**2. Current immunotherapies**

### **2.1 Cancer vaccines**

Cancer vaccines involve exogenous administration of tumor antigens that can stimulate an adaptive immune system against tumor cells. The basic requirements for cancer vaccines include the delivery of tumor-specific antigens to antigen-presenting cells (APCs) such as dendritic cells (DCs), DC activation, activation of both T cell subsets and infiltration into the tumor microenvironment to exert durable responses [30]. Vaccine strategies have been employed against primary brain tumor targets using a variety of antigen substrates, including peptides, full-length proteins, RNA, and DNA in various formulations including antigens alone, antigens in combination with various local or systemic adjuvants, or dendritic cell vaccines. Though vaccination strategies have demonstrated a survival benefit in early phase clinical trials, there have yet to be any phase III clinical trials in patients with GBM demonstrating survival benefit. However, vaccination strategies continue to hold great promise with the rationale and hope that they would stimulate effective tumor-specific immunity, target tumor cells but not normal brain, and provide immunological memory against tumor recurrence [31].

#### *2.1.1 Single peptide vaccines*

Multiple single peptide vaccines have been generated to target a variety of tumor antigens including mutated isocitrate dehydrogenase 1 (IDH-R132H), survivin, Wilms Tumor 1 (WT1), and epidermal growth factor receptor variant III (EGFRvIII). Peptide vaccinations are highly specific and provide the benefit of reduced off-target effects, preventing autoimmune toxicities.

Mutated IDH1 defines a molecular subtype of diffuse glioma. A phase I trial of an IDH1(R132H)-specific peptide vaccine was conducted in 33 patients with newly diagnosed WHO grade 3 and 4 astrocytomas [32]. This study met its primary safety endpoint and demonstrated a three-year progression-free rate of 63% and a threeyear death-free rate of 84% [33]. This study assessed intratumoral inflammatory reactions associated with the use of vaccines by the presence of pseudoprogression. Intriguingly, this study found high frequencies of pseudoprogression, 37.5% in the treatment group compared to 16.7% in a molecularly matched control cohort, indicating intratumoral inflammatory reactions. In one patient with pseudoprogression, the analysis found that a cluster of T cells was dominated by a single IDH1(R132H)-reactive T cell receptor.

Survivin is an anti-apoptotic protein expressed in malignant gliomas. One early phase study assessed the survivin peptide vaccine in nine patients with survivinpositive malignant gliomas and found it to be safe and tolerable [34]. The treatment group had a median PFS of 17.6 weeks and a median OS of 86.6 weeks compared to an analysis of phase II chemotherapy trials of patients with recurrent glioma with a PFS of 10 weeks and OS of 30 weeks [35]. A phase II trial was initiated with the survivin peptide vaccine in 63 participants with newly diagnosed glioblastoma [36]. In 2020, a trial update found 96.8% of patients did not experience disease

#### *Immunotherapy against Gliomas DOI: http://dx.doi.org/10.5772/intechopen.101386*

progression within 6 months with a 93.5% survival rate a year after diagnosis [37]. This is an ongoing study.

Wilms Tumor 1 (WT1) is a pleiotropic transcription factor with functional roles in GBM that range from driving cellular proliferation [38] to inhibiting apoptosis [38, 39]. An uncontrolled nonrandomized phase II trial of WT1 peptide vaccination for patients with recurrent WT1-positive GBM was conducted with 21 patients. This study demonstrated that the vaccination was safe and produced a clinical response with a median PFS period of 20.0 weeks, median overall survival after initial vaccination of 36.7 weeks, and a 6 month PFS of 33.3% [40]. The median PFS and median OS found in this study were said to be comparable to various combination regimens of chemotherapy and/or radiotherapy.

Epidermal growth factor receptor (EGFR) amplification is enriched in the classical subset of GBM and is seen in 57.4% of primary GBM patients [41, 42]. Epidermal growth factor receptor variant III (EGFRvIII) regulates EGFR activity by inducing the expression of EGFR ligands [43]. A phase II trial assessed the immunogenicity of an EGFRvIII-targeted peptide vaccine [44]. The 6-month PFS after vaccination was 67% (versus 59% in the historical cohort) with a median overall survival of 26.0 months (versus 15.0 months in the matched control group) [45]. However, no benefit was observed in a randomized phase III trial [46]. Further analysis found significant loss of EGFRvIII expression in a subset of patients with tumor tissue available at recurrence in both those that received the vaccine and in those receiving standard-of-care chemoradiation [47].

To date, single peptide vaccines have yet to lead to clinical benefit in phase III trials in brain cancers. The EGFRvIII work hints that the selection of a single molecular target as a peptide vaccine might be inadequate to overcome the considerable challenges of tumor antigen down-regulation and tumor heterogeneity. Thus, targeting multiple targets could lead to robust durable responses. Thus, studies investigating multi-peptide vaccines, with several tumor antigen targets, have now been initiated.
