Understanding and enhancing mechanisms of priming in cancer immunotherapy

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DESCRIPTION (provided by applicant): Malignant brain tumors are the leading cause of cancer-related death in people under age 35. Novel therapies that selectively target residual migratory glioma cells after surgery are urgently needed. Therapies that will be effective against these extremely heterogeneous tumors should have broad molecular targets. Immunotherapy using autologous tumor cell lysate vaccines targeting multiple tumor antigens is a promising approach being tested in numerous clinical trials. However, complete tumor regression is rarely achieved. The effect of cell culture conditions during vaccine production on the immune response and clinical outcome is poorly understood. Moreover, although tumor-reactive T cells may be correlated to prolonged survival in select patients, the functional heterogeneity of responding T cells and their relation to antibody response and clinical outcome is inadequately defined. We discovered that the oxygen concentration used to culture tumor cells during vaccine production flips an immunologic switch, dictating whether cytotoxic T lymphocytes (CTL) or antibody production dominate in the resulting immune response. Glioma cells grown in physiologic brain oxygen (5% O2) have enhanced adjuvant properties, are enriched for a cancer stem cell phenotype, and increase expression of known immunogenic glioma antigens relative to cells grown in the conventional oxygen level (20% O2). Furthermore, glioma-bearing mice vaccinated with glioma lysates prepared from 5% O2 cultures mixed with CpG oligodeoxynucleotides (ODN) as an adjuvant exhibit a three- fold increase in tumor infiltrating T cells and significantly increased survival relative to mice vaccinated with lysates from 20% O2 cultures. We propose to elucidate the effect that oxygen concentration used during vaccine production has on the immune response and clinical response in an innovative large animal model of glioma. We have established that pet dogs with spontaneous gliomas represent an outstanding animal model in which surgery, steroids, and postoperative chemotherapy can be given similar to human patients, lending great translational relevance to our findings. In specific aim 1, we will determine the difference in survival between dogs with glioma treated by surgery, chemotherapy, and vaccination with glioma lysate / CpG ODN prepared from cells cultured in 5% or 20% O2. Tumor burden and toxicity will be determined similar to human patients. In specific aim 2, the frequency of "polyfunctional" CTLs that secrete multiple effector cytokines and degranulate to kill tumor cells will be determined and correlated with tumor-reactive antibody response and survival. The deliverables of this study will be: i) new knowledge relating oxygen tension used in vaccine production to T and B cell responses and patient survival, ii) validation of immune monitoring assays useful in predicting which patients may respond to immunotherapy, iii) efficacy and safety data in the only useful large animal model of glioma in the world to justify accelerated clinical trial design in human glioma patients. PUBLIC HEALTH RELEVANCE: Glioma is an aggressive brain tumor that is very difficult to treat. Vaccines have been tested in glioma patients with suboptimal results. We have developed a novel vaccine with increased efficacy in mouse models. In this project we will determine if vaccination can increase the survival of pet dogs with glioma as a prelude to human clinical trials.