The application of the conditioning regimen of total lymphoid irradiation (TLl) and anti-thymocyte globulin (ATG) to leukemia and lymphoma patients undergoing hematopoietic cell transplantation (HCT) at the Stanford Medical Center has resulted in extension of the transplant procedure to the elderiy, and a very low incidence of acute graft versus host disease (GVHD) and transplant related mortality. However, the incidence of tumor relapse during the first 3 years after transplantation was about 50%. The patients with mixed chimerism had a relapse rate that was significantly higher than those with complete chimerism. The goals of the research program are to further study two new approaches for prevention and/or treatment of tumor relapse after HCT in mice that can be applied to clinical trials. In the first approach, we found that a subset of freshly isolated CD8+ memory T cells has potent graft anti-tumor (GVT) activity without inducing GVHD. The infusion of the latter cells into mixed chimeric mice with lymphoma relapse after transplantation resulted in conversion to complete chimerism and tumor cures after conditioning with conventional total body irradiation (TBI). We will determine whether this approach can be used in combination with the safer TLl based conditioning in mouse strain combinations that are MHC matched and mismatched, and study the molecular and cellular basis of tumor cures. We will apply the same approach in Phase l/ll clinical trials of patients with lymphoma relapse or at high risk for relapse due to mixed chimerism. In the second approach we will combine immunotherapy and allogeneic HCT for the prevention and treatment of lymphoma relapse by immunizing the donors to the idiotype protein tumor antigen. Our preliminary studies showed that the combination results in a marked increase in GVT activity. We will study the ability of infused CD8+ memory T cells from immunized donors to cure lymphoma relapse, and the molecular basis of enhanced GVT activity In both murine and human studies, recipients will be monitored for tumor burden, severity of GVHD, levels of chimerism and persistence of donor cells and CD8+ memory T cell clones.

Public Health Relevance

The development of successful new approaches to prevent or treat relapses of non-Hodgkin's lymphoma after reduced intensity conditioning for HCT would make a marked impact on long term patient survival. Currently tumor relapse is the main cause of death after transplantation, now that acute GVHD and transplant related mortality afflict less than 5% of patients including the elderly.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA049605-24A1
Application #
8476445
Study Section
Project Start
1997-05-01
Project End
2018-03-31
Budget Start
2013-06-03
Budget End
2014-03-31
Support Year
24
Fiscal Year
2013
Total Cost
$150,528
Indirect Cost
Name
Stanford University
Department
Type
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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Hongo, D; Tang, X; Baker, J et al. (2014) Requirement for interactions of natural killer T cells and myeloid-derived suppressor cells for transplantation tolerance. Am J Transplant 14:2467-77
Florek, Mareike; Sega, Emanuela I; Leveson-Gower, Dennis B et al. (2014) Autologous apoptotic cells preceding transplantation enhance survival in lethal murine graft-versus-host models. Blood 124:1832-42
Benjamin, Jonathan; Chhabra, Saurabh; Kohrt, Holbrook E et al. (2014) Total lymphoid irradiation-antithymocyte globulin conditioning and allogeneic transplantation for patients with myelodysplastic syndromes and myeloproliferative neoplasms. Biol Blood Marrow Transplant 20:837-43
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Logan, Aaron C; Vashi, Nikita; Faham, Malek et al. (2014) Immunoglobulin and T cell receptor gene high-throughput sequencing quantifies minimal residual disease in acute lymphoblastic leukemia and predicts post-transplantation relapse and survival. Biol Blood Marrow Transplant 20:1307-13
Logan, A C; Zhang, B; Narasimhan, B et al. (2013) Minimal residual disease quantification using consensus primers and high-throughput IGH sequencing predicts post-transplant relapse in chronic lymphocytic leukemia. Leukemia 27:1659-65
Colonna, Lucrezia; Florek, Mareike; Leveson-Gower, Dennis B et al. (2013) IL-17 gene ablation does not impact Treg-mediated suppression of graft-versus-host disease after bone marrow transplantation. Biol Blood Marrow Transplant 19:1557-65
Shamloo, Amir; Manchandia, Milan; Ferreira, Meghaan et al. (2013) Complex chemoattractive and chemorepellent Kit signals revealed by direct imaging of murine mast cells in microfluidic gradient chambers. Integr Biol (Camb) 5:1076-85

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