A glance at drug delivery systems and emerging immunotherapeutic strategies for the treatment of glioblastoma

Glioblastoma (GBM) represents the most common and aggressive primary brain tumor with a very poor prognosis and a 5-years survival rate lower than 10%. GBM worldwide incidence is about two to three per 100000 adults per year. The standard treatment of a new diagnosed GBM encompasses surgical debulking with subsequent radiation therapy and concomitant chemotherapy. Given the tumor heterogenicity, the difficult intracranial location, as well as the onset of multidrug resistance mechanisms, new tailored approaches, such as drug delivery systems and immunotherapy, have recently gained an increasing interest. Indeed, for central nervous system (CNS) tumors, the blood-brain barrier (BBB) represents the main challenge in developing therapeutics: due to the BBB, the 100% of large molecules and the 98% of small molecules fail to achieve sufficient therapeutic doses at the brain. To this purpose, nanocarriers drug delivery systems represent promising platforms for improving compounds solubility and reducing side effects, allowing for the effective co-delivery of multiple therapeutics to the target cells. Furthermore, exploration of the tumor microenvironment has revealed that the evading immune destruction is one of the GBM diagnostic hallmarks. Since this discovery, the activation of immune system has received increasing attention in the field of oncology and, in some cases, has changed the paradigm of cancer treatment from chemotherapy to immunotherapy. The crucial factor of immunotherapy success relies on its ability to reverse tumor-mediated immunosuppression. This book chapter gives an overview of current innovative approaches to GBM focusing on the therapeutic benefit of drug delivery systems and immunotherapeutic agents. Additionally, the final section of the chapter provides an overview of the recent clinical trials using immune checkpoint inhibitors (ICIs), i.e. monoclonal antibodies (mAbs) blocking cytotoxic T‑lymphocyte‑associated protein 4 (CTLA‑4) and programmed cell death‑1 (PD-1/PD-L1a), and indoleamine 2,3‑dioxygenase‑1 (IDO 1) inhibitors. Although ICIs have shown limited efficacy and sometimes severe immune-related adverse events when used as monotherapy, promising results have been reported for IDO1 inhibitors used in combination with other ICIs or immune adjuvant approaches, such as chemo-, radio- and photo-dynamic therapies, suggesting an emerging strategy for a more successful antitumoral immune response. With this chapter, we aim to provide an overview of the current and future perspective of GBM treatment, aimed mainly at pharmaceutical students and researchers in the field of clinical drug research