We have developed a strategy of therapeutic vaccination against lymphoma that we interdigitate with conventional autologous hematopoietic cell transplantation (autoHCT). Autologous tumor cells are activated ex vivo with a TLR9 ligand (CpG oligonucleotide), irradiated, and then used as a vaccine to induce a T cell immune response in the patient against the tumor. The immune T cells are collected and then re-infused into the patient immediately after autoHCT. The goal is to allow the T cells to expand in the patient during the period of immunologic recovery and to mediate immune rejection of residual tumor. This strategy has a number of important features: -Simplicity: No tumor antigens need be identified in advance;instead the whole tumor cell is the vaccine. The activation step employs an "off the shelf, chemically defined substance (CpG oligonucleotide) with a track record of safety and effectiveness as an immune stimulant in lymphoma. -Feasibility: We have now performed the entire treatment strategy under our IND without adverse effects. -Homeostatic T cell proliferation: We have shown in preclinical models that during the immediate post transplantation period adoptively transferred T cells expand and that T effector cells preferentially do so over T regulatory cells, resulting in powerful therapeutic effects. We have initiated a clinical trial for patients newly diagnosed with Mantle Cell Lymphoma and have accrued 35 patients during the first 3 years. Sixteen of these patients have completed the entire treatment program and nine of eleven evaluable patients have achieved the primary endpoint of CR with negative minimal residual disease (MRD) assays at one year. Since our original goals of feasibility and of inducing anti-tumor immune responses have been achieved we are now expanding the trial with a defined goal of freedom from MRD at one year of greater than or equal to 85% using a highly sensitive method of measurement, high-throughput sequencing.

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Sega, Emanuela I; Leveson-Gower, Dennis B; Florek, Mareike et al. (2014) Role of lymphocyte activation gene-3 (Lag-3) in conventional and regulatory T cell function in allogeneic transplantation. PLoS One 9:e86551
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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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