New hope to prevent ALL relapse after transplant

In this issue of Blood, Naik et al¹ report on their initial clinical efforts to use donor-derived multiple leukemia antigen–specific T cells following allogeneic hematopoietic stem cell transplantation (HSCT) to prevent relapse in patients with B-cell and T-cell acute lymphoblastic leukemia (ALL).

According to the most recent data from the Center for International Blood and Marrow Transplant Research, relapse remains the primary cause of treatment failure after allogeneic HSCT for ALL and, for that matter, all hematologic malignancies. As such, there is a tremendous need for better methods to prevent and treat this significant clinical problem. The mainstay of relapse prevention and treatment after allogeneic HSCT for leukemias has been the use of donor lymphocyte infusions (DLIs)²; however, the use of DLIs has had extremely limited clinical efficacy in ALL. Indeed, it was noted quickly that the relative clinical benefit of DLIs for the treatment of myeloid malignancies after allogeneic HSCT was not observed in ALL.³ Similarly, the very limited studies of prophylactic DLIs after transplantation to prevent ALL relapse have had disappointing results.⁴ The lack of efficacy with DLIs in ALL has been attributed to the limited proliferative capacity of ALL-reactive T cells, and what limited antileukemic activity these T cells may have is dependent on the antigenic disparity between the donor and the patient.⁵ To add relative insult to injury, there is also an inherent risk for graft-versus-host disease with lack of clinical benefit after DLI. Although the patient numbers are relatively small, the results reported by Naik and colleagues demonstrate the feasibility of this novel preventive strategy with intriguing clinical and biologic insights.

The use of antigen-specific T-cell infusions for the treatment of leukemia is not a novel concept. Greenberg and colleagues at the Fred Hutchinson Cancer Research Center isolated a high-affinity Wilms’ tumor antigen 1 (WT1)-specific T-cell receptor from normal donor repertoires and inserted it into Epstein-Bar virus–specific donor CD8⁺ T cells to minimize the risk of graft-versus-host disease and enhance the survival of transferred T cells.⁶ These genetically modified cells were then given prophylactically to 12 patients with acute myeloid leukemia in remission following allogeneic HSCT. At the time of this report, the relapse-free survival was 100% at a median follow-up of 44 months, with minimal to no graft-versus-host disease; however, other clinical efforts similar to this have been relatively limited and focused almost exclusively on acute myeloid leukemia.

Prior preclinical work from the Center for Cell and Gene Therapy at the Baylor College of Medicine demonstrated the feasibility of generating multiple leukemia antigen–specific T cells from stem cell donors of patients with myeloid leukemia.⁷ As reported by Naik et al, the Baylor group successfully generated clinically relevant numbers of multiple leukemia antigen–specific T cells that targeted the tumor-associated antigens PRAME, WT1, and survivin, which are frequently expressed on B-cell and T-cell ALL cells, from all 15 donors of patients with ALL who were undergoing allogeneic HSCT. In this process, donor peripheral blood mononuclear cells were cocultured with monocyte-derived dendritic cells that were pulsed with overlapping peptide libraries spanning survivin, WT1, and PRAME. None of the generated cell lines from each donor reacted against nonmalignant patient-derived cells, which was a product release criterion over concerns for graft-versus-host disease. Eleven of the 15 products were infused into patients within 6 months posttransplant. There were no cases of acute graft-versus host disease; 1 patient developed chronic graft-versus-host disease. The investigators observed that there was an increase in the frequency of T cells responding to PRAME, WT1, and survivin shortly after the cell products were infused. Interestingly, they also observed an increased frequency of T cells responding to other leukemia-associated antigens (eg, MAGE-A4, MART1, NYESO1), suggestive of epitope spreading. Although the clinical numbers were very small, the increased frequency of T cells responding to the targeted and nontargeted tumor antigens correlated with the patients’ ability to maintain their respective remissions.

The results of this early clinical study are highly encouraging from several perspectives. The demonstration that sufficient numbers of clinical-grade cells could be generated from all 15 donors demonstrates that this can be a potentially practical treatment option once it is scaled up for larger patient numbers. The observation of minimal toxicity, particularly graft-versus-host disease, suggests a relatively good safety profile. Finally, the additional observation of increased frequencies of leukemia antigen–specific T cells and a correlation with remission persistence is also encouraging, but it needs to be confirmed in larger numbers of patients. However, given the lack of effective strategies to prevent relapse of ALL after allogeneic HSCT, this approach deserves further clinical investigation. It would also be of interest to investigate its potential as a method to treat ALL relapse, for which there have also been few to no clinical options until recently, with the significant introduction of anti-CD19 chimeric antigen receptor T cells.⁸ However, this revolutionary therapy is limited to B-cell ALL; as such, there may be a potential role for donor-derived multiple leukemia antigen–specific T cells in the treatment of T-cell ALL relapses. Taken altogether, through ongoing translational research, we are beginning to see significant advancements in the prevention and treatment of relapse after allogeneic HSCT, which, I hope, in turn, will result in proportionate improvements in patient outcomes.