A major complication of allogeneic hematopoietic stem cell transplantation (allo-HCT) is acute graft-versus-host disease (aGvHD). aGvHD is an immunologically mediated disease, that contributes substantially to transplant- related morbidity and mortality. The overall incidence of aGvHD is between 35% and 50% depending upon donor-recipient histocompatibility differences and carries approximately a 50% mortality rate. T regulatory cells (Tregs), a phenotypically diverse subset of lymphocytes that promote and maintain immunological tolerance, have been extensively researched as a cellular therapy for aGvHD. Preclinical trials have demonstrated that the presence of IL-10-producing T regulatory type 1 (Tr1) cells or the forkhead box P3 (FOXP3) T regulatory cells (FOXP3+Tregs) correlates with aGvHD modulation and enhanced transplantation tolerance after allo-HCT. T- allo10 cells are a cell product containing donor-derived Tr1 cells primed with host-derived tolerogenic dendritic cells (DC-10) to induce immune tolerance. We have FDA approval (IND# 17292 ) for a Phase 1 clinical trial of escalating doses of T-allo10 cells in pediatric and young adult patients receiving mismatched related or unrelated HCT for hematologic malignancies, and 2 patients have been successfully treated. The primary endpoints of the Phase 1 trial are 1) the feasibility of producing the T-allo10 product in our GMP facility and 2) the safety of the administration of the T-allo10 product.
Aim 1 is the completion of this trial including the immunological evaluation of the T-allo10 product and the longitudinal assessment of the HCT patients for the persistence of the infused Tr1 cells using TCR clonotypic analyses and the immune reconstitution. Tr1 containing T-allo10 cells offer enormous promise, but are a mixed cell product also containing T effector cells, that potentially reduce their effectiveness. Although polyclonal FOXP3+Tregs have shown some efficacy in enhancing tolerance post- transplant, the infused cells have limited in vivo survival, and the isolation of pure FOXP3+Tregs is difficult. Therefore, we have developed ?second-generation? Tr1 cells and FOXP3+Tregs by lentiviral-vector (LV) gene transfer into CD4+ T effector cells. LV-mediated gene transfer of FOXP3 into CD4+ T cells creates ?FOXP3+Treg-like? (CD4FOXP3) cells. Similarly, ?Tr1-like? (CD4IL-10) cells can be obtained via LV-IL-10 expression in human CD4+ T effector cells. In preliminary experiments, we have demonstrated that 3rd party polyclonal CD4IL-10 and CD4FOXP3 T cells can suppress GvHD in a humanized model of immune deficient mice.
In Aims 2 and 3 we will compare autologous polyclonal and alloAg-specific CD4IL-10 and CD4FOXP3 for their prevention of aGvHD, their impact on hematopoietic stem cell (HSC) engraftment, immune reconstitution, tolerance and GvL activity in preclinical studies. These studies will provide preclinical data toward developing future therapies, that will improve the outcomes of patients receiving allo-HCT.
Acute graft versus host disease (aGvHD) is caused by the attack of donor immune cells against recipient tissues after allogeneic hematopoietic stem cell transplant; T regulatory cells (Tr1 and FOXP3+Tregs) have been a focal point of research to prevent aGvHD and induce immunological tolerance. Using patient samples from our ongoing T-allo10 Phase 1 clinical trial, we will longitudinally evaluate recipients for the presence of T-allo10 derived Tr1 cells using TCR clonotypic and immune reconstitution analyses. At the same time using gene transfer techniques, we will generate and analyze ?second-generation? Tr1 cells and FOXP3+Tregs.
Showing the most recent 10 out of 307 publications
