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Pearce et al. Neuroimmunol Neuroinflammation 2018;5:47 I http://dx.doi.org/10.20517/2347-8659.2018.46 Page 3 of 16

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CD4 and CD8 T-cells can further differentiate into effector or memory T-cells, which are essential in
[10]
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delivering a robust secondary immune response after re-exposure to antigen . CD8 effector T-cells attack
tumor cells by releasing perforin and granzyme cytotoxic molecules and producing pro-inflammatory
cytokines TNF and IFN-γ. During antigen clearance, most CD8 effector T-cells undergo apoptosis, with
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a small margin surviving. When high levels of antigens persist in an environment, these remaining CD8
T-cells progress into a state of T-cell exhaustion. This situation is commonly seen in cancers with solid
tumors like GBM. In the T-cell exhaustive state, inhibitory receptors are overexpressed, cytokine signaling
[12]
pathways are dysregulated, and altered metabolic fitness occurs , leading to altered T-cell functioning
and unrestrained tumor growth. Novel strategies and new approaches have been developed in attempts to
circumvent these hurdles to immunotherapy for gliomas.

ADOPTIVE T-CELL TRANSFER
Adoptive T-cell transfer (ACT) involves the collection and ex vivo expansion of autologous anti-tumor T
lymphocytes. These cells are then reinfused into the patient, delivering a potent and focused response. This
approach provides the immune system and tumor microenvironment with an already abundant, activated
T-cell population that can proliferate in vivo to maintain antitumor functions. ACT therapy can provide
benefits to immunocompromised patients as it eliminates the need for self-induced antigen presentation.
This feature, along with the ability for T-cells to bypass the BBB, suggests that ACT may be particularly
[13]
effective in brain tumor treatment .

There are several avenues to the ACT approach, but the furthest advanced is the chimeric antigen receptor
T-cell (CAR T) therapy. After isolating T-cells from the patient, these cells are genetically engineered to
express receptors that mediate tumor cell destruction after reinfusion to patients. CAR T targeting of B cell
marker CD19 has shown great efficacy in lymphoblastic leukemia and B cell lymphomas, but applications
in the treatment of solid tumors have only begun to be explored [14,15] . Progress has been made in CAR T
treatments for brain tumor targeting, particularly utilizing epidermal growth factor receptor (EGFR)vIII
[Table 1]. Given that EGFRvIII is known to be prevalent in gliomas, CAR was directed against EGFRvIII
[16]
and used in a phase I clinical trial for recurrent GBM . All patients given CAR T EGFRvIII intravenous
infusions exhibited decreased expression of EGFRvIII in tumors, indicative of CAR on-target effects.
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Flow cytometric analysis of CD3 T-cells detected engraftment of CAR T-EGFRvIII cells in the peripheral
blood. These findings demonstrated CAR T transient growth advantage as compared to endogenous
lymphocytes, and that rescue of normal T-cell activity can be achieved. This is especially applicable to
immunocompromised patients previously administered doses of TMZ and radiation. None of the infused
subjects presented symptoms of tumor toxicity nor cytokine release syndrome, and there was no cross-
[17]
reactivity of wild type EGFR .

Other clinical trials have shown that through administration of glioma associated antigen IL13Rα2 in CAR
T-cells, patients with recurrent GBM showed transient, anti-tumor responses. In metastatic GBM, significant
tumor regression could be observed after 4-1BB co-stimulation and a mutated IgG4-Fc linker was incorporated
into administered CAR T-cells which enhance antitumor potency and reduced off target interactions. While
both intracavitary and intraventricular administration of CAR T populations was performed, intraventricular
[18]
administration was found to achieve regression of all CNS tumors . These preliminary findings illustrate the
potential for CAR T mass manufacture, designed to address function and toxicity deficiencies.

Challenges in transitioning ACT to the clinic include the risk of inducing graft vs. host disease, which
may arise through allogeneic T-cell transfusion. Identification of toxicity prior to human administration
is another challenge, largely due to the lack of representative immune systems in pre-clinical models.
Introduction of a robust T-cell population carries its drawbacks. Off-targeting can present as cross-reactivity
of the T-cell receptor with an antigen that possesses similar structure to the target antigen. This can result in