Identification of glioma-associated antigens for brain tumor immunotherapy

Glioma is a tumor occurring in the brain and one of the most devastating cancers, affecting children and young adults and having a very high morbidity with poor prognosis. The propensity of glioma cells to invade normal brain structures and to resist current treatments makes new therapeutic strategies an urgent need for this disease. Among them, tumor immunotherapy, defined as use of the immune system to fight cancer, is showing very promising results in many malignancies. The knowledge that the rules governing immune responses in other tissues are also valid for the brain has allowed development of immunotherapy for glioma. Among currently investigated glioma immunotherapies, T cell vaccines and adoptive cell therapy are restrained by the availability of tumor-derived antigens specifically expressed on tumor cells but absent, or expressed at very low levels, on normal cells, to avoid collateral damage on healthy parts of the body. Thus, for glioma, an incessant search for tumor-associated antigens has been ongoing, and we contributed to this field by identifying novel glioma-associated peptides with demonstrated presentation at the tumor cell surface, which we will present in the first part of this thesis. These results have been readily translated into clinical application via formulation of a peptide vaccine (IMA950) that is currently being tested with Poly-ICLC in grade IV glioma patients in our institution with promising results. We will present this trial and preliminary immunomonitoring data in the second part of this work. Then, to further extend the use of the IMA950 peptide vaccine to patients with less aggressive disease, who are more prone to develop clinically relevant immune responses, we assessed expression of the IMA950 antigens in a series of glioma patients with grade II and III tumors. This will be developed in the third part of this report. Finally, the discussion will integrate some early results on the effect of radiotherapy and chemotherapy on the immune system of patients, in order to understand how to better combine our vaccine with standard treatments. All in all, we will show that our research resulted in the development of a new peptide vaccine for patients with glioma, which is in clinical trial and can be proposed through all tumor grades