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.
|Dao, Tao; Korontsvit, Tatyana; Zakhaleva, Victoria et al. (2017) An immunogenic WT1-derived peptide that induces T cell response in the context of HLA-A*02:01 and HLA-A*24:02 molecules. Oncoimmunology 6:e1252895|
|Peled, Jonathan U; Devlin, Sean M; Staffas, Anna et al. (2017) Intestinal Microbiota and Relapse After Hematopoietic-Cell Transplantation. J Clin Oncol 35:1650-1659|
|Getta, Bartlomiej M; Roshal, Mikhail; Zheng, Junting et al. (2017) Allogeneic Hematopoietic Stem Cell Transplantation with Myeloablative Conditioning Is Associated with Favorable Outcomes in Mixed Phenotype Acute Leukemia. Biol Blood Marrow Transplant 23:1879-1886|
|Barba, Pere; Ratan, Ravin; Cho, Christina et al. (2017) Hematopoietic Cell Transplantation Comorbidity Index Predicts Outcomes in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndromes Receiving CD34+ Selected Grafts for Allogeneic Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant 23:67-74|
|Barba, Pere; Hilden, Patrick; Devlin, Sean M et al. (2017) Ex Vivo CD34+-Selected T Cell-Depleted Peripheral Blood Stem Cell Grafts for Allogeneic Hematopoietic Stem Cell Transplantation in Acute Leukemia and Myelodysplastic Syndrome Is Associated with Low Incidence of Acute and Chronic Graft-versus-Host Disease Biol Blood Marrow Transplant 23:452-458|
|Boudreau, Jeanette E; Giglio, Fabio; Gooley, Ted A et al. (2017) KIR3DL1/ HL A-B Subtypes Govern Acute Myelogenous Leukemia Relapse After Hematopoietic Cell Transplantation. J Clin Oncol 35:2268-2278|
|Ghosh, Arnab; Smith, Melody; James, Scott E et al. (2017) Donor CD19 CAR T cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity. Nat Med 23:242-249|
|Fischer, Julius C; Bscheider, Michael; Eisenkolb, Gabriel et al. (2017) RIG-I/MAVS and STING signaling promote gut integrity during irradiation- and immune-mediated tissue injury. Sci Transl Med 9:|
|Goldberg, Jenna D; Zheng, Junting; Ratan, Ravin et al. (2017) Early recovery of T-cell function predicts improved survival after T-cell depleted allogeneic transplant. Leuk Lymphoma 58:1859-1871|
|Ito, Reiko; Hale, Laura P; Geyer, Susan M et al. (2017) Late Effects of Exposure to Ionizing Radiation and Age on Human Thymus Morphology and Function. Radiat Res 187:589-598|
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