Improved Engraftment without Graft-Versus-Host Disease After MHC-Mismatched Cord Blood Transplantation with Photochemically Treated Donor Lymphocytes.

Abstract

Abstract 2425Poster Board II-402 Introduction:Unrelated cord blood transplantation (CBT) is associated with a risk of graft rejection due in part to a limiting cellular content of the CB unit. Increasing the cellular content of the CB unit mitigates the graft rejection risk, but methods to use adjuvant immuno-modulatory cell co-infusions have also been tested with some success. We have investigated the co-infusion of photochemically (psoralen S59) treated mature donor T lymphocytes in a major histocompatibility complex (MHC) [H2-haplotype] mismatched murine transplant model as a new method to facilitate engraftment of donor CB cells. Methods:We analyzed the rates of donor hematopoietic cell engraftment, graft versus host disease (GVHD), and long-term survival in H2 haplotype disparate (C57BL/6®AKR) mice after CBT. Three different experimental groups were transplanted after sublethal radiation. Group 1 received allogeneic full term newborn peripheral blood alone, group 2 was transplanted with the same donor cells and unmanipulated donor T cells, and group 3 was transplanted with the similar donor cells and psoralen (S-59) treated donor T cells. Results:We observed a low rate of donor engraftment after transplantation with cord blood alone (Group 1). There was better engraftment but a high rate of fatal GVHD after transplantation with cord blood and unmodified donor T-cells (Group 2). The best results were observed after transplantation with 3 × 106 nucleated cord blood cells and 9 ×106 S-59 treated T cells (Group 3b). The engraftment rate was 75% compared to 12.5% after transplantation with 6 × 106 CB cells alone (p=0.04). The long-term survival in group 3 was 100% and the rate and severity of GVHD were minimal. Engraftment observed after CBT with unmodified donor T-cells (group 2) was accompanied by severe GVHD and poor survival. Donor myeloid, B cells and T cells were documented in the spleen and bone marrow of Group 3 mice by 30 days after CBT, although full hematological recovery was delayed until 50-60 days after CBT. Conclusions:These results show improved cord blood engraftment kinetics across a disparate H2 haplotype by adding psoralen-treated donor T lymphocytes. Co-transplantation of psoralen treated lymphocytes with CB cells facilitated durable engraftment of donor MHC high/c-kit+ cells in the marrow and splenic compartments with complete but delayed hematopoietic recovery. The low GVHD risk and excellent long-term survival observed in this murine model suggests the potential for clinical application.Treatment GroupCB dose (× 106)T-cell dose (× 106)GVHD (score 1–10)EngraftmentSurvival1 (CB alone)0.5 – 10-1/37 (3)1/37 (2.7%)36/37 (97%)2 (CB + T)1.0 – 3.03.03/8 (6)3/8 (38%)4/8 (50%)3a (CB + S59T)0.5 – 3.01.0 – 3.00/161/16 (6.3%)16/16 (100%)3b (CB + S59T)3.09.01/8 (3)6/8 (75%)*8/8 (100%)3c (CB + S59T)6.03.00/63/6 (50%)6/6 (100%)*p value=0.007, compared to group 1 transplanted with similar nucleated cord blood cell dose. Disclosures:No relevant conflicts of interest to declare.