Enhanced Immune Reconstitution and Reduced GvHD Risk with T-allo10 Infusion Post Aβdepleted-HSCT in Pediatric and Young Adult Patients with Hematologic Malignancies

Allogeneic hematopoietic stem cell transplantation (HSCT) has been historically hindered by the scarcity of HLA-matched donors. TCRαβ+ T-cell and CD19+ B-cell-depleted (αβdepleted) HSCT has expanded the utilization of HLA-mismatched donors by reducing the incidence of severe graft-versus-host disease (GvHD). However, αβdepleted-HSCT still presents challenges such as viral reactivations (∼50%) and leukemic relapse (25-30%) due to suboptimal immune reconstitution (IR).To address these hurdles, we combined αβdepleted-HSCT with a newly developed T-cell immunotherapy known as T-allo10. T-allo10 is generated in vitro from donor CD4+ T cells and enriched in type 1 regulatory T (Tr1) cells, which are host alloantigens specific and, therefore, suppress host-reactive TCRαβ+ T cells causing GvHD. Additionally, T-allo10 contains polyclonal naive and memory TCRαβ+ T cells, crucial for pathogen and tumor antigen responses. Our hypothesis posits that the infusion of T-allo10 following αβdepleted-HSCT will: a) expedite IR by providing a source of TCRαβ+ T cells that support immune responses and facilitate the development of donor-derived naive T cells, and b) modulate undesired anti-host immune responses through the function of alloantigen-specific Tr1 cells. Thus, T-allo10 infusion aims to enhance IR, reduce the risks of infections and leukemic relapse, without severe GvHD.In this phase I/Ib trial conducted at Stanford Children's Health, we enrolled 14 pediatric and young adult patients with hematologic malignancies (NCT 04640987), with 13/14 patients receiving the T-allo10 infusion (Table 1). No dose-limiting toxicities (DLTs) were observed. Grade II acute GvHD developed in 4 patients (2 in Cohort 1 and 2 in Cohort 3, 29%), with 2 patients progressing to chronic GvHD. Importantly, 63% of the evaluable patients (5 out of 8) achieved the IR efficacy endpoint (Fig 1), doubling the historical control rate of 31%. This endpoint is defined as the attainment of ≥50 CD3+CD4+ T cells/mcl by Day +60 post αβdepleted-HSCT, which indicates successful IR. Notably, the infusion of T-allo10 resulted in an increase in TCRαβ+ CD3+CD4+ T cells with a memory phenotype in all patients, with preliminary analyses suggesting that this correlates with reduced incidence of severe infections. Furthermore, Tr1 cells were detectable in the peripheral blood shortly after T-allo10 infusion, reaching the highest levels at day +7 post-infusion (20.4% of memory CD4+ T cells). These findings support our hypothesis that the adoptive transfer of T-allo10 promotes IR without escalating the risk of GvHD.In conclusion, the results obtained from the phase I portion of this clinical trial demonstrate the ability of T-allo10 infusion of improving IR while mitigating the risk of GvHD in pediatric and young adult patients with hematologic malignancies post-αβdepleted-HSCT.