Glioblastoma multiforme, the most aggressive form of glioma, is a lethal brain tumor with a dismal median survival of 15-19 months. Immunotherapy is a promising adjuvant therapy for malignant brain tumors. Lack of adequate, endogenous antigen presentation and the immune suppressive nature of the tumor microenvironment present significant hurdles that need to be overcome in order to mount an effective immune response, capable of tumor elimination. Vaccination with tumor-derived antigen has sought to overcome inadequate antigen presentation, yet has shown to been inefficient at complete tumor elimination. Functionally unresponsiveness, anergy, can be induced in immune cells when antigen recognition occurs without proper costimulation. To test if additional costimulation was necessary to achieve a functional immune response, costimulatory molecules 41BBL, CD80, GITRL and OX40L, fused to the Fc portion of human immunoglobulin, were tested in combination with tumor vaccine. Vaccine/Fc-OX40L yielded the most potent response resulting in complete tumor regression in the majority of animals and the generation of immunological memory capable of rapidly clearing tumor upon tumor rechallenge. Additionally, combining vaccine/Fc-OX40L with the standard of care chemotherapy resulted in regression of 100% of glioma tumors, however 80% of these animals developed fatal secondary lymphoid malignancy. These data demonstrate Fc-OX40L has incredibly potent activity against experimental gliomas relative to the other molecules tested. In addition, it reveals a potential hazard in combining mutagenic chemotherapeutics with immunotherapy.
Lymphocytes isolated from vaccine/Fc-OX40L treated animals had enhanced cytolytic activity and increased proliferative capacity, compared to controls. Additional analysis demonstrated a CD4 T cell, NK, and B cell dependent, and CD8 T cell independent mechanism of action. The presence of tumor reactive antibody in the serum of treated mice and deposition of antibody at the tumor site, combined with the observation that loss of the Fc receptor negatively affected the ability of animals to control tumor growth generated interest in antibody-mediated mechanisms. Tumor infiltration of perforin expressing NK, NKT, and neutrophil-like cells in vaccine/Fc-OX40L treated animals may provide a possible mechanism of tumor killing. Further understanding the necessary effector cells and mechanisms involved in tumor elimination will aid in the design of future immunotherapy approaches.
University of Minnesota Ph.D. dissertation. May 2012. Major: Molecular, Cellular, Developmental Biology and Genetics. Advisor: John R. Ohlfest, Ph.D. 1 computer file (PDF); x, 129 pages.
Murphy, Katherine Anne.
Immune-based tumor regression induced by Fc-OX40L in a murine model of glioma.
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