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Page 691 Sharma et al. Cancer Drug Resist 2023;6:688-708 https://dx.doi.org/10.20517/cdr.2023.82

We summarized the most common immunotherapies that have been evaluated in glioblastoma in either
preclinical or clinical trials [Figure 1]. The most widely tested immunotherapies in glioblastoma (like in all
other cancers) are immune checkpoint inhibitors (ICIs). Immune checkpoint molecules are typically
expressed on the surface of immune cells, and they play a crucial role in maintaining immune balance,
preventing excessive immune activation, and avoiding auto-immune response. This function of immune
regulation is achieved through the interaction of immune checkpoints with their corresponding ligands on
other cells, and cancer cells often hijack this communication mechanism to suppress the anti-tumor
immunity and evade immune surveillance [53-55] . A common working mechanism of ICIs is to block the
inhibitory signal to the immune cells (usually from cancer cells) through an antibody binding to the
checkpoint or its ligand to disengage their interaction. Since the discovery of the first immune checkpoint,
cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), more than a dozen of these checkpoint molecules
have been identified to date, such as PD1 and its ligand PD-L1/L2, TIM3, lymphocyte activation gene-3
(LAG3), and TIGIT . Among various ICIs, α-PD-1 has been widely studied as a monotherapy or in a
[54]
[56]
combination of either radiation or radiation plus TMZ in multiple trials (CheckMate 143, 498 and 548) [57-59] .
Overall, the clinical outcome has been rather murky in both primary and recurrent glioblastoma due to
multiple resistance mechanisms, including high tumor heterogeneity, low mutational burden, systemic
immunosuppression, and local immune dysfunction .
[60]
CAR-T therapy has been studied in glioblastoma . The targets of these CARs in clinical trials span from
[61]
growth signaling receptors (EGFR/EGFRvIII, Her2), cytokine receptors (IL13Rα2), immune checkpoint
(B7-H3) to even matrix metalloproteinase (MMP2), and disialoganglioside (GD2) . Besides very limited
[62]
responders, including pediatric patients with diffuse intrinsic pontine glioma (DIPG) [63,64] , most trials failed
to demonstrate a sustained clinical benefit, mainly due to CAR-T-associated severe side effects, including
cytokine release syndrome and high grade of neurotoxicity [65,66] .

Cancer vaccines have also been explored in glioblastoma trials with minimal success. A peptide vaccine
targeting EGFRvIII called rindopepimut has been tested in various trials, with only one trial (phase II)
reporting a marginal increase in median overall survival of 12.0 months with rindopepimut plus
bevacizumab compared to 8.8 months with bevacizumab plus vaccine placebo . The main limitation of
[67]
EGFRvIII vaccine is that the expression of EGFRvIII is only limited in some glioblastoma patients, and
there is also an intra-tumoral heterogeneous pattern of EGFRvIII expression, which further hinders the
overall immune response to the tumor. Another cancer vaccine strategy is to use patient-derived dendritic
cells with ex vivo exposure to glioblastoma neoantigens. For instance, ICT-107 and DCVax-L both used
patient autologous dendritic cells with pulse to either peptides designed based on patient tumors (ICT-107)
or autologous tumor lysates (DCVax-L). Both trials have reached phase 3 and had an acceptable safety
profile, though the efficacy was minimal [68,69] .

Oncolytic virus (OV) can be viewed as a gene & immuno-hybrid therapy. Typically, an OV exerts its anti-
tumor function through a dual mode of action - tumor cell killing (lysis) and induction of systemic anti-
tumor immunity . An OV can selectively infect and lyse cancer cells, and various viruses have been
[70]
employed to develop oncolytic viruses . Upon lysis of tumor cells due to OV replication, many tumor
[71]
antigens will be released, leading to a local and systemic anti-tumor reaction . One of the main issues
[72]
associated with OV therapy is the host’s anti-viral immune response to the OV . Currently, a modified
[73]
herpes simplex virus type 1, named teserpaturev or G47Δ, is the only OV that received conditional approval
(in Japan) for glioblastoma treatment , and many more oncolytic viruses are currently in clinical trials for
[74]
glioblastoma treatment (reviewed by Suryawanshi & Schulze ). Among them, a retroviral OV called
[75]
Toca511 reached phase III clinical trial, but was terminated due to its failure to improve survival and meet