Phase 1/1b Study of T-allo10 Infusion after HLA-Partially Matched αβ depleted-HSCT in Children and Young Adults with Hematologic Malignancies: Preliminary Results.

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only cure for the majority of pediatric patients with acute leukemia. However, its use has been limited by the availability of HLA-matched donors. Recently, αβ+ T-cell and CD19+ B-cell depleted (αβdepleted) HSCT has enabled a significant broadening of the use of HLA-partially matched related and unrelated donors. Still, the rate of viral reactivations (~50%) and leukemic relapse (25-30%) after αβdepleted-HSCT remains high, mostly because of the poor immune reconstitution due to extensive ex vivo αβ T-cell depletion and use of pre-HSCT serotherapy. Adoptive immunotherapy improving immune reconstitution and graft-versus-leukemia (GvL) immune response after αβdepleted-HSCT, without increasing the risk of GvHD would dramatically improve patient outcomes. Methods: We have developed an innovative T-cell immunotherapy, the T-allo10 drug product. T-allo10 product comes from donor CD4+ T cells and is composed of 1) regulatory type 1 T (Tr1) cells differentiated in vitro, which are specific for the host alloantigens and suppress host-reactive TCRαβ+ T cells that cause GvHD, and 2) polyclonal naive and memory TCRαβ+ T cells that can respond to pathogens and tumor antigens. In addition, activated Tr1 cells acquire cytotoxic activity against myeloid cells, suggesting they may also contribute to the GvL effect mediated by the TCRαβ+ T cells in acute myeloid leukemia. We hypothesized that the infusion of T-allo10 after αβdepleted-HSCT will expedite immune reconstitution by providing a source of TCRαβ+ T cells and supporting the generation of donor derived naive T cells, therefore reducing the risk of infections and leukemic relapse, without increasing the risk of GvHD. We are testing our hypothesis in a single center, non-randomized, non-controlled open-label Phase I/Ib trial in children and young adults with hematologic malignancies receiving αβdepleted-HSCT (Figure 1). Results: At present, we have enrolled 6 patients in the Phase I portion of the study, and 5/6 received the T-allo10 infusion. No DLT (grade IV acute GvHD, grade 3 and 4 treatment-related adverse events) have been observed so far. Two patients achieved the efficacy endpoint, reaching the threshold of 50 CD3+CD4+ T cells/mcl by Day +60 post αβdepleted-HSCT. Conclusion: Our preliminary data show that the T-allo10 cell infusion is safe and well tolerated when manufactured from a haploidentical donor. Antigen-specific Tr1 cells contained in the T-allo10 drug product are detectable in the recipients and traceable by TCR clonotype analysis.