Project 6 Project 6 proposes novel clinical trials to reduce non-leukemic mortality associated with allogenic HSCT for treatment of leukemias and myelodysplasia (MDS), particularly in older patients and in patients lacking an HLA-matched sibling donor and to treat post transplantation viral disease and leukemic relapse. There are 6 clinical trials under 2 specific aims.
Aim1 includes 3 phase II clinical trials of TCD grafts to speed marrow and immune reconstitution.
Aim 1 A will evaluate the ability of TCD-PBSC (CliniMACS) given after one of 2 reduced intensity regimens using only chemotherapy, as compared to our standard high intensity, TBI containing regimen to secure consistent engraftment, low rates of GVHD, TRM and relapse and high DFS.
Aim 1 8 clinically translates Dr. van den Brink's studies done during this grant period to use palifermin and leuprolide to protect the thymic stroma and promote early, robust recovery of T cell immunity, thereby reducing TRM due to infection in older patients (median age >50).
Aim I C, also derived from trials conducted in the current grant, will evaluate whether addition of haplotype disparate TCD-PBSC to a double cord blood (CB) graft provides earlier hematopoietic reconstitution, thereby reducing early TRM while maintaining the low incidence of relapse observed following double CB grafts.
Aim 2 includes 3 trials of adoptive cellular therapy. Effective prevention of GVHD, as developed at our center, allows for adoptive cell therapies in the absence of post-transplant immuno-suppressive drugs to prevent GVHD.
Aim 2 A is a 2- armed Phase II extension ofthe Phase I trial conducted in the current grant period to evaluate treatment of CMV infections with a) CMVpp65-specific T-cells derived from seropositive HSCT donors of b) partially HLA matched 3rd party CMV-CTL for patients receiving CBs or transplants from CMV seronegative donors.
Aim 2 B derives from studies conducted in the current grant and extends our Phase I trial of single dose WT1 -CTL to multiple dosing for treatment of patients with recurrence of WT-1 + leukemias.
Aim I C is a phase I trial of donor-derived EBV-CTL transduced to express a CD19-specific chimeric antigen receptor for the treatment of GDI 9+ leukemias.
These trials test novel transplant and post transplant strategies which show promise of improving prospects for sustained DFS in adults and children with acute leukemia, MDS and lymphoma, particularly older patients and patients lacking an HLA matched sibling donor. They will also test adoptive therapies which may be broadly applied to patients with severe viral infection or leukemia relapse.
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|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|
|Haak, Bastiaan W; Littmann, Eric R; Chaubard, Jean-Luc et al. (2018) Impact of gut colonization with butyrate-producing microbiota on respiratory viral infection following allo-HCT. Blood 131:2978-2986|
|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|
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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|
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|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|
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