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.
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.
|Zerboni, Leigh; Sung, Phillip; Sommer, Marvin et al. (2018) The C-terminus of varicella-zoster virus glycoprotein M contains trafficking motifs that mediate skin virulence in the SCID-human model of VZV pathogenesis. Virology 523:110-120|
|Muffly, Lori; Sheehan, Kevin; Armstrong, Randall et al. (2018) Infusion of donor-derived CD8+ memory T cells for relapse following allogeneic hematopoietic cell transplantation. Blood Adv 2:681-690|
|Tavallaee, Mahkam; Steiner, David F; Zehnder, James L et al. (2018) Coexistence of BRAF V600E and TERT Promoter Mutations in Low-grade Serous Carcinoma of Ovary Recurring as Carcinosarcoma in a Lymph Node: Report of a Case. Int J Gynecol Pathol :|
|Du, Jing; Paz, Katelyn; Thangavelu, Govindarajan et al. (2017) Invariant natural killer T cells ameliorate murine chronic GVHD by expanding donor regulatory T cells. Blood 129:3121-3125|
|Spinner, Michael A; Fernández-Viña, Marcelo; Creary, Lisa E et al. (2017) HLA-mismatched unrelated donor transplantation using TLI-ATG conditioning has a low risk of GVHD and potent antitumor activity. Blood Adv 1:1347-1357|
|Costa, Helio A; Neal, Joel W; Bustamante, Carlos D et al. (2017) Identification of a Novel Somatic Mutation Leading to Allele Dropout for EGFR L858R Genotyping in Non-Small Cell Lung Cancer. Mol Diagn Ther 21:431-436|
|Chen, Yi-Bin; Efebera, Yvonne A; Johnston, Laura et al. (2017) Increased Foxp3+Helios+Regulatory T Cells and Decreased Acute Graft-versus-Host Disease after Allogeneic Bone Marrow Transplantation in Patients Receiving Sirolimus and RGI-2001, an Activator of Invariant Natural Killer T Cells. Biol Blood Marrow Transplant 23:625-634|
|Xu, Liwen; You, Xiaoqing; Zheng, PingPing et al. (2017) Methodologic Considerations in the Application of Next-Generation Sequencing of Human TRB Repertoires for Clinical Use. J Mol Diagn 19:72-83|
|Paul, Jed; Sahaf, Bita; Perloff, Spenser et al. (2016) High-throughput allogeneic antibody detection using protein microarrays. J Immunol Methods 432:57-64|
|Pierini, Antonio; Strober, William; Moffett, Caitlin et al. (2016) TNF-? priming enhances CD4+FoxP3+ regulatory T-cell suppressive function in murine GVHD prevention and treatment. Blood 128:866-71|
Showing the most recent 10 out of 307 publications