Toward safer haploidnetical hematopoietic stem cell transplantation.

Abstract

The use of haploidentical HSCT is gaining momentum using either megadose T-cell depleted (TCD) myeloablative HSCT, or T cell replete nonmyeloablative HSCT in conjunction with cyclophosphamide post-transplant (PTCY). However, the risks of myeloablative protocols in the former or prolonged immunosuppression in the later, adversely impacting GVL and anti-pathogen immunity are challenging. Recently, we demonstrated in a stringent BM allografting murine model, that combining megadose TCD HSCT with PTCY, enabled durable chimerism induction without GVHD in the absence of any immune suppression after CY. The outcome of this approach in onea patientwith multiple myeloma and one with Hodgkin's disease indicate it might offer an attractive safe protocol for haploidentical HSCT. In addition, preclinical experiments show that donor type anti-third party central memory veto T cells that are administrated with a megadose TCD HSCT can potentially offer an editional toolfor saferconditioning protocols. Moreover, proof of concept murine studies demonstrate that genetically manipulated veto cells armed with specific receptors against cancer cells, can survive for months in allogeneic recipients, laying the rational for the use of "off-the shelf " Veto-CAR T cells.