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to the tumor through cross-reactivity or as an adjuvant. Currently, clinical applications of virotherapy in pe-
diatric brain tumors are limited to approaches using oncolytic viruses or viruses as gene transfer platforms.

Oncolytic viruses
Oncolytic viruses show promise in treating pediatric brain tumors. At least 50 clinical trials are ongoing us-
ing oncolytic viruses to treat cancer patients, mostly adults with non-CNS solid tumors. The oncolytic virus
talimogene laherparepvec (TVEC), a modified type I herpes simplex virus for adults with advanced melano-
[24]
ma, is the first oncolytic virus to receive FDA approval . Mechanistically, oncolytic viruses predominantly
function through a combination of tumor cell lysis and stimulation of the innate immune system through
[25]
DAMP and pathogen-associated molecular patterns (PAMP) . Initially, oncolytic viruses were engineered
for selective tumor tropism and direct cytotoxicity. However, oncolytic viruses are now regarded as immu-
[26]
notherapy for which efficacy depends on activating an endogenous anti-tumor immune response .
TVEC enters tumor cells through nectin adhesion molecules and replicates within tumor cells that have
[24]
dysfunctional anti-viral pathways . The virus induces tumor cell death and causes DAMP and PAMP ex-
pression within the tumor. Additionally, the viral genome is genetically modified to increase MHC class I
expression and to secrete GM-CSF, which promotes dendritic cell accumulation and antigen presentation to
[24]
prime an adaptive immune response . Taken together, this first-in-class agent represents how oncolytic vi-
ruses can be modified to stimulate innate immunity and readily combined with conventional and immune-
based therapies. TVEC is undergoing clinical evaluation with checkpoint inhibitors and agents that target
the MAP kinase pathway, which is activated in melanoma.

To date, at least five oncolytic viruses have been evaluated clinically in children with brain tumors: recombi-
[30]
[29]
nant poliovirus [27,28] , adenovirus , reovirus , herpesvirus [31,32] , and new castle disease virus [33,34] .
PVSRIPO, is a recombinant, live attenuated, nonpathogenic oncolytic virus containing the oral poliovirus
Sabin type 1 in which the internal ribosomal entry site (IRES) is replaced with the IRES from human rhino-
virus. PVSRIPO is administered intratumorally for adults with recurrent glioblastoma via convection-en-
hanced delivery and enters cells expressing the poliovirus receptor, CD155, which is ubiquitously expressed
on malignant glioma. PVSRIPO is directly cytotoxic and induces a marked inflammatory response. Inter-
estingly, dendritic cells express CD155 and are infected by PVSRIPO. Whereas PVSRIPO lyses tumor cells
expressing CD155, the virus induces interferon-dominant activation of dendritic cells and tumor-specific
[35]
CD8+ T cells . PVSRIPO was well-tolerated in adults with recurrent glioblastoma (GBM) with some en-
[36]
couraging responses and is being evaluated in a phase II trial in adults with recurrent GBM in combina-
tion with lomustine. PVSRIPO is also being used to treat children with recurrent supratentorial malignant
[28]
glioma as a phase Ib trial .

Currently, three other early-phase trials using oncolytic viruses are ongoing for children with brain tumors.
HSV G207, a modified type 1 herpesvirus, is delivered intratumorally to children with recurrent or progres-
sive supratentorial malignant brain tumors. HSV G207 is cytotoxic and replicates within infected cells, then
infects neighboring cells following cell lysis. Subsequent cohorts of patients will receive a single dose of ra-
diation, which has been shown to increase viral activity in pre-clinical studies and was well-tolerated in an
[38]
[37]
adult phase I trial . Wild-type reovirus preferentially infects and kills cancer cells in its unmodified form
and induces an interferon-dominant immune response following intravenous administration in adults with
[39]
brain tumors . Reovirus is being evaluated in combination with GM-CSF in children with recurrent malig-
[30]
nant brain tumors . Newcastle disease virus (NDV) also induces selective tumor cell death and stimulates
the innate immune system. NDV has been used clinically in cancer patients for decades with scattered clini-
[40]
cal responses . Currently, NDV is administered intratumorally in children with diffuse intrinsic brainstem
glioma to induce tumor lysis. Tumor antigens are then harvested systemically and used to prime autologous