Adoptive Immunotherapy of Tr1 Cells to Improve Outcome of Allo-HSCT Treatment for Pediatric AML
Acute Myeloid Leukemia (AML) accounts for one fourth of acute pediatric leukemias, but causes over half of the pediatric leukemic deaths. In contrast to the tremendous success in treating acute lymphocytic leukemia (ALL) in the last three decades, improvements in AML therapy have been limited. Chemotherapy and allogeneic hematopoietic stem cell transplant (allo-HSCT) are established treatment methods, particularly after relapse, but graft versus host disease (GvHD) hinders the success. Further, for allo-HSCT to cure AML, an intact graft versus leukemia (GvL) transplant response is required. Prevention of GvHD without affecting GvL is a key challenge in allo-HSCT treatment of pediatric AML.
A diverse population of donor T cells mediates the therapeutic benefits of GvL, but these donor T cells also cause GvHD. Isolating the GvL effect while reducing or eliminating GvHD could have a transformative impact on quality of life and survival of pediatric AML allo-HSCT recipients. In preliminary work we have shown that the donor T cell subtype, adaptive Treg type 1 (Tr1) cells, show great promise as a potential therapeutic that can diminish GvHD and improve GvL response.
We propose experiments focused on the demonstration that Tr1 cells specifically kill AML leukemic blasts from pediatric patients. Secondly, we propose the development of a Tr1-cell based clinical protocol for therapeutic application that could dramatically improve pediatric AML patient survival after allo-HSCT treatment.