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.
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.
|Boudreau, Jeanette E; Hsu, Katharine C (2018) Natural Killer Cell Education and the Response to Infection and Cancer Therapy: Stay Tuned. Trends Immunol 39:222-239|
|Lin, Richard J; Ho, Caleb; Hilden, Patrick D et al. (2018) Allogeneic haematopoietic cell transplantation impacts on outcomes of mantle cell lymphoma with TP53 alterations. Br J Haematol :|
|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-Benoît 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|
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