Recently direct evidence supporting the contribution of effector cells derived from the donor to the anti-leukemic effects of a marrow graft has been provided by several groups including our own, who have found that among patients transplanted for CML over 70 percent of recipients of unmodified or T cell depleted marrow allografts who have relapsed post transplant can be reinduced into durable molecular remissions by treatment with infusions of high doses of donor-derived peripheral blood monounclear cells (PBMC). At present, the nature of the leukemia reactive cells(s) in adoptively transferred PBMC that incude remissions is unknown. Such leukemia-selective effectors may include T-cells reactive against leukemia-specific antigens or alloantigens preferentially expressed on leukemic cells or reactive against leukemia-specific oncogene fusion products, as recently described by our group, as well as natural killer cells exhibiting HLA-non-restricted cytotoxic activity. This project will focus on the development of strategies of adoptive cell therapy, and T cell therapy generated in vivo (active specific immunotherapy). incorporating selected or targeted effector cells that are able to distinguish leukemic cells. Human leukemias bearing fusion gene tragets that will serve as models in this project include CML and Ph+ ALL (p210 and p190 targets), AML-M2, t(8-21) (p92) and AML-M4, inv (16) (p67).
The Aims are: 1) To develop effective strategies for generating and selecting potentially immunogenic leukemia fusion gene peptides. 2) To sensitize and propagate in vitro, leukemia associated fusion gene peptide-specific T lymphocytes and to characterize these cells as to their antigen-specificity and their relative proliferative and cytotoxic responses against HLA-matched peptide loaded normal targets in comparison with leukemic cells bearing the fusion gene. 3) To assess the leukemia-specific activity of fusion gene peptide-specific T cells, in comparison with alloreactive T cells and NK cells both in vitro and in vivo, after adoptive transfer into xenografted SCID mice bearing the targeted human leukemia or a normal hematopoietic cell graft. These experiments constitute a """"""""proof- of-principle"""""""" for this approach. The results of these preclinical studies will be used to formulate clinical trials to assess the antileukemic activity of vaccinating donors, or patients with CML, PH+ALL or AMLs bearing fusion gene products.
|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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