BBB Seminar: Gaetano Finocchiaro
Immunotherapy of glioblastoma multiforme
Unit of Molecular Neuro-Oncology, Neurological Institute C. Besta, Milan, Italy
Glioblastomas (GB), as other cancers, may evolve and become clinically evident through immunoediting of the immune system, implying that a number of potential epitopes arising during the evolution of glioma have been selected against by the immune system and are not expressed anymore (Pellegatta et al., 2011). This may not be sufficient to escape the immune system, as GB creates a highly immune-suppressive immune environment that is based upon the release of a number of cytokines and chemokines, TGF-beta being the most relevant one. This environment is responsible for the increased presence of T-regulatory cells (T-regs, characterized by expression of the transcription factor FoxP3) infiltrating the tumor. Cancer immunotherapy is attempting to re-expose tumors to the control of the immune system (Mellman et al., 2011). Ipilimumab, a monoclonal antibody to the negative regulator of T cells CTLA4, has shown efficacy in patients with advanced melanomas. Dendritic cells (DC), the most potent of antigen presenting cells (Steinman, 2011), also showed efficacy in patients with metastatic prostate cancer. Decreased frequency of T-regs and decreased expression of CTLA4 after DC immunotherapy were correlated with longer survival of GB patients (Fong et al., 2012). We are also using DC immunotherapy to treat first line and recurrent GB (Nava et al., 2012). Initial results on recurrent GB have shown prolonged survival in patients with a significant increase of NK cells in peripheral blood after vaccination (Pellegatta et al., 2013). Interactions with chemotherapy and the identification of novel targets are important areas to be investigated in order to improve the efficacy of immunotherapy in GB and other tumors.
Fong, B., Jin, R., Wang, X., Safaee, M., Lisiero, D.N., Yang, I., Li, G., Liau, L.M., and Prins, R.M. (2012). Monitoring of regulatory T cell frequencies and expression of CTLA-4 on T cells, before and after DC vaccination, can predict survival in GBM patients. PLoS One 7, e32614.
Mellman, I., Coukos, G., and Dranoff, G. (2011). Cancer immunotherapy comes of age. Nature 480, 480–9.
Nava, S., Dossena, M., Pogliani, S., Pellegatta, S., Antozzi, C., Baggi, F., Gellera, C., Pollo, B., Parati, E.A., Finocchiaro, G., and Frigerio, S. (2012). An optimized method for manufacturing a clinical scale dendritic cell-based vaccine for the treatment of glioblastoma. PloS One 7, e52301.
Pellegatta, S., Cuppini, L., and Finocchiaro, G. (2011). Brain cancer immunoediting: novel examples provided by immunotherapy of malignant gliomas. Expert Rev. Anticancer Ther. 11, 1759–74.
Pellegatta, S., Eoli, M., Frigerio, S., Antozzi, C., Bruzzone, M.G., Cantini, G., Nava, S., Anghileri, E., Cuppini, L., Cuccarini, V., Ciusani. E., Dossena, M., Pollo, B., Mantegazza, R., Parati, E.A. and Finocchiaro, G. (2013). The natural killer cell response and tumor debulking are associated with prolonged survival in recurrent glioblastoma patients receiving dendritic cells loaded with autologous tumor lysates. OncoImmunology 2, e23401.
Steinman, R.M. (2011). Decisions about dendritic cells: past, present, and future. Annu. Rev. Immunol. 30, 1-22.
Host: Martha Chekenya Enger, Department of Biomedicine