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production of the well-characterized immunosuppressive factors such as transforming growth factor-β,
[90]
interleukin-10, prostaglandin E2, and gangliosides . These tumors also secrete the chemoattractants
such as monocyte chemoattractant protein-1, colony stimulating factor-1, granulocyte/macrophage colony
stimulating factor-1, and hepatocyte growth factor to recruit microglia to the local tumor microenvironment
in order to support tumor cell proliferation and tumor growth, as well as secrete factors that lead to local
immunosuppression and inhibition of the remaining immune system cells that are now unavailable to
[43]
attack this tumor . Finally, these tumors also have immunosuppressive antigens on their cell membrane
surfaces and secrete factors that lead to further inhibition of the immune system from properly attacking
[91]
these tumors . With these mechanisms in place in glioblastomas, it becomes essential to first understand
the immunosuppressive mechanisms employed by these tumors before delving into the immunotherapy/
immunomodulation mechanisms that have been showing such preclinical promise and possibly to explain
the lack of translation of this promise into the clinical realm.

Despite the immunosuppressive action inherent in glioblastoma, this tumor has been the subject of multiple
studies using multiple immunomodulatory methods besides HDAC inhibitors. One of the more exciting
strategies is the use of “trained” T cells directed towards known tumor antigens, also known as CAR-T cell
therapy. This therapy modality has been applied towards glioblastoma, with mixed results for a variety of
reasons. These barriers to successful therapy include the previously-discussed barriers to cellular delivery and
immunosuppressive microenvironment as well as proper selection of appropriate glioblastoma antigens to
[10]
train the T cells . However, a recently published high-profile case study has shown regression of recurrent
[92]
GBM following the use of this CAR-T cell therapy , heralding this particular treatment modality as
extraordinarily effective in certain cases and in certain tumor types. Ultimately, this treatment modality
shows considerable promise and with initial Phase I trials suggesting that this therapy is safe without dose-
limiting side effects, this strategy will be very likely to continue to be considered as our lists of GBM antigenic
[93]
targets as well as continue to increase as our understanding of these tumors becomes more robust .
Another immunomodulatory treatment modality that has shown promise in recent years is the use of
immune checkpoint inhibitors, which are agents that help “unblock” the regulation induced by tumor cells
on the immune system, priming the tumor cells for killing. Specific immune checkpoint proteins that have
been investigated for immunotherapy of GBM include: PD-1/PD-L1, CTLA-4, T cell immunoglobulin and
[11]
mucin containing protein-3, and indoleamine-(2,3)-dioxygenase . The rationale behind these therapies
involves the use of monoclonal antibodies designed to target these surface markers in order to increase the
tumor’s susceptibility to immune attack by cytotoxic T cells [Figure 3]. These immune checkpoint proteins
restrain immune responses and thereby prevent T cells from killing the tumor cells. When these proteins
are gridlocked with monoclonal antibodies, the restraints on the immune responses are released and T
cells turn into weapons to kill tumor cells. Specific to glioblastoma, these therapies have been explored as a
[94]
promising crop of new therapeutic targets . While these targets have shown promise in clinical trials, the
ultimate assessment of these agents are mixed at best. Each of these agents has been speculated to be a useful
therapeutic modality when combined with other chemotherapy, radiation, or with other immunomodulatory
[95]
treatments . Unfortunately, these strategies have yet to show the promising results in the clinical realm.

Finally, GBM is the target of yet another immunomodulatory treatment modality, the use of vaccine therapy
to prime the immune system to fight the tumor directly and recognize recurrences, much in the same way
our immune system already does with many infectious agents. These strategies have utilized multiple targets
in an attempt to activate the immune system in a way where it is able to eradicate the tumor, which include:
peptide vaccines, polyvalent dendritic cell vaccines, and heat shock protein vaccines. Again, akin to many
other agents discussed in this article, these agents have shown mixed results depending on which clinical
trial you examine and have been only suggested to supplement the already established standard-of-care
[96]
treatments . The movement for vaccine strategies for the treatment of GBM allows for considerable targeted