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presence on tumors is indicative of survival outcomes, because ligand expression is dependent on CD8
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T-cells and IFN-γ secretion. However, CD8 dependence may be specific to melanoma patients, as PD-L1
checkpoint inhibition therapy has demonstrated improved survival with non-small cell lung cancer even
[62]
if classified as PD-L1 negative . Similarly, expression of PD-L1 has not been definitively correlated with
[63]
prognosis in GBM, suggesting the ligand is not a reliable biomarker . Recent work has aimed to explain
the immune-resistance of some tumors. Genes in β-catenin, peroxisome proliferator-activated receptor-γ,
and fibroblast growth factor receptor 3 pathways were found to be responsible for failed T cell priming and
recruitment in the urothelial bladder tumor microenvironment in mice. This ultimately led to poor results in
[64]
checkpoint inhibitor treatment . Similar results were found in another study. β-catenin presence in murine
BP-SIY tumors is responsible for preventing migration of effector T cells and a robust immune response
[65]
succeeding ACT . In application to transcriptome signatures, these data may allow for more reliable tumor-
specific biomarkers options and could improve effectiveness in the total patient population. Because higher
mutational load of the tumor has been associated with more effective immunotherapeutic outcomes using
[66]
checkpoint inhibitors, assays exploring tumor mutational burden are also currently being pursued .

These preclinical studies suggest that the mechanism of checkpoint inhibitors is more complex than once
thought. Until recently, our gaps in understanding the mechanisms regarding checkpoint inhibition
were mostly due to the absence of in vivo models representative of the human immune system. However,
headway has been made in the development of new models. For instance, we know an exhausted CD8 +
T-cell population surrounds GBM tumors in humans and that this state is achieved through prolonged
[67]
exposure to the tumor antigen . To emulate these conditions in the laboratory, a murine model was
generated by infection with chronic lymphocytic choriomeningitis virus followed by induction of murine
[68]
glioma. This tumor positively responded to anti PD-1 treatment . A model for human hematopoietic and
immune systems was generated in nonobese diabetic Cg-PrkdcscidIL2rgtm1Wjl/Sz mice by transplantation
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of human CD34 hematopoietic progenitor and stem cells. Patient-derived tumor xenografts in this model
[69]
responded positively to PD-1 checkpoint inhibitor pembrolizumab . Studies utilizing these models should
provide a more clear representation of the mechanisms and effects of checkpoint inhibition on human
tumors. Through continued efforts, distinct biomarkers can be established for these therapies, and a push for
additional clinical trials pursued.

VACCINE THERAPIES
Peptide Vaccines
Peptide vaccines have been widely studied for immunotherapy due to their cost-effectiveness, reproducibility,
specificity, and low risk of generating an autoimmune response. Peptide vaccines stimulate the immune
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system by activating CD8 and CD4 T-cells via APCs. By developing peptides specific to tumors,
peptide vaccines can be used to induce an anti-tumor immune response to combat GBM. A limitation
of this therapy, however, is the capability of GBM cells to down-regulate MHC-I expression and increase
prostaglandin E2 production, which in turn downregulates MHC-II expression on APCs. Furthermore,
patient MHC heterogeneity and changes in MHC expression restrict the use of peptide vaccines. To
overcome MHC-dependence, long synthetic peptides encoding multiple MHC class I and II epitopes have
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been developed which are more efficiently processed by DCs and associated with increased CD4 and CD8
T lymphocyte activation [70,71] .
Antigens used in peptide vaccines can be tumor-specific antigens which are often the products of mutations
or splice variants, or tumor-associated antigens which are overexpressed gene products that can be expressed
in tumor cells. While tumor-specific antigens result in precise targeting of the tumor, they are not expressed
by a majority of the patient population. Conversely, tumor-associated antigens are shared by a larger patient
[72]
population and have been more preferentially used in vaccines as immunotherapies . Adjuvants often
supplement antigens to improve immunogenicity. Common adjuvants include PAMPs, damage-associated
molecular patterns, or cytokines that can activate APCs and lymphocytes.