**9. Conclusions**

**vaccination therapy** uses administration of the antigens to activate an antitumor immune response. There is a vaccine targeting the mutant of epidermal growth factor receptor EGFRvIII (only expressed in GBM cells in about 20–25% of cases) – rindopepimut. Vaccination with dendritic cells is based on their ability to absorb all kinds of antigens and to secrete interleukin-2, thus activating T lymphocytes and initiating an efficient and specific immune response [85]. The application of tumor-derived heat shock proteins as tumor antigen carrier may be effective in boosting immune response. **Antibody-based immunotherapy** refers to the use of specific interaction between antibodies and antigens to block negative immune regulatory molecules that would have been preventing activated T cells from attacking the cancer cells. The most promising class of drugs that emerged is based on immune checkpoint inhibitors. Nivolumab and pembrolizumab are antibodies targeting the receptor programmed cell death-1 (PD-1) receptor of lymphocytes. Ipilimumab is an antibody that binds cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), which would have inhibiting cytotoxic T lymphocyte to destroy cancer cells. **Adoptive cell therapy** is based on infusion of activated immune effector cells into cancer patients with the goal to enhance antitumor immunity. Immune effector cells include lymphokine-activated killer (LAK) cells, natural killer (NK) cells, T cells, tumor-infiltrating lymphocytes (TILs), cytotoxic T lymphocyte (CTLs), tumor antigen-specific TCR-transgenic T cells and chimeric antigen receptors-modified T cells (CAR T) [86]. This approach would be

**Gene therapy** is designed for delivery of genetic material, usually transgenes or viruses, into cells for therapeutic purposes. There are four types of gene therapy proposed for the treatment of GBM: suicide gene therapy, immunomodulatory gene therapy, tumor-suppressor gene therapy, and oncolytic virotherapy. **Suicide gene therapy** uses genes that encode enzymes able to convert a non-toxic drug into an active cytotoxic compound. The herpes simplex virus (HSV) type 1 thymidine kinase (tk) gene has been used as a "suicide gene", allowing to tumor cells to produce high levels of tk. Ganciclovir is the systemically injected prodrug, that will be converted by tk into a toxic metabolite. This compound is incorporated into DNA of actively proliferating tumor cells, and consequently blocks DNA replication and inhibits cell division. Apoptosis underlies the mechanism of cytotoxicity [87]. Another "suicide gene" is cytosine deaminase (CD), an enzyme capable to convert an antifungal drug, 5-fluorocytosine (5-FC), into the highly toxic compound 5-fluorouracil (5-FU). This is again converted into molecules which interfere with RNA processing and DNA synthesis and apoptosis invariably occurs. **Immunomodulatory gene therapy** induces or augments an enhanced specific antitumoral immune response, overcoming the tumor-induced immunosuppression. **Tumor-suppressor gene therapy** aims to restore the function of a tumor-suppressor gene lost or functionally inactivated in cancer cells. They play a critical role in maintaining genome integrity and in regulating cell proliferation, differentiation, and apoptosis. In GBM, there is at least one tumor-suppressor gene mutated or deleted in all cases; in 91% of patients, 2 or more of these tumor-suppressor genes are inactivated [88]. Correcting the genetic abnormalities in the glioma cells has been demonstrated to suppress tumor growth via induction of apoptosis and cell cycle arrest. Genes encoding p53, p16, or phosphatase and tensin homolog (PTEN) can be candidates for this type of therapy. **Oncolytic virotherapy** employs replication-competent viruses with natural or engineered tropism and activity against tumors. They specifically infect and replicate in target tumor cells. During progeny particle release, tumor

beneficial to non-responsive patients and non-immunogenic tumors.

26 Brain Tumors - An Update

Effective treatment in GBM remains one of the most formidable challenge in neuro-oncology. Treatment is multimodal and despite significant advances in diagnostic technology, surgical technique, radiation, chemotherapy and targeted therapy, the prognosis remains poor. Largescale research efforts are required to understand the molecular biology of brain tumors and to discover novel therapies. Synergistic multimodal strategies and individualized treatments are likely to be the best approach of these complex tumors to finally improve survival and quality of life of the patients.
