Allogeneic hematopoietic stem cell transplantation, often referred to as """"""""bone marrow transplantation"""""""", represents a curative therapy for many individuals with leukemia, lymphoma, multiple myeloma, and myelodysplastic syndrome. However, the broadened application of transplantation therapy of these cancers is limited by two immune reactions that are mediated primarily by T cells, namely graft-versus-host disease (GVHD;T cell attack of donor cells against the patient) and graft rejection (or the host-versus-graft response;HVGR). GVHD is the main cause of lethality after transplantation. The HVGR results in the need to administer toxic doses of chemotherapy prior to transplanation, and thereby results in the current limitation of transplantation to individuals having a closely matched donor either from within the family or through the National Marrow Donor Program. Our laboratory focuses on new T cell graft engineering strategies designed to prevent GVHD and graft rejection. In murine models, we have shown that donor Th2 cells, which are generated ex vivo in the presence of the immune modulation drug rapamycin, can potently inhibit GVHD while preserving a component of the beneficial graft-versus-tumor (GVT) effect;furthermore, such Th2 cells effectively prevent the rejection of fully genetically mis-matched hematopoietic stem cells. We have made significant progress in translating these findings to the clinic. We have developed a method for generating human Th2 cells in rapamycin, and we have initiated a clinical trial investigating these cells in patients with refractory hematologic malignancy. Current data are consistent with our murine data, as recipients of Th2 cells grown in rapamycin have a low rate of acute GVHD;furthermore, administration of Th2 cells has allowed for a significant reduction in the amount of preparative chemotherapy required to achieve engraftment of the allograft. Such allogeneic Th2 cells are currently being evaluated on two clinical protocols. In the first protocol, NIH Clinical Center Protocol #04-C-0055, patients with refractory hematologic malignancy such as leukemia, lymphoma, and multiple myeloma are receiving a low-intensity transplant that is supplemented with donor Th2 cells;currently, approximately 125 patients have received therapy on this protocol. In the second protocol, NIH Clinical Center Protocol #08-C-0088, patients with refractory and metastatic renal cell carcinoma are receiving a low-intensity transplant that is supplemented with multiple infusions of donor Th2 cells. Of note, both of these protocols are being implemented in a multi-center manner, with Hackensack University in New Jersey serving as the multi-center site. Relevant cancer sites: Non-Hodgkins Lymphoma, Multiple Myeloma. Relevant Research Areas: Bone Marrow Transplantation, Organ Transplantation Research, Hematology/Lymph, Stem Cell Research, Clinical Research.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIASC010288-16
Application #
8763703
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
16
Fiscal Year
2013
Total Cost
$627,158
Indirect Cost
Name
National Cancer Institute Division of Clinical Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Mossoba, Miriam E; Halverson, David C; Kurlander, Roger et al. (2015) High-Dose Sirolimus and Immune-Selective Pentostatin plus Cyclophosphamide Conditioning Yields Stable Mixed Chimerism and Insufficient Graft-versus-Tumor Responses. Clin Cancer Res 21:4312-20
Fisher, Virginia; Khuu, Hanh; David-Ocampo, Virginia et al. (2014) Analysis of the recovery of cryopreserved and thawed CD34+ and CD3+ cells collected for hematopoietic transplantation. Transfusion 54:1088-92
Bevans, Margaret F; Mitchell, Sandra A; Barrett, John A et al. (2014) Symptom distress predicts long-term health and well-being in allogeneic stem cell transplantation survivors. Biol Blood Marrow Transplant 20:387-95
Castiello, Luciano; Mossoba, Miriam; Viterbo, Antonella et al. (2013) Differential gene expression profile of first-generation and second-generation rapamycin-resistant allogeneic T cells. Cytotherapy 15:598-609
Baird, Kristin; Steinberg, Seth M; Grkovic, Lana et al. (2013) National Institutes of Health chronic graft-versus-host disease staging in severely affected patients: organ and global scoring correlate with established indicators of disease severity and prognosis. Biol Blood Marrow Transplant 19:632-9
Foglietta, M; Neelapu, S S; Kwak, L W et al. (2013) Neoantigen and tumor antigen-specific immunity transferred from immunized donors is detectable early after allogeneic transplantation in myeloma patients. Bone Marrow Transplant 48:269-77
Salit, Rachel B; Fowler, Daniel H; Dean, Robert M et al. (2013) Host lymphocyte depletion as a strategy to facilitate early full donor chimerism after reduced-intensity allogeneic stem cell transplantation. Biol Blood Marrow Transplant 19:1509-13
Fowler, Daniel H; Mossoba, Miriam E; Steinberg, Seth M et al. (2013) Phase 2 clinical trial of rapamycin-resistant donor CD4+ Th2/Th1 (T-Rapa) cells after low-intensity allogeneic hematopoietic cell transplantation. Blood 121:2864-74
Shaffer, Brian C; Modric, Marko; Stetler-Stevenson, Maryalice et al. (2013) Rapid complete donor lymphoid chimerism and graft-versus-leukemia effect are important in early control of chronic lymphocytic leukemia. Exp Hematol 41:772-8
Floisand, Y; Brinch, L; Gedde-Dahl, T et al. (2012) Ultra-short course sirolimus contributes to effective GVHD prophylaxis after reduced-intensity allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 47:1552-7

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