Veto cells for safer nonmyeloablative haploidentical HSCT and CAR T cell therapy

Haploidentical donors are a readily available source for mismatched hematopoietic bone marrow transplantation. The application of this regimen is constantly increasing with the advent of methods that overcome T-cell alloreactions that occur due to human-leukocyte-antigen disparity between host and donor. One successful method to overcome both graft rejection and graft-vs-host disease is transplantation of large numbers T-cell-depleted (TCD) haploidentical stem cell grafts (haploSCT), after myeloablative conditioning. The success of stem cell dose escalation is attributed to a unique immunoregulatory cell-property, termed "veto-activity." However, engraftment of mismatched hematopoietic stem cells following reduced-intensity conditioning still represents a major challenge. Here, we describe how the addition of post-transplant high-dose cyclophosphamide can promote immune tolerance induction after megadose TCD haploSCT, following nonmyeloablative conditioning. We also discuss ways of harnessing the immune regulatory properties of adoptively transferred "veto" cells to support mixed chimerism further and confer tolerance to cell-therapies, such as CAR-T cells. These approaches will soon be tested in phase 1-2 clinical studies and may prove to be a safe and efficacious treatment for many disorders such as hemoglobinopathies, autoimmune diseases, and as a prelude for organ tolerance. Moreover, this approach could pave the way for "off-the-shelf" cell-therapy agents, making them cheaper and easily obtainable.