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Page 10 of 16 Pearce et al. Neuroimmunol Neuroinflammation 2018;5:47 I http://dx.doi.org/10.20517/2347-8659.2018.46

Clinical trials involving tumor-associated antigens have not shown significant benefit. Survivin, an inhibitor
of apoptosis protein family, is highly expressed in all four subtypes of GBM. A phase I clinical trial found
that SurVaxM, a survivin peptide vaccine, did not improve OS, though it was shown to induce cellular and
[76]
humoral immune responses and has moved on to a phase II trial. Similarly, a phase I/II clinical trial using
IMA-950, a multi-peptide vaccine, did not significantly improve OS in combination with polyriboinosinic-
[77]
polyribocytidylic acid-polylysine carboxymethylcellulose and TMZ treatment . Similar to SurVaxM, IMA-
+
+
950 induced a measurable increase in CD8 and CD4 T-cell response. Lack of correlation between improved
outcomes and a peripheral immune response is a common theme among peptide vaccines, and suggests a
disrupted interaction between peripheral immune cells and GBM cells due to the immunosuppressive tumor
microenvironment.

Recently, efforts have turned to developing personalized peptide vaccines based on analysis of patients’
resected tumors. A phase I clinical trial assessed actively personalized vaccination (APVAC) for improving
+
immunogenicity and survival in GBM patients. APVAC induced a CD4 T-cell driven immune response
[78]
in 90% of patients, with a median OS of 29 months . However, APVAC was less-tolerated than previous
peptide vaccines, with adverse events including anaphylactic reactions and cerebral edema which must be
addressed for personalized vaccines to advance.

Overall, peptide vaccines have been shown to induce an immune response without a corresponding
improvement in OS. The lack of correlation may be attributed to the immunosuppressive tumor
microenvironment. Combination therapies with checkpoint inhibitors may provide a more robust response
with better survival outcomes. Personalized vaccine therapies offer a unique and potentially effective way
to not only prevent initial tumor progression but also recurrent tumor development, and warrant further
investigation. An active clinical trial is currently pursuing combining personalized peptide vaccines with
checkpoint inhibitors, and will hopefully elucidate the benefit of these combined therapies (NCT03422094).

Induced pluripotent stem cells vaccines
Stem cell vaccines comprised of embryonic stem cells (ESCs) have been studied for their ability to generate
antitumor immunity. This is largely attributed to the common markers expressed by both tumors and
[79]
ESCs . Studies investigating administration of ESC vaccines prior to tumor induction demonstrated
that pre-vaccination could effectively halt tumor growth. However, ethical concerns regarding ESCs limit
progress. Focus has now shifted towards induced pluripotent stem cells (iPSCs), which are stem cells
derived from somatic cells in combination with Oct3/4, Sox2, c-Myc, and Klf4 transcription factors. The
exposure of somatic cells to these transcription factors promotes oncogenic transformation and tumor
[80]
antigen expression . This can lead to improved immunogenicity and more precise targeting of tumor cells.
Additionally, iPSCs can be generated from a patient’s own tissue and may provide a better representation of
a patient’s tumor immunogens, although this procedure is not cost-effective.

The use of non-autologous iPSC vaccines can provide a more commercially viable option for iPSC based
vaccines. Vaccines generated from iPSCs genetically engineered to express GM-CSF have been shown to
[81]
suppress lung tumor growth in mice prior to tumor induction as well as in pre-established tumors . More
recently, an iPSC vaccine comprised of iPSCs with DNA adjuvant CpG demonstrated tumor regression
and significantly longer survival in murine models of breast cancer and melanoma. Additionally, treated
mice developed antibody titers against iPSCs and tumor cells and were able to protect against tumor
[82]
rechallenge . These data suggest iPSC vaccines may be applicable to other solid tumors, such as GBM.
DC vaccines
DCs act as the bridge between the innate and adaptive immune system, collecting antigens and presenting
them to lymphocytes. DC presentation of antigens to lymphocytes leads to activation of various T- cell
populations. These T-cells’ respective types and specificity are dependent on the antigens presented by