T-allo10 Infusion after αβ depleted-HSCT in Children and Young Adults with Hematologic Malignancies: Improved Immune Reconstitution in the Absence of Severe GvHD
Hematologic malignancies are the most common cancer in children and young adults, and current treatment options do not offer long-term cures. αβdepleted-Hematopoietic Stem Cell Transplantation (HSCT) has increased the number of patients who can safely receive transplants to treat pediatric patients with acute leukemia. However, this strategy cannot provide fast reconstitution of the immune system which is critical for infection fighting functions and preventing leukemia relapse. We have developed an innovative T-cell immunotherapy, the T-allo10 drug product. When the product is given after αβdepleted-HSCT, it has the potential to accelerate recovery of immune responses without graft versus host disease (GvHD), thus improving cancer-free outcomes for children with leukemia. We report the preliminary results of the Phase I/Ib clinical trial in children and young adults with hematologic malignancies receiving αβdepleted-HSCT (NCT 04640987). At present, we have enrolled 9 patients in the Phase I portion of the study, and 8 of the 9 patients were treated with T-allo10. No dose limiting toxicity was observed in any of the patients and 3 out of the 6 evaluable patients achieved the immune reconstitution threshold by Day +60 post αβdepleted-HSCT and compared favorably to historical controls. Our preliminary data show that T-allo10 infusion after αβdepleted-HSCT is safe, expedites CD4+ T cells immune reconstitution and does not increase the risk of GvHD.
The use of allogeneic hematopoietic stem cell transplantation (HSCT) for treating pediatric patients with acute leukemia has been limited by the availability of HLA-matched donors. αβ+ T-cell and CD19+ B-cell depletion (αβdepleted) has significantly broadened the use of HLA-mismatched related and unrelated donors. However, the incidence of viral reactivations (~50%) and leukemic relapse (25-30%) after αβdepleted-HSCT remains significant, mostly because of the poor immune reconstitution (IR) due to extensive ex vivo αβ T-cell depletion and use of pre-HSCT serotherapy. We have developed an innovative T-cell immunotherapy, the T-allo10 drug product. T-allo10 product is derived from donor CD4+ T cells and is enriched in regulatory type 1 T (Tr1) cells differentiated in vitro, which are host alloantigens specific and therefore suppress host-reactive TCRαβ+ T cells causing GvHD. It also contains polyclonal naive and memory TCRαβ+ T cells able to respond to pathogens and tumor antigens. We hypothesized that the infusion of T-allo10 after αβdepleted-HSCT will expedite IR by providing a source of TCRαβ+ T cells which can support the generation of donor-derived naive T cells, therefore reducing the risk of infections and leukemic relapse, without increasing the risk of GvHD. Here we report the preliminary results of a single center, non-randomized, non-controlled open-label Phase I/Ib trial in children and young adults with hematologic malignancies receiving αβdepleted-HSCT (NCT 04640987). At present, we have enrolled 9 patients (see Table 1 for details) in the Phase I portion of the study: 8/9 received the T-allo10 infusion. No DLT (grade IV acute GvHD, grade 3 or 4 treatment-related adverse events) have been observed. Three out of the 6 patients evaluable (50%) achieved the IR efficacy endpoint (See Figure 1), reaching the threshold of 50 CD3+CD4+ T cells/mcl by Day +60 post αβdepleted-HSCT, comparing favorably to our historical controls (31%).