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 types of cancer, to enhance treatment effectiveness, reduce toxicities and infectious complications, and stimulate tumor resistance.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
3P01CA023766-35S1
Application #
8907356
Study Section
Special Emphasis Panel (ZCA1-RPRB-B (O1))
Program Officer
Merritt, William D
Project Start
1998-09-01
Project End
2018-03-31
Budget Start
2014-07-01
Budget End
2015-03-31
Support Year
35
Fiscal Year
2014
Total Cost
$58,683
Indirect Cost
$24,957
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Tarek, N; Gallagher, M M; Chou, J F et al. (2015) KIR and HLA genotypes have no identifiable role in single-unit dominance following double-unit umbilical cord blood transplantation. Bone Marrow Transplant 50:150-2
Hubbard-Lucey, Vanessa M; Shono, Yusuke; Maurer, Katie et al. (2014) Autophagy gene Atg16L1 prevents lethal T cell alloreactivity mediated by dendritic cells. Immunity 41:579-91
Dubrovsky, Leonid; Pankov, Dmitry; Brea, Elliott Joseph et al. (2014) A TCR-mimic antibody to WT1 bypasses tyrosine kinase inhibitor resistance in human BCR-ABL+ leukemias. Blood 123:3296-304
Maguire, William F; McDevitt, Michael R; Smith-Jones, Peter M et al. (2014) Efficient 1-step radiolabeling of monoclonal antibodies to high specific activity with 225Ac for ?-particle radioimmunotherapy of cancer. J Nucl Med 55:1492-8
Olson, Amanda L; Dahi, Parastoo B; Zheng, Junting et al. (2014) Frequent human herpesvirus-6 viremia but low incidence of encephalitis in double-unit cord blood recipients transplanted without antithymocyte globulin. Biol Blood Marrow Transplant 20:787-93
Curran, Shane A; Romano, Emanuela; Kennedy, Michael G et al. (2014) Phenotypic and functional activation of hyporesponsive KIRnegNKG2Aneg human NK-cell precursors requires IL12p70 provided by Poly(I:C)-matured monocyte-derived dendritic cells. Cancer Immunol Res 2:1000-10
Dahi, P B; Ponce, D M; Devlin, S et al. (2014) Donor-recipient allele-level HLA matching of unrelated cord blood units reveals high degrees of mismatch and alters graft selection. Bone Marrow Transplant 49:1184-6
Dahi, Parastoo B; Ponce, Doris M; Devlin, Sean et al. (2014) "No wash" albumin-dextran dilution for double-unit cord blood transplantation is safe with high rates of sustained donor engraftment. Biol Blood Marrow Transplant 20:490-4
Tyler, Eleanor M; Jungbluth, Achim A; Gnjatic, Sacha et al. (2014) Cancer-testis antigen 7 expression and immune responses following allogeneic stem cell transplantation for multiple myeloma. Cancer Immunol Res 2:547-58
Pai, Sung-Yun; Logan, Brent R; Griffith, Linda M et al. (2014) Transplantation outcomes for severe combined immunodeficiency, 2000-2009. N Engl J Med 371:434-46

Showing the most recent 10 out of 304 publications