 trial.1 In addition, following the T-cell transfer, these patients received 2 injections of a mutated WT1 peptide vaccine with adjuvant targeting the same WT1 HLA*2402-restricted 235-243 epitope. Impressive increments of WT1-specific T-cell frequencies were observed in vivo as evaluated using MHC-tetramer analyses. Increases of up to 16% of CD8+ T cells were seen, with simultaneous transient decreases in the blast population.
This study confirms the safety of adoptively transferred WT1 TCR-transduced autologous T lymphocytes and describes a notable persistence of these cells in vivo. However, the clinical responses have been limited, and it will, therefore, be critical to build and expand on the results of this phase 1 study. First, generation and expansion of αβTCR-transduced T cells for adoptive transfer to the desired, more effective dose levels remain a logistical challenge. In this phase 1 dose escalation trial, none of the patients of a planned cohort 3, intended to receive 5 × 109 cells per dose, actually received treatment at this dose level. These patients received one-fifth of the intended dose. Furthermore, experience administering T cells transduced with the CD19-chimeric antigen receptor for patients with B-cell malignancies have convincingly shown that preceding lymphodepleting chemotherapy markedly improves T-cell persistence and clinical responses in vivo.10 In the current study using WT1 TCR-transduced T cells, only a few patients received low-dose chemotherapy prior to T-cell infusion. Therefore, one approach to improve clinical outcome in this setting would be to condition patients with lymphodepleting chemotherapy prior to T-cell infusion.
Second, despite the authors’ conclusion that the use of the WT1 vaccine may not have significantly contributed to the overall response, a combination adoptive T-cell transfer and vaccine approach to enhance or maintain an initial immune response is desirable and logical. In this study, the authors administered only 2 T-cell infusions followed by 2 subcutaneous injections of mutated WT1 vaccine. It appears that repeated dosing of T cells and additional injections of the WT1 vaccine might also enhance T-cell persistence and clinical response in this patient population. Alternatively, the addition of a checkpoint inhibitor may provide a tool to enhance tumor-specific immune responses and improve clinical outcome. Overall, this study offers a new platform to enhance the specific targeting of WT1 in patients with myeloid malignancies using combination immune-based therapies.
Conflict-of-interest disclosure: The author declares no competing financial interests.
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