General AML

Phase I study of WT1-specific T-cell receptor gene transduced lymphocytes in AML and MDS

In the November 2017 issue of Blood, Isao Tawara from Mie University Graduate School of Medicine, Mie, Japan, and colleagues reported results from their phase I first-in-human, cell dose-escalating  trial (UMIN000011519), which evaluated the safety and the cell kinetics of  adoptive transfer of Wilms’ Tumor 1 (WT1)-specific T-cell receptor (TCR)-T-cells in patients with refractory Acute Myeloid Leukemia (AML) and high-risk Myelodysplastic Syndrome (MDS).

Overall, eight patients with WT1 positive refractory AML or high-risk MDS were administered either 2 x 108 cells/dose (Cohort 1, n = 3) or 1 x 109 cells/dose (Cohort 2, n = 5) of WT1-specific TCR-T cells (prepared ex vivo specifically for each patient). WT-1-specific TCR-T cells were given intravenously twice, on Days 0 and 28. After the second transfer, 300 µg mutated WT-1235-243 peptide vaccine with adjuvant were subcutaneously administered on Days 30 and 44. Clinical response and safety were evaluated on Day 58 (end of study period).

Key findings:
  • Safety
    • No adverse events > grade 3 were observed in patients
    • Dose limiting toxicities did not occur
  • Cell kinetics
    • TCR-T cells were detected in Peripheral Blood (PB) for 8 weeks at levels proportional to the initial dose administered
    • On Day 58, five patients demonstrated persistent T cells
    • TCR-T cells were detected at a higher level in the BM than in the PB
  • Clinical response
    • Transient decrease in blast counts in Bone Marrow (BM) were observed in two patients and this associated with hematopoiesis recovery
    • Five patients with persistent T cells survived longer than 12 months with one alive to date
    • Median survival = 15.9 months

In summary, WT1-specific TCR-redirected T-cell therapy for AML was concluded by the authors to be “safe”. Additionally, the T cells persisted in vivo and trafficked to BM where they retained the ability to mount immune responses to WT1 thus providing further anti-leukemic effects in patients with refractory AML. 

In accompanying commentary article, Guenther Koehne from Memorial Sloan Kettering Cancer Center, FL, US,  commented on the findings of this study by Tawara et al. He agreed that the results of this phase I study confirmed the safety of adoptively transferred WT1 TCR-transduced autologous T cells. He highlighted, however, that the clinical responses in this phase I study have been limited, and thus suggested that it would be crucial to “build and expand” on the results of this phase I study.

Firstly, Koehne noted that only a few patients were administered low-dose chemotherapy prior to T-cell infusion and suggested that an approach to improve clinical efficacy in this trial would be to condition patients with lymphodepleting chemotherapy prior to T-cell infusion as this strategy has been shown to improve T- cell persistence and clinical responses using CD19 chimeric receptor for patients with B-cell malignancies.  Secondly, despite conclusion by Tawara et al. that the use of WT1 vaccine may not have contributed to the overall response, Koehne suggested that “a combination adoptive T-cell transfer and vaccine approach to enhance or maintain an initial immune response is required” to improve clinical response. Lastly, only two T-cell infusions followed by two subcutaneous injections of mutated WT1 vaccine were administered to patients in this phase I study and Koehne proposed that repeated dosing and additional injections might improve the response and T cell persistence.

Guenther Koehne concluded by stating that the findings by Tawara et al. offer a “new platform to enhance specific targeting of WT1” in AML patients using combination immune-based therapies. 

Abstract

Wilms’ tumor 1 (WT1) is constantly expressed in leukemic cells of acute leukemia and myelodysplastic syndrome (MDS). A T-cell receptor (TCR) that specifically reacts with WT1 peptide in the context of HLA-A*24:02 has been identified. We conducted a first-in-human trial of TCR–gene transduced T-cell (TCR–T-cell) transfer in patients with refractory acute myeloblastic leukemia (AML) and high-risk MDS to investigate the safety and cell kinetics of the T cells. The WT1-specific TCR-gene was transduced to T cells using a retroviral vector encoding small interfering RNAs for endogenous TCR genes. The T cells were transferred twice with a 4-week interval in a dose-escalating design. After the second transfer, sequential WT1 peptide vaccines were given. Eight patients, divided into 2 dose cohorts, received cell transfer. No adverse events of normal tissue were seen. The TCR-T cells were detected in peripheral blood for 8 weeks at levels proportional to the dose administered, and in 5 patients, they persisted throughout the study period. The persisting cells maintained ex vivo peptide-specific immune reactivity. Two patients showed transient decreases in blast counts in bone marrow, which was associated with recovery of haematopoiesis. Four of 5 patients who had persistent T cells at the end of the study survived more than 12 months. These results suggest WT1-specific TCR-T cells manipulated by ex vivo culture of polyclonal peripheral lymphocytes survived in vivo and retained the capacity to mount an immune reaction to WT1. This trial was registered at www.umin.ac.jp as #UMIN000011519.

References
  1. Tawara I. et al. Safety and persistence of WT1-specific T-cell receptor gene-transduced lymphocytes in patients with AML and MDS. Blood. 2017 Nov 2; 130 (18): 1985–1994. DOI:  10.1182/blood-2017-06-791202.
  2. Koehne G. Targeting WT1 in hematologic malignancies? Blood. 2017 Nov 2; 130 (18): 1959–1960. DOI: 10.1182/blood-2017-09-805358.