We propose an integrated, multidisciplinary program of basic and clinical research addressing challenges to the success of allogeneic HSCT used to treat of AML, ALL and MDS in older adults and patients lacking a histocompatible donor. The program's central theme of this program is: The exploration of novel approaches whereby injuries to normal host tissues induced by conditioning, infection and GVHD can be reduced or prevented, and resistance to pathogens and recurrent leukemia selectively enhanced. The program includes 6 research projects and 3 cores. Project 1 examines NK cell development, the role of KIR engagement of HLA ligand expressed by host and donor in modulating NK function, and, particularly, the contributions of activating KIRs, 2DS1 and 3Ds1 to resistance against leukemic relapse and CMV infections. Project 2 examines receptor ligand interactions governing monocyte response to stimuli from the microflora including their activation, mobilization and tissue distribution, and their capacity to both stimulate and participate in GVHD. Project 3 examines how T-cells when stimulated with allogeneic monocyte-derived dendritic cells in the presence of JAK-2 inhibitors induced into a durable state of anergy and the effects of JAK-2 inhibitors on responses are tumor antigens presented by other functionally distinct types of dendritic cells. Project 4 evaluates the regulation of IL-22, its role in the stimulation of enteri and thymic epithelial repair and its potential to reduce toxicities, modulate GVHD and enhance resistance to infection. Project 5 tests new monoclonal antibodies specific for WT1 peptide/HLA complexes, long-lived EBV T-cells transduced to express TCRs or chimeric antigen receptors specific for WT1/HLA complexes and new heteroclitic vaccines for adoptive immunotherapy of WT-1+ leukemias, Project 6 proposes 6 clinical trials testing new conditioning and both T-cell depleted and cord blood HSCT to reduce toxicities, potentiate hematopoietic and thymopoietic recovery and reduce TRM and new adoptive T-cell therapies for CMV infections or recurrent leukemia . The 3 cores include: Core A which provides all patient samples and evaluate grafts pre and post HSCT, Core B Biostatistics and Core C administrative support and oversight.

Public Health Relevance

Research conducted in this program should ultimately lead to improvements in results of allogeneic HSCT for acute leukemia and MDS, through reductions in acute toxicities, infection and relapse. The new drugs, antibody and cell based immuno therapies and vaccines may also be broadly applied to patients with other

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-B (O1))
Program Officer
Merritt, William D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Sloan-Kettering Institute for Cancer Research
New York
United States
Zip Code
Ataie, Niloufar; Xiang, Jingyi; Cheng, Neal et al. (2016) Structure of a TCR-Mimic Antibody with Target Predicts Pharmacogenetics. J Mol Biol 428:194-205
Richardson, Paul G; Riches, Marcie L; Kernan, Nancy A et al. (2016) Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood 127:1656-65
Hasan, A N; Selvakumar, A; Shabrova, E et al. (2016) Soluble and membrane-bound interleukin (IL)-15 Rα/IL-15 complexes mediate proliferation of high-avidity central memory CD8(+) T cells for adoptive immunotherapy of cancer and infections. Clin Exp Immunol 186:249-265
Spitzer, Barbara; Perales, Miguel-Angel; Kernan, Nancy A et al. (2016) Second Allogeneic Stem Cell Transplantation for Acute Leukemia Using a Chemotherapy-Only Cytoreduction with Clofarabine, Melphalan, and Thiotepa. Biol Blood Marrow Transplant 22:1449-54
Park, Jae H; Geyer, Mark B; Brentjens, Renier J (2016) CD19-targeted CAR T-cell therapeutics for hematologic malignancies: interpreting clinical outcomes to date. Blood 127:3312-20
Xiong, Huizhong; Keith, James W; Samilo, Dane W et al. (2016) Innate Lymphocyte/Ly6C(hi) Monocyte Crosstalk Promotes Klebsiella Pneumoniae Clearance. Cell 165:679-89
Jiang, Yanwen; Ortega-Molina, Ana; Geng, Huimin et al. (2016) CREBBP Inactivation Promotes the Development of HDAC3 Dependent Lymphomas. Cancer Discov :
Shono, Yusuke; Docampo, Melissa D; Peled, Jonathan U et al. (2016) Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice. Sci Transl Med 8:339ra71
Hobbs, G S; Kaur, N; Hilden, P et al. (2016) A novel reduced intensity conditioning regimen for patients with high-risk hematological malignancies undergoing allogeneic stem cell transplantation. Bone Marrow Transplant 51:1010-2
Huang, Yao-Ting; Neofytos, Dionysios; Foldi, Julia et al. (2016) Cytomegalovirus Infection after CD34(+)-Selected Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant 22:1480-6

Showing the most recent 10 out of 392 publications