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Page 4 of 16 Pearce et al. Neuroimmunol Neuroinflammation 2018;5:47 I http://dx.doi.org/10.20517/2347-8659.2018.46

Table 1. Clinical trials using adoptive T-cell transfers to treat gliomas
Diagnosis (newly
Identifier Trial name Treatment Phase diagnosed or
reoccurring)
NCT02844062 Pilot study of autologous anti-EGFRvIII CAR T-cells in Autologous anti-EGFRvIII CAR T I Reoccurring
recurrent GBM
NCT03283631 Intracerebral EGFRvIII CAR-T-cells for recurrent GBM Autologous anti-EGFRvIII CAR T I Reoccurring
(intercept)
NCT03389230 Memory-enriched T-cells in treating patients with Leukapheresis, autologous I Reoccurring
recurrent or refractory grade III-IV glioma HER2(EQ)BBζ/CD1 9t+
NCT03423992 Personalized CAR T immunotherapy for patients with Autologous anti-EGFRvIII, IL13Rα2, I Reoccurring
recurrent malignant gliomas HER2, CD133, EphA2, GD2 CAR T
NCT02208362 Genetically modified T-cells in treating patients with IL13Rα2-specific, hinge-optimized, I Reoccurring
recurrent or refractory malignant glioma 41BB-costimulatory
CAR/truncated CD19-expressing
autologous T lymphocytes
NCT02209376 Autologous T-cells redirected to EGFRvIII - with a chimeric CAR T-EGFRvIII T-cells I Patients with residual
antigen receptor in patients with EGFRVIII + GBM

EGFR: epidermal growth factor receptor; CAR T: chimeric antigen receptor T-cell; GBM: glioblastoma multiforme; HER2: human epidermal
growth factor receptor 2

[19]
cytotoxic effects to otherwise healthy tissue . Conversely, toxicities can also arise through on-target effects.
This generally manifests as successful binding to the antigen expressed in environments not specific to the
[20]
tumor . Cytokine release syndrome is another condition that results from the release of mass quantities
[21]
of cytokines, an indirect result of the release of mass quantities of T-cells . However, downregulation in
the prevalence of these cytokines can be achieved by receptor blockage. Specifically, in treatment focused
on acute lymphoblastic leukemia, a patient administered tocilizumab (an IL-6 receptor inhibitor) was able
to reverse cytokine storm syndrome symptoms yet still maintained the T-cell population and continued
[22]
to derive benefits from ACT therapy . Thus, while these side effects are serious, continued refinement
protocols can be made so symptoms are less severe and more manageable.

Current efforts in ACT aim to target solid tumors and optimize gene transfer. Methods of achieving gene
transduction to T lymphocytes include retroviral and lentiviral gene delivery. Positive efficacy in gene
transduction may be observed, but integration of genes may prefer certain areas of the genome over others.
Poor integration of genes could result in mutagenesis and overexpression or disruption of nearby genes in
T-cells [23,24] . Additionally, patients’ immune systems may react to the vectors themselves, and these genotoxic
events may interfere with T-cell delivery. To circumvent these issue, engineering of CAR T-cells by piggyBac
and Sleeping Beauty transposons has gained momentum [25,26] . These methods offer reduced manufacture
cost, increased simplicity, and less good manufacturing practice requirements. Gene expression remains
unperturbed and foreign proteins that could result in adverse effects are absent. Treatments utilizing
[27]
Sleeping Beauty have just reached phase I clinical trials . Optimization and precision of these transposon
systems may prove crucial to improved ACT safety.

NK CELLS
NK cells demonstrate potent anti-tumor immunity. Unlike T-cells, transfusions of NK cells are not
complicated by graft-host-disease. NK cells detect and eliminate cell abnormalities and are found in
[28]
lymphoid and non-lymphoid organs . Activated NK cells secrete perforin and granzymes to induce
apoptosis in target cells. Ligands like killer immunoglobulin-like receptors are expressed on healthy cells
and can inhibit the destructive activity of NK cells. Antibodies, cytokines, natural cytotoxicity receptors and
[29]
transmembrane protein NK2GD on infected or transformed cells provide activating signals to NK cells .
Conversely, downregulation of MHC-I in tumor cells depletes inhibitory signals to NK cells. It is these shifts
between activating and inhibitory signals that allow NK cells to selectively target abnormal cells. This is the
[30]
premise of anti-tumor NK cell immunotherapies .