T cells are very potent eliminators of residual cancer cells in children with leukemia after allogeneic hematopoietic stem cell transplant (alloHSCT) through the graft-versus-leukemia (GVL) effect. T cells are typically transfused into patients in the stem cell graft or as a separate donor lymphocyte infusion (DLI). The major limitation is that these same T cells can also attack and damage normal body tissues in the patient, causing graft-versus-host disease (GVHD). GVHD contributes to significant morbidity and mortality after alloHSCT. Although a variety of medications are available to treat GVHD, these medications also suppress the ability of T cells to mediate a beneficial GVL effect. The long-term objective of this proposal is to develop novel therapies that preserve the GVL benefit of alloHSCT while successfully preventing GVHD. Because GVHD produces inflammatory cytokines, such as gamma interferon (IFN?), that activate the immune system, this project will utilize mouse models of alloHSCT to inhibit STAT1 signaling in plasmacytoid dendritic cells (pDCs) to make alloHSCT recipients resistant to the effects of IFN?. Adoptively transferring STAT1-deficient pDCs, a novel cellular therapy, will allow the usage of a high dose of DLI to treat leukemia safely without causing GVHD. Lastly, it will also develop and screen a variety of approved drugs that target STAT1 on GVL activity using a relevant alloHSCT model with pediatric leukemia. The ultimate goal is to support the research priorities of the National Cancer Institute by developing research that will lead to novel therapies for leukemia. This proposal will provide the foundation for bringing drugs that target STAT1 forward to the clinic as a means of improving the safety and efficacy of alloHSCT, and ultimately improving survival in patients with leukemia.
Leukemia is largely incurable in adults and is also the leading cause of nonaccidental death in children. Current chemotherapy and hematopoietic stem cell transplant (HSCT) regimens have improved cure rates substantially, but also cause significant morbidity and mortality. This proposal will provide the foundation for bringing novel drugs that target a molecule called STAT1 as a means of improving the safety and efficacy of HSCT, and ultimately improving the ability of clinicians to treat patients with high-risk or refractory leukemia.
| Lieberman, Nicole A P; DeGolier, Kole; Haberthur, Kristen et al. (2018) An Uncoupling of Canonical Phenotypic Markers and Functional Potency of Ex Vivo-Expanded Natural Killer Cells. Front Immunol 9:150 |
| Forsberg, Matthew H; Das, Amritava; Saha, Krishanu et al. (2018) The potential of CAR T therapy for relapsed or refractory pediatric and young adult B-cell ALL. Ther Clin Risk Manag 14:1573-1584 |
| Piscopo, Nicole J; Mueller, Katherine P; Das, Amritava et al. (2018) Bioengineering Solutions for Manufacturing Challenges in CAR T Cells. Biotechnol J 13: |
| Wolfe, Adam D; Capitini, Christian M; Salamat, Shahriar M et al. (2018) Neck Rhabdoid Tumors: Clinical Features and Consideration of Autologous Stem Cell Transplant. J Pediatr Hematol Oncol 40:e50-e54 |
| Chapelin, Fanny; Capitini, Christian M; Ahrens, Eric T (2018) Fluorine-19 MRI for detection and quantification of immune cell therapy for cancer. J Immunother Cancer 6:105 |
| Bouchlaka, Myriam N; Moffitt, Andrea B; Kim, Jaehyup et al. (2017) Human Mesenchymal Stem Cell-Educated Macrophages Are a Distinct High IL-6-Producing Subset that Confer Protection in Graft-versus-Host-Disease and Radiation Injury Models. Biol Blood Marrow Transplant 23:897-905 |
| Bouchlaka, Myriam N; Ludwig, Kai D; Gordon, Jeremy W et al. (2016) (19)F-MRI for monitoring human NK cells in vivo. Oncoimmunology 5:e1143996 |
| Elsaid, M Y; Capitini, C M; Diamond, C A et al. (2016) Successful matched unrelated donor stem cell transplant in Hemoglobin Bart's disease. Bone Marrow Transplant 51:1522-1523 |
| Li, Y; Bouchlaka, M N; Wolff, J et al. (2016) FBXO10 deficiency and BTK activation upregulate BCL2 expression in mantle cell lymphoma. Oncogene 35:6223-6234 |
| McDowell, Kimberly A; Hank, Jacquelyn A; DeSantes, Kenneth B et al. (2015) NK cell-based immunotherapies in Pediatric Oncology. J Pediatr Hematol Oncol 37:79-93 |
Showing the most recent 10 out of 12 publications
