Hematopoietic Cell Transplant Co-Morbidity Index (HCT-CI): Ability to Predict Outcomes in Haploidentical (HI) Hematopoietic Stem Cell Transplantation (HSCT)

Abstract

s / Biol Blood Marrow Transplant 20 (2014) S211eS256 S245 of Medicine, Section of Hematology-Oncology, University of Illinois Hospital & Health Sciences System, Chicago, IL Our previous studies have shown the ability of human CD34+ cells to stimulate T cell alloproliferative responses in-vitro. Here, we investigated the anti-CD34 T cell alloreactivity invivo by co-transplanting human CD34+ cells and allogeneic T cells of an incompatible individual into NSG mice. Human CD34+ cells (2x105/animal) were transplanted with allogeneic T cells at different ratios ranging from 1:50 to 1:0.5, or without as a control. Engraftment of human CD 45+ cells was analyzed by flow cytometry at 1, 2, 4, or 8 weeks. Marrow engraftment of human CD45+cells was significantly decreased in mice transplanted at any CD34:T cell ratio compared to control mice that did not receive T cells. Transplantation of T cells resulted in graft failure since >98% of human CD45+ cells in the marrow and spleen of NSG mice were CD3+. A normal CD4:CD8 T cell ratio was detected and CD4+ cells were mostly CD45RA+. Mice transplanted with CD34+ and allogeneic T cells at 1:1 ratio were sacrificed at 1, 2, or 4 weeks to analyze the kinetics of human cell engraftment in the bone marrow and spleen. At 2 weeks post transplant, the bone marrow showed CD34-derived myeloid cells, whereas the spleen showed only allo-T cells. At 4 weeks, all myeloid cells had been rejected and only T cells were detected both in the bonemarrow and spleen. Based on our previous in-vitro studies showing that T cell alloreactivity against CD34+ cells is mainly due to B7:CD28 costimulatory activation, we injected the mice with CTLA4-Ig (Abatacept, Bristol Myers Squibb) from d-1 to d+28 post transplantation of CD34+ and allogeneic T cells. We found that treatment of mice with CTLA4-Ig prevented rejection and allowed CD34+ cells to fully engraft the marrow of NSG mice at 4 weeks with an overall 13 + 7% engraftment of human CD45+ marrow cells (n1⁄45). These included 53 + 9% myeloid CD33+ cells, 22 + 3% CD14+ monocytes, 7 + 2% CD1c myeloid dendritic cells, and 4 + 1% CD34+ cells while CD 19 B cells were only 3% and CD3+ T cells 0.5 + 1%. Persistent myeloid engraftment was found at d+56 after stopping CTLA4-Ig on d+28. Here we demonstrate that costimulatory blockadewith CTLA4-Ig can prevent Tcell mediated rejection of incompatible human CD34+ stem cells. We also show that the NSGmodel can be utilized to test in-vivo immunotherapy strategies aimed at engrafting human stem cells across HLA barriers. These results will prompt the design of future clinical trials of CD34+ cell transplantation for patients with severe non-malignant disorders, such as sickle cell anemia, thalassemia, immunodeficiencies or aplastic anemia. Figure 1. Overall Survival by HCT-CI Score 379 Hematopoietic Cell Transplant Co-Morbidity Index (HCT-CI): Ability to Predict Outcomes in Haploidentical (HI) Hematopoietic Stem Cell Transplantation (HSCT) Neil D. Palmisiano, Sameh Gaballa, Onder Alpdogan, Matthew Carabasi, Joanne Filicko, Margaret Kasner, Ubaldo Martinez, John L. Wagner, Mark Weiss, Neal Flomenberg, Dolores Grosso. Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University,