Transferred WT1-Reactive CD8+ T Cells Can Mediate Antileukemic Activity and Persist in Post-Transplant Patients

Donor-derived WT1-specific CD8+ T cells transferred after hematopoietic cell transplantation mediate antileukemic activity and can establish persistent responses without toxicity to normal tissues in high-risk leukemia patients. Targeting Leukemic Cells for Destruction After a patient is diagnosed with leukemia, the first line of treatment is generally chemotherapy. If it doesn’t work, the patient can get a bone marrow transplant, which can sometimes cure otherwise untreatable leukemia. However, for patients who have already relapsed after a transplant, or whose cancer has particularly unfavorable characteristics, few options remain. Such patients’ prognosis is generally very poor, with a high risk of relapse and death from leukemia. Immune cells derived from the donor bone marrow can help fight the cancer by attacking malignant cells inside the graft recipient. At the same time, however, they often attack the recipient’s healthy cells as well and cause graft-versus-host disease (GVHD), which can itself be lethal. Now, Chapuis and coauthors report a way to harness the power of the donors’ immune cells against some leukemias, without triggering GVHD in the bone marrow recipients. In this pilot trial, the authors enrolled 11 patients who had leukemia with poor prognostic characteristics and who had each undergone a bone marrow transplant. The patients then received T cells that were derived from their respective donors and selected for their ability to recognize Wilms tumor antigen 1 (WT1). Very small amounts of WT1 are present in some healthy cells, but its expression in malignant cells is much greater and corresponds to the aggressiveness of the cancer. In the first seven patients, the authors found that T cells that recognized WT1 could suppress the leukemia temporarily, but the new cells disappeared within 14 days, and the cancer rebounded. In the last four patients, the authors tried a modified protocol, pretreating the cells with interleukin-21 (IL-21) before infusion into the recipients. T cells pretreated with IL-21 developed characteristics of memory cells, including a greatly extended life span. At this time, all four patients who received IL-21–treated T cells are still alive, with no recurrence of their cancer up to 30 months after the T cell infusion. Notably, none of the patients who received WT1-specific T cells in this study have developed GVHD, supporting the idea that WT1 targeting is specific to the tumor cells and safe for patient use. The study by Chapuis et al. is a small pilot trial, and its results must be replicated with larger groups of patients before this protocol can become standard practice. Nevertheless, the combination of targeting WT1 in leukemia and pretreating leukemia-targeting T cells with IL-21 to extend their life span looks very promising and offers a potential safe and effective treatment for patients who have few other options. 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 overexpressed in leukemias that contributes to the malignant phenotype, represents an opportunity to promote antileukemic activity without inducing GVHD. HLA-A*0201–restricted WT1-specific donor-derived CD8+ cytotoxic T cell (CTL) clones were administered after HCT to 11 relapsed or high-risk leukemia patients without evidence of on-target toxicity. The last four treated patients received CTL clones generated with exposure to interleukin-21 (IL-21) to prolong in vivo CTL survival, because IL-21 can limit terminal differentiation of antigen-specific T cells generated in vitro. Transferred cells exhibited direct evidence of antileukemic activity in two 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 after HCT survive without leukemia relapse, GVHD, or additional antileukemic treatment. CTLs 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 or 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.