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Page 6 of 16 Landi et al. Neuroimmunol Neuroinflammation 2018;5:29 I http://dx.doi.org/10.20517/2347-8659.2018.35

There are two main ways mAbs can promote an immune response: ADCC and immune modulation. MAbs
can trigger ADCC, in which cells of the innate immune system, specifically NK cells and phagocytes, lyse a
tumor cell coated with antibodies containing Fc regions. There are no mAbs for primary brain tumors that
function primarily by ADCC. Bevacizumab is a mAb that inhibits angiogenesis by binding to vascular endo-
thelial growth factor (VEGF), a pro-angiogenesis cytokine. Bevacizumab is not strictly an immunotherapy
but may have immunomodulatory effects, such as enhanced T cell recruitment and dendritic cell matura-
[52]
tion and migration related to an inhibitory VEGF effect . Bevacizumab is effective in some children with
[54]
recurrent low-grade glioma and FDA approved for recurrent GBM in adults , but is not immunotherapy
[53]
in the sense that it does not elicit an anti-tumor immune response. Similarly, monoclonal antibodies recog-
nizing epidermal growth factor receptor (EGFR), block EGFR signaling in tumor cells and may, to a lesser
extent, promote ADCC. Erlotinib, an anti-EGFR mAb, is ineffective against recurrent pediatric malignant
[56]
glioma and ependymoma . Newer generation EGFR mAbs have been developed with improved ADCC
[55]
[57]
characteristics but have not been evaluated in pediatric brain tumors .
Immunomodulatory monoclonal antibodies
MAbs can also promote anti-tumor immunity through immune modulation. Checkpoint inhibitors are an
example of this and will be discussed separately. CD40 is a TNF receptor superfamily member expressed
broadly on dendritic cells, B cells, and monocytes, as well as some tumor cells. Binding to the natural ligand
[58]
CD40L expressed on T helper cells causes immune cell activation . Agonistic CD40 mAbs activate antigen
presenting cells and cytotoxic myeloid cells and have induced clinical responses in adults with lymphoid
[59]
[58]
tumors . The CD40 agonistic antibody APX005M, delivered intravenously, is being evaluated in a phase
I trial for children with recurrent malignant brain tumors and newly diagnosed diffuse intrinsic pontine
[60]
glioma .
CD47 is an integrin-associated protein ubiquitously expressed on human cells. In the context of tumor
immunology, CD47 serves as a “don’t-eat-me” signal for macrophages . The anti-CD47 mAb Hu5F9-G4
[61]
currently is in early phase trials for adults with lymphoid and non-CNS solid tumors. While not yet used
clinically for primary brain tumors, Hu5F9-G4 has shown promising preclinical activity in vivo against or-
[62]
thotopic xenograft models of malignant pediatric brain tumors .
Immunoconjugates
Several immunoconjugates have reached the clinic in pediatric brain tumors as a form of immunotherapy.
Immunoconjugates consist of an antibody fragment joined to some sort of effector molecule. Examples of
effector molecules include immunotoxins, radioisotopes, and immune ligands. Immunoconjugates using
immunotoxins are most prevalent and are typically comprised of a toxin coupled to a single-chain variable-
region antibody fragment (scFv) that binds a tumor antigen. As a class, immunoconjugates typically have
a short half-life following administration and are given directly into the tumor by convection enhanced
delivery.

[63]
The EGFR gene is frequently amplified in adult GBM but not in pediatric GBM . However, most pediat-
ric glial tumors overexpress EGFR, making it an attractive target for immunotherapy for pediatric brain
tumors . D2C7-IT is an immunoconjugate comprised of a scFv that recognizes for both wild-type EGFR
[63]
[64]
and the deletion variant EGFRvIII fused to the pseudomonal exotoxin PE38KDEL . Upon binding EGFR,
D2C7-IT is internalized and inhibits protein synthesis and causes tumor cell death. In a phase 1 trial in
adults with malignant glioma, D2C7-IT induces inflammation within the tumor bed and has produced some
clinical responses . D2C7-IT will be evaluated in a phase I trial in children with recurrent, EGFR-positive
[65]
malignant glioma at Duke.

Podoplanin is a tumor-associated glycoprotein highly expressed on pediatric malignant glioma and medul-
[66]
loblastoma . A recombinant anti-podoplanin immunotoxin containing the pseudomonal exotoxin is effec-