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Table 1. Virotherapy trials for pediatric brain tumors
Trial/therapy Description NCT/reference
Recombinant poliovirus, Phase Ib trial evaluating PVSRIPO in children with recurrent supratentorial malignant NCT03043391
PVSRIPO glioma [27]
Modified type I herpesvirus, Phase 1 trial evaluating HSV G207 alone or with single radiation dose in children with NCT02457845
HSV G207 recurrent supratentorial malignant brain tumors [32]
Wild-type reovirus Phase I trial evaluating reovirus in combination with GM-CSF in children with recurrent NCT02444546
malignant brain tumors [30]
Newcastle disease virus Phase I trial evaluating newcastle disease virus in combination with autologous DC in [33]
children with brainstem glioma
Modified adenovirus, Phase I trial evaluating Ad-RTS-hIL-12, a vector for viral gene therapy, in children with NCT03330197
Ad-RTS-hIL-12 progressive supratentorial tumors and diffuse intrinsic pontine glioma [47]

[34]
dendritic cells .
Viral gene therapy
Viruses are highly adept at introducing foreign genes and utilizing host machinery for protein expression.
The human genome contains a large number of endogenous retroviral sequences, and roughly 8% of the hu-
[41]
man genome derives from infectious retroviruses . Retroviruses, which predominantly infect dividing cells
and stably integrate into the host genome, are useful for viral gene therapy. The lentivirus genus of retrovi-
ruses can transduce slowly-dividing or quiescent cells, overcoming in part the limitation that retroviruses
must transduce dividing cells . In cancer immunotherapy, retroviral transduction is typically performed
[42]
ex vivo to genetically modify immune cells and not to deliver a direct therapeutic benefit.

Toca-511, however, uses a retroviral replicating vector to selectively transduce cancer cells with a yeast-de-
rived cytosine deaminase gene following intratumoral administration. The prodrug 5-fluorocytosine is given
systemically and selectively converted fluorouracil (5-FU) in tumor cells expressing cytosine deaminase.
This platform illustrates how viruses are useful as a form of gene therapy and has shown clinical efficacy
in adults with glioblastoma. Toca-511 has been studied preclinically in medulloblastoma models and has a
[43]
strong rationale for clinical evaluation in children .
Compared to retroviruses, adenoviruses more readily transduce non-dividing cells . Adenovirus vectors
[44]
[45]
typically have smaller DNA capacity and are more immunogenic, which can limit gene expression in vivo .
One adenovirus gene therapy platform is being evaluated clinically in children with brain tumors: The mod-
ified adenovirus, Ad-RTS-hIL-12, is injected intratumorally and uses an oral activator ligand to toggle IL-12
expression within the tumor. In early phase adult studies in recurrent GBM, this platform was well-tolerated,
[46]
and preliminary data showed correlation between tumor response and IL-12 secretion . Ad-RTS-hIL-12 is
being evaluated in children with progressive supratentorial tumors and diffuse intrinsic pontine glioma .
[47]
Table 1 lists notable virotherapy trials for pediatric brain tumors.

MONOCLONAL ANTIBODIES AND IMMUNOCONJUGATES
Similar to oncolytic viruses and tumor-directed viral gene therapy, monoclonal antibodies (mAb) and im-
munoconjugates can be used as immunotherapy to elicit an innate immune response. MAb directed against
tumor-specific antigens have varied mechanisms of action, which are often incompletely understood, even
in clinically effective products. For example, the HER2-specific mAb trastuzumab improves survival in pa-
tients with advanced HER2-positive breast cancer and is FDA approved in this disease . Several anti-tumor
[48]
mechanisms of trastuzumab have been identified, including antibody-dependent cell-mediated cytotoxicity
[49]
(ADCC) involving Fc receptors on phagocytes , inhibition of HER2 signaling [50,51] , and downregulation of
[51]
HER2 cell-surface expression .