Haploidentical and neonatal combined transplant generates GVL effect in a murine model of haplo-cord transplant.

Abstract

Abstract Favorable outcomes after hematopoietic stem cell transplant depend on the availability of HLA-matched donors, which varies significantly by family size and ancestry. Alternative donor transplants, including haploidentical (HT) and umbilical cord blood (UCT), are viable alternatives that allow for a greater degree of HLA mismatch, albeit with inferior outcomes due to increased graft-versus-host disease (GVHD) and poor engraftment, respectively. Haplo-cord transplant is a combined graft transplant approach that overcomes the limitations of UCT by transient engraftment of the haploidentical graft, resulting in exceptional outcomes, including reduced GVHD and rapid engraftment compared to either HT or UCT alone. Recent studies of T cell-replete haplo-cord have also consistently demonstrated less relapse than HT alone. The biology underlying haplo-cord transplant, however, remains entirely unknown. Here, we report the first murine model of haplo-cord transplant, which will allow for mechanistic studies into its associated graft-versus-leukemia (GVL) effect. mNeon-expressing C1498 murine AML cells were used to establish disease in immunocompetent F1 C57BL/6J x DBA/2 mice, resulting in both circulating leukemia and disseminated organ infiltration, with mortality at a median of 21 days. Leukemic mice developed B cell lymphopenia and an expansion of Ly6C+ monocytes in the blood. Animals with active, established disease were conditioned with lethal irradiation and transplanted with adult marrow, which significantly improved survival but still resulted in uniform mortality. The presence of a major histocompatibility mismatch between the donor and leukemia did not improve survival compared to HLA-matched transplant. As a model for UCT, neonatal blood was trialed as a graft source but failed to rescue lethally irradiated mice due to very low levels of hematopoietic stem and progenitor cells (HSPC). However, transplantation of neonatal liver in combination with blood effectively reconstituted all major lineages of hematopoiesis in lethally irradiated hosts. Haplo-neonatal transplant recipients established robust haploidentical engraftment with dominant chimerism in neutrophils, monocytes, B cells, and NK cells. Interestingly, haplo-neonatal transplant also promoted residual host-derived chimerism. In C1498-bearing mice, combined haploidentical and neonatal transplant resulted in significantly improved survival from leukemia compared to either graft alone, indicative of a GVL effect. Interestingly, elimination of the histocompatibility mismatch from the haploidentical donor abrogated the improved survival in haplo-neonatal transplant.