Donor-derived multiple leukemia antigen-specific T-cell therapy to prevent relapse after transplant in patients with ALL

Abstract

Hematopoietic stem cell transplant (HSCT) is a curative option for patients with high-risk acute lymphoblastic leukemia (ALL), but relapse remains a major cause of treatment failure. To prevent disease relapse, we prepared and infused donor-derived multiple leukemia antigen-specific T cells (mLSTs) targeting PRAME, WT1, and survivin, which are leukemia-associated antigens frequently expressed in B- and T-ALL. Our goal was to maximize the graft-versus-leukemia effect while minimizing the risk of graft-versus-host disease (GVHD). We administered mLSTs (dose range, 0.5 × 107 to 2 × 107 cells per square meter) to 11 patients with ALL (8 pediatric, 3 adult), and observed no dose-limiting toxicity, acute GVHD or cytokine release syndrome. Six of 8 evaluable patients remained in long-term complete remission (median: 46.5 months; range, 9-51). In these individuals we detected an increased frequency of tumor-reactive T cells shortly after infusion, with activity against both targeted and nontargeted, known tumor-associated antigens, indicative of in vivo antigen spreading. By contrast, this in vivo amplification was absent in the 2 patients who experienced relapse. In summary, infusion of donor-derived mLSTs after allogeneic HSCT is feasible and safe and may contribute to disease control, as evidenced by in vivo tumor-directed T-cell expansion. Thus, this approach represents a promising strategy for preventing relapse in patients with ALL.

Graphical abstract

Figure 1.

Characterization and in vivo fate of donor-derived mLSTs. (A-C) Characterization of donor-derived mLSTs. (A) Phenotype and memory/activation profile. (B) Specificity of mLSTs as measured by IFNγ ELIspot for 15 products generated using all 3 antigens as a stimulus. Data are shown as mean SFCs ± SEM/2 × 10⁵ and each color represents an individual antigenic specificity. (C) Lack of in vitro mLST cytolytic activity against normal recipient cells at effector/target ratios from 40:1 to 5:1. (D) In vivo behavior of mLSTs in patients who remain in remission (n = 6). Expansion of T cells specific for targeted TAAs (left) and other nontargeted TAAs (right) in patients who responded to therapy. Results are reported as mean SFCs ± SEM/2 × 10⁵ at each specified time point. (E) In vivo behavior of mLSTs in patients who relapsed. Lack of T-cell expansion against either targeted (left) or nontargeted TAAs (right) immediately after infusion in patients 3 and 12 who eventually relapsed. Results are reported as SFC/2 × 10⁵ at each specified time point. Arrows indicate the time of relapse.