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 5-years survival rate lower than 10%. GBM worldwide incidence is about two to three per 100000 adults per year, and the standard treatment encompasses surgical debulking with subsequent radiation therapy and concomitant chemotherapy.

Given its heterogenicity, its intracranial location and the onset of multidrug resistance mechanisms, new tailored approaches, such as immunotherapy and drug delivery systems, have recently gained increasing interest. In recent years, tumor microenvironment exploration has revealed that immune response evasion is one of the crucial GBM diagnostic hallmarks. Since this discovery, the possibility to reverse tumor-mediated immunosuppression has received increasing attention, changing the paradigm of cancer treatment from chemotherapy to immunotherapy. On the other hand, the blood-brain barrier (BBB) represents the main challenge in developing therapeutics for central nervous system (CNS) tumors; for instance, 100% of large molecules and 98% of small molecules fail to achieve sufficient therapeutic doses at the brain. To this purpose, nanotechnology-based drug delivery systems represent promising platforms to improve drug bioavailability, reduce side effects and allow the co-delivery of multiple drugs to the target cells.

This chapter gives an overview of current innovative approaches to GBM focusing on the therapeutic benefit of immunotherapeutic agents and drug delivery systems. In particular, we aim to provide a summary of the recent clinical trials using immunomodulator, 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), vaccination therapy. Although ICIs and vaccines have shown limited efficacy when used as monotherapy, promising results have been reported for their combination with immune adjuvants, such as chemo, radio- and photodynamic therapies, suggesting an emerging strategy for a more successful antitumoral immune response. With this chapter, we aim to provide an overview of the state-of-the-art and future perspective of GBM treatment, mainly addressed to pharmaceutical students and researchers in the field of clinical drug research.

---

Keywords: Blood-Brain Barrier (BBB), Blood-Brain Tumor Barrier (BBTB), Clinical trials, Combination approach, Drug Resistance, Glioblastoma, Immune Checkpoint Inhibitors (ICIs), Immunotherapy, Long-term Immune Memory, Nanocarriers, Nanomedicine, Vaccine.