The program project """"""""Biology and Genetics of Marrow Allografts for Leukemia"""""""" is an integrated multidisciplinary program of basic and clinical research aimed at elucidating genetically controlled molecular characteristics of lymphoid normal hematopoietic and leukemic cells distinguishing a normal marrow donor from an allogeneic related or unrelated leukemic host which can induce, sustain or modulate the cellular interactions which contribute to engraftment or rejection, tolerance or graft-versus-host disease, leukemic resistance or relapse and immune reconstitution or prolonged immune deficiency. In this project, we propose to identify and characterize at the molecular level, microvariant disparities within the HLA complex and minor alloantigens expressed on donor hematopoietic cells which can stimulate marrow allograft rejection and are targeted by host T-cells in vivo. The contribution of these allodisparities to impairments or delays in the functional development of donor T-cells within the environment of an allogeneic leukemic host and their capacity to interact effectively with donor or host derived antigen-presenting cells will also be assessed. The anti-leukemic properties of a marrow allograft will be reexamined, through prospective studies of patients transplanted with conventional or T-cell depleted HLA-matched related and T-cell depleted HLA-compatible unrelated grafts correlating frequencies of host-reactive donor T-cells, and donor derived LAK cells capable of lysing host leukemic targets with the capacity of the graft to replace host cells in both lymphoid and hematopoietic lineages and to eradicate residual host leukemic cells detectable by pcr-amplified DNA hybridization techniques. A novel animal model system is also proposed for examining and characterizing human donor cell interactions with host leukemic cells both in vivo and in vitro which may contribute to the leukemic resistance conferred by a marrow allograft. Finally, novel approaches are proposed for molecular detection of CMV infection and the generation of donor lymphoid cells responsive to CMV antigens to augment host resistance in the post- transplant period. To complement and extend this program of basic research, the Program of Experimental Therapeutics in Transplantation proposes a series of randomized trials and single armed phase I and II studies designed to identify and assess potentially more effective cytoreduction regimens, novel T-cell depletion techniques, antibody targeted radiotherapy and strategies incorporating adoptive transfers of leukemia or virus reactive cells. By integrating these trials with ongoing laboratory investigations of the genetic and cellular basis of interactions between donor and host controlling engraftment, functional reconstitution of hematopoiesis and immunity, and resistance to leukemia and opportunistic viral infections, it is expected that new insights into the unique biology of marrow allografts and improved approaches to their application can be achieved.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Sloan-Kettering Institute for Cancer Research
New York
United States
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Malard, Florent; Labopin, Myriam; Cho, Christina et al. (2018) Ex vivo and in vivo T cell-depleted allogeneic stem cell transplantation in patients with acute myeloid leukemia in first complete remission resulted in similar overall survival: on behalf of the ALWP of the EBMT and the MSKCC. J Hematol Oncol 11:127
Luduec, Jean-BenoƮt Le; Kudva, Anupa; Boudreau, Jeanette E et al. (2018) Novel multiplex PCR-SSP method for centromeric KIR allele discrimination. Sci Rep 8:14853
Shah, Gunjan L; Moskowitz, Craig H (2018) Transplant strategies in relapsed/refractory Hodgkin lymphoma. Blood 131:1689-1697
Avanzi, Mauro P; Yeku, Oladapo; Li, Xinghuo et al. (2018) Engineered Tumor-Targeted T Cells Mediate Enhanced Anti-Tumor Efficacy Both Directly and through Activation of the Endogenous Immune System. Cell Rep 23:2130-2141
Staffas, Anna; Burgos da Silva, Marina; Slingerland, Ann E et al. (2018) Nutritional Support from the Intestinal Microbiota Improves Hematopoietic Reconstitution after Bone Marrow Transplantation in Mice. Cell Host Microbe 23:447-457.e4
Velardi, Enrico; Tsai, Jennifer J; Radtke, Stefan et al. (2018) Suppression of luteinizing hormone enhances HSC recovery after hematopoietic injury. Nat Med 24:239-246
Moskowitz, Craig H (2018) Should all patients with HL who relapse after ASCT be considered for allogeneic SCT? A consult, yes; a transplant, not necessarily. Blood Adv 2:821-824
Kim, Seong Jin; Huang, Yao-Ting; Foldi, Julia et al. (2018) Cytomegalovirus resistance in CD34+ -selected hematopoietic cell transplant recipients. Transpl Infect Dis 20:e12881
Maslak, Peter G; Dao, Tao; Bernal, Yvette et al. (2018) Phase 2 trial of a multivalent WT1 peptide vaccine (galinpepimut-S) in acute myeloid leukemia. Blood Adv 2:224-234
DeFilipp, Zachariah; Peled, Jonathan U; Li, Shuli et al. (2018) Third-party fecal microbiota transplantation following allo-HCT reconstitutes microbiome diversity. Blood Adv 2:745-753

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