The major determinant for peptide vaccine-mediated immunogenicity is antigen choice. TAAs, given their expression on normal cells, usually elicit a subdued immune response due to central tolerance. On the other hand, TSAs, given their exclusive presentation on tumor cells, generally elicit a robust immune response similar to the immune response seen against antigens of infectious diseases.

The advantage of TAAs is their high frequency of expression in gliomas, making it possible to give most patients off-the-shelf synthetic tumor antigen peptides. Furthermore, by giving patients a cocktail of peptides, a broader immune response targeting multiple tumor subsets can be elicited. In contrast, TSAs are unique to the tumor and thereby peptides from these antigens may result in a highly tumor-focused immune response.

The mutated protein EGFRvIII, as discussed previously, represents an ideal target for anti-tumor immunotherapy. Our laboratory constructed a 13-amino-acid peptide spanning the vIII mutation and conjugated it to keyhole limpet hemocyanin (KLH). A phase II clinical trial showed that patients with EGFRvIII-positive newly diagnosed GBM, when vaccinated with rindopepimut, the EGFRvIII peptide, had a median survival of 26 months compared with the control historical cohort, which had a median survival of 15 months [70]. These positive results led to the start of a currently ongoing phase III clinical trial with the EGFRvIII peptide vaccine (Table 12.2).

However, given the heterogeneous nature of malignant brain tumor and peptide HLA restrictions, the drawback of single peptide vaccinations is that they may only be effective in a percentage of patients, and in the case of tumor-specific peptides only in the subset of patients expressing the mutated peptide. Trials are ongoing to determine whether combinations of multiple peptides will result in clinically effective peptide vaccination strategies (Table 12.2). Furthermore, increased research on neoantigens, antigens that spontaneously arise in individuals during the course of tumor progression, may lead to personalized solutions in which a patient’s tumor is sequenced after resection and peptide vaccinations are constructed based on the mutanome. Even though major challenges remain, such as locating immunogenic mutations and quickly constructing immunogenic peptides, clinical trials employing a personalized peptide pool approach have commenced (Table 12.2).

Whole tumor lysate can be used as a source of antigen and has the advantage of providing a tumor-specific repertoire of all potentially immunogenic epitopes. The rich repertoire of tumor-associated antigens contains epitopes for both CD8+ and CD4+ T cells, which is important as the parallel presentation of MHC Class I and II antigens could result in a stronger anti-tumor response and boost CD8+ T cell memory [71]. The use of tumor lysate and its encompassing antigen repertoire could also eliminate the time-consuming task of discovering strongly immunogenic antigens.

Tumor lysates can either be obtained from autologous tumor cells, which are taken from the patient, or from an allogenic cell line. Autologous tumor cells are only useful in patient-specific anti-tumor immunotherapies while allogenic tumor cells can be stored at cell banks and vaccines can be created en masse at GMP facilities [72]. Given alone, tumor lysates are administered with a strong adjuvant hapten to provoke a strong inflammatory response and increase their immunogenicity. In a murine glioma model, a CpG-tumor lysate vaccine given subcutaneously had a cure rate of up to 55% and showed significantly longer survival times than tumor lysate or CpG alone. Given their potential to be immunosuppressive, an alternative approach, discussed below, is to create dendritic cell vaccinations by pulsing dendritic cells with tumor lysate [73].

Dendritic cells (DCs), with their powerful antigen-presenting function and unique ability to activate naïve T cells, form a crucial link between the innate and adaptive immune system. As sentinel members of the innate immune system, DCs scavenge for foreign antigens (PAMPs) and in response release cytokines. As members of the adaptive immune response, DCs take up pathogenic antigens, process them internally, and present them on their cell surface, thereby activating naïve, effector, and memory T cells and B cells, as well as maintaining tolerance against self-antigens [74]. In fact, DCs are described as the most potent endogenous activators of de novo T cell and B cell responses [75].