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Page 6 of 16 Pearce et al. Neuroimmunol Neuroinflammation 2018;5:47 I http://dx.doi.org/10.20517/2347-8659.2018.46

Table 2. Progress using natural killer cells against cancer clinical trials
Identifier Trial name Treatment Phase Diagnosis
NCT03383978 Intracranial injection of NK- 92/5.28.z (HER2. NK-92/5.28.z (HER2. I GBM
taNK) cells in patients with recurrent HER2- taNK) injection
positive GBM (Quilt 3.C001) (CAR2BRAIN)
NCT00909558 Safety and effectiveness study of autologous NK Autologous NK/NK I Glioma, squamous cell lung cancer,
and NK T-cells on cancer T-cell immunotherapy pancreatic cancer, colon cancer
NCT00823524 Donor NK cells after donor stem cell transplant Donor NK cell infusion I/II Brain and central nervous system
in treating patients with advanced cancer tumors
NCT03081780 Open label NK cell infusion (FATE-NK100) with FATE-NK100 I Refractory acute myelogenous
Subq IL-2 in adults with AML leukemia, relapsed AML
NK: natural killer; GBM: glioblastoma multiforme; HER2: human epidermal growth factor receptor 2; AML: acute myelogenous leukemia

CHECKPOINT INHIBITORS
Checkpoint inhibitors are a rapidly advancing field and involve the exploitation of tumor checkpoint
regulators. Immune checkpoints regulate the life cycle of the cellular immune response by either activation
of signals or by inhibition of activating processes. Tumor checkpoint regulators are mechanisms by which
tumors evade immune system recognition through expression of neoantigens. These antigens emulate those
[39]
of healthy tissue . Checkpoint inhibition blocks tumor cell evasion and allows for T-cells to overcome the
immunosuppressive tumor microenvironment. However, clinical trial outcomes and patient responses differ
between cancer types. Thus, investigation of external influences on checkpoint mechanisms ought to be
further explored.

Inhibitors generated for therapeutic use are found as chemically synthesized monoclonal antibodies or
recombinant forms of ligands or receptors. Such checkpoint targets include the programmed death receptor 1
(PD-1) and its ligand (PD-L1) or cytotoxic T-lymphocyte associated protein 4 (CTLA-4) receptor and its
ligands CD80 and CD86. These pathways are responsible for restriction of T-cells in peripheral tissues during
inflammatory response or for down-regulation of co-stimulatory T-cells, respectively [40-42] . Although the
PD-1 and CTLA-4 pathways are not the only mechanisms which provide cancer cells protection from T-cell
surveillance, PD-1 and CTLA-4 have exhibited profound outcomes in regard to tumor regression, appear to
possess an immunodominant role as compared to other immune checkpoints, and their mechanisms are the
most understood. It has been shown that PD-L1 is highly expressed on tumor cells and that coordination
+
[43]
between PD-1/PD-L1 can inhibit CD8 T-cell function . Administration of PD-L1 inhibitors results in
regression of a number of tumor types [44-49] . CTLA-4 blockade has shown efficacy in murine melanoma,
prostate cancer, and pancreatic carcinoma studies [50,51] . The latter demonstrated particular success when
[52]
combined with PD-1 inhibition, as survival was prolonged even after tumor rechallenge . This finding is
applicable to cancer cells that remain concealed within the body following tumor resection.

Despite checkpoint inhibitor success in various cancer types, use of this therapy against brain tumors has
yet to be extensively pursued. Preclinical assessments in orthotopic, immunocompetent murine models have
identified the most effective checkpoint pathway against GBM. When administered alone, PD-1 inhibition
has a 50% long term survival rate in mice. Combined treatment with PD-1 and CTLA-4 inhibition was
[53]
found to achieve 75% long term survival . These results paralleled those found in a melanoma clinical
[54]
trial that utilized the same combination of inhibitors, indicating improved effectiveness . Furthermore,
checkpoint inhibitor OX-2 glycoprotein (CD200) has been found to be highly expressed in a number of
[55]
human brain tissue samples, including astrocytomas, meningiomas, and GBM tumors . This pathway
has been investigated in canine models with high-grade gliomas. Although CD200 canine clinical trials
are still ongoing, regression of tumors and absence of inhibitor toxicity has indicated therapeutic promise,
and treated groups have already demonstrated an increase of 615 days of survival as compared to control
[56]
subjects . Another pursuit made to target meningioma and other rare CNS tumors is an ongoing, Phase II