Making a Cold Tumor Hot: The Role of Vaccines in the Treatment of Glioblastoma

Abstract

The use of immunotherapies for the treatment of brain tumors is a topic that has garnered considerable excitement in recent years. Discoveries such as the presence of a glymphatic system and immune surveillance in the central nervous system (CNS) have shattered the theory of immune privilege and opened up the possibility of treating CNS malignancies with immunotherapies. However, despite many immunotherapy clinical trials aimed at treating glioblastoma (GBM), very few have demonstrated a significant survival benefit. Several factors for this have been identified, one of which is that GBMs are immunologically "cold," implying that the cancer does not induce a strong T cell response. It is postulated that this is why clinical trials using an immune checkpoint inhibitor alone have not demonstrated efficacy. While it is well established that anti-cancer T cell responses can be facilitated by the presentation of tumor-specific antigens to the immune system, treatment-related death of GBM cells and subsequent release of molecules have not been shown to be sufficient to evoke an anti-tumor immune response effective enough to have a significant impact. To overcome this limitation, vaccines can be used to introduce exogenous antigens at higher concentrations to the immune system to induce strong tumor antigen-specific T cell responses. In this review, we will describe vaccination strategies that are under investigation to treat GBM; categorizing them based on their target antigens, form of antigens, vehicles used, and pairing with specific adjuvants. We will review the concept of vaccine therapy in combination with immune checkpoint inhibitors, as it is hypothesized that this approach may be more effective in overcoming the immunosuppressive milieu of GBM. Clinical trial design and the need for incorporating robust immune monitoring into future studies will also be discussed here. We believe that the integration of evolving technologies of vaccine development, delivery, and immune monitoring will further enhance the role of these therapies and will likely remain an important area of investigation for future treatment strategies for GBM patients.

Keywords: T cells; dendritic cells; glioblastoma; heat shock protein; neoantigen; peptide; tumor antigen; vaccine.

Figure 1

Principle of Cancer Vaccination. (A) Vaccine selection and preparation – Upon selection of suitable candidates a vaccine platform is chosen which includes either peptides, DNA or RNA. This platform is then packaged into a vehicle which includes either dendritic cells (DCs), viral vectors, heat shock proteins (HSPs), or montanide. The vaccine is then combined or paired with an adjuvant in an effort to boost the efficacy of the vaccine. Common choices of adjuvants include tetanus toxoid, poly-ICLC, imiquimod, GM-CSF, immune checkpoint inhibitors, as well as many others. (B) Vaccines can be administered intra-venously, intra-nodally, intra-dermally, or intra-muscularly. (C) Antigens are then presented by APCs to naïve or memory T cells in the lymph node. For GBM, presentation most commonly occurs in the deep-seated cervical lymph node. (D) Primed T cells migrate to the site of the tumor where they mount an anti-tumor immune response.