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Table 3. Clinical trials using checkpoint inhibitors to treat central nervous system tumors
Identifier Trial name Treatment Phase Diagnosis (newly
diagnosed or reoccurring)
NCT02866747 A study evaluating the association of hypofractionated Durvalumab (PD-L1), I/II Reoccurring
stereotactic radiation therapy and durvalumab for patients radiotherapy
with recurrent GBM (STERIMGLI)
NCT02311920 Immune-related DLTs Pilimumab (CTLA-4), I Both
nivolumab (PD-1), TMZ
NCT03173950 Immune checkpoint inhibitor nivolumab in people with select Nivolumab (PD-1) II Newly diagnosed
rare CNS cancers
NCT02617589 An investigational immuno-therapy study of nivolumab Nivolumab (PD-1), III Newly diagnosed
compared to TMZ, each given with radiation therapy, for radiotherapy, TMZ
newly-diagnosed patients with GBM (CheckMate 498)
NCT02320058 An investigational immuno- therapy study to evaluate safety Ipilimumab (CTLA-4), II Both
and effectiveness in patients with melanoma that has spread nivolumab (PD-1)
to the brain, treated with nivolumab in combination with
ipilimumab, followed by nivolumab by itself (CheckMate 204)

GBM: glioblastoma multiforme; PD-1: programmed death receptor 1; PD-L1: programmed death receptor ligand 1; DLTs: dose limiting
toxicities; CTLA-4: cytotoxic T-lymphocyte associated protein 4; TMZ: temozolomide; CNS: central nervous system

clinical trial utilizing PD-1 inhibitor nivolumab (NCT03173950). This progress emphasizes the importance of
continued clinical efforts with checkpoint inhibitors.

Combinatorial methods using checkpoint inhibitors have also been under investigation [Table 3]. Mice
implanted with GL261 gliomas treated with both stereotactic radiotherapy and PD-1 inhibitors have shown
improved median survival compared to untreated mice. This is thought to be due to increased MHC-I
+
expression and inhibited PD-1 expression, ultimately provoking an increased CD8 effector T and decreased
Treg population. 15%-40% of mice became long-term survivors, and mice rechallenged with GL261
[57]
demonstrated systemic immunity . Nivolumab coupled with radiotherapy presents a similar treatment
combination, and the therapy is currently being explored in one of the first phase III clinical trials for GBM.
The results have not yet been published (NCT02617589). Investigation of anti-PDL1 durvalumab combined
with hypofractionated stereotactic radiotherapy to target recurrent GBM has paved the way for a phase
II clinical trial, with an absence of serious adverse events and dose-related toxicity related to treatment
in patients (NCT02866747). Combined administration of nivolumab and ipilimumab to patients with
untreated melanoma metastatic to the brain demonstrated success in a phase II clinical study, with OS rates
reaching 92.3% and 82.8% at 6 and 9 months respectively (NCT02320058). Four-1BB is another antibody
that prompts CD8 and memory T cell proliferation upon activation. A study in mice combining radiation,
+
CTLA-4 blockade, and 4-1BB activation achieved a minimum of 50% long-term tumor free survival, and
+
the treatment increased populations of CD4 and CD8 tumor infiltrating lymphocytes. Tumor cells were
+
[58]
also rejected after re-challenge . Finally, a study utilized the catabolic tryptophan enzyme indoleamine
2,3 dioxygenase 1 (IDO), because it is upregulated in 90% of GBM cases, absent in healthy tissue and is also
known to play a significant immunosuppressive role in the tumor microenvironment. Combined inhibitors
for CTLA-4, PD-L1, and IDO (1-methyl-tryptophan) were administered to mice and resulted in 100%
[59]
survival . Because unperturbed CTLA-4, PD-L1, and IDO pathways greatly augment immunosuppression,
it is thought that pathway inhibition should reduce Tregs and result in positive survival outcomes.

One challenge in checkpoint inhibition therapy is identifying which patients might derive the greatest
benefit. Prognostic biomarkers must still be defined. The current means of predicting treatment outcome
for the PD-1/PD-L1 pathway is by immunohistochemistry of cytologic tumor samples. This method is
not completely reliable, as samples are susceptible to contamination and the interpretation of ambiguous
findings [60,61] . CTLA-4 does not have clinically relevant biomarkers.

Further confounding the process, it is possible that the expression of checkpoint ligands or receptors on
tumors may not always be reliable in determining treatment outcomes. In melanoma, for instance, PD-L1