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One of the central challenges for any active immunization approach is how to elicit an immune response
against relatively weak “self” tumor antigens. Interestingly, cytomegalovirus (CMV) nucleic antigens are
[97]
ubiquitously expressed in human malignant glioma , and an adult patient treated with a DC vaccine pulsed
[98]
with GBM tumor lysate developed a robust T cell response against the CMV antigen pp65 . The relative
ease of eliciting an immune response against viral antigens contrasts with the difficulty of immunization
against “self” tumor antigens and makes CMV an attractive target for immunotherapy. Dendritic cells
[99]
targeting pp65 lead to long-term survival in small numbers of adults with newly diagnosed GBM , and
survival correlated with DC migration in a CCL3-depedant fashion [100] . This DC platform targeting CMV
antigens will be evaluated in children with malignant glioma and recurrent medulloblastoma at Duke.

Peptide vaccines
Manufacturing DC vaccines is costly, and poor DC migration following administration remains a challenge.
Accordingly, active immunization strategies that stimulate endogenous DC activation are appealing, such
as peptide vaccines, which inject tumor peptides with adjuvants, usually adjacent to lymph nodes. A few
peptide vaccines for children with brain tumors are in early phase testing. One trial using a peptide vaccine
targeting the H3.K27M neoantigen for HLA-A2+ children with H3K27M mutated glioma is underway [101] . A
second peptide trial targeting the CMV epitopes pp65 and glycoprotein B is also underway for children with
recurrent malignant glioma and medulloblastoma [102] . Additionally, a peptide trial using glioma-associated
antigens for HLA-A2+ children with malignant brainstem and non-brainstem gliomas, including low-grade
glioma, is underway [103] . This platform has been well tolerated and effective at generating an anti-tumor im-
mune response [104] . At least four children with progressive, low-grade glioma have had sustained partial re-
sponses, providing evidence that peptide vaccines, typically given with Montanide adjuvant, can generate an
endogenous anti-tumor response [105] . Montanide is a water-in-oil emulsion that acts as an adjuvant in these
vaccines by enhancing CD4+ and CD8+ T cell response against antigens in the vaccine [106] .

Recently, highly personalized, neoantigen vaccines are gaining momentum. Initial clinical studies with
cancer vaccines used whole tumor lysates, which contain a mixture of self-antigens and undefined neoanti-
gens. These vaccines elicited broad immune responses but were generally ineffective. Using next-generation
sequencing to identify DNA and RNA sequences of neoantigens and advanced algorithms to predict MHC I
and MHC II loading, vaccines can be created that target specific neoantigens and hold promise for improv-
[92]
ing outcomes . This personalized neoantigen approach was effective in some advanced melanoma patients,
and combination with checkpoint blockade expanded the repertoire of neoantigen-specific T cells and
further improved efficacy [107] . Table 3 lists notable past and current active immunization trials for pediatric
brain tumors.

ADOPTIVE CELLULAR THERAPY
Adoptive cellular therapy (ACT) involves manipulating effector immune cells ex vivo before transfer back to
a patient with cancer. Initially, ACT for brain tumors used tumor-infiltrating lymphocytes (TIL) harvested
from the tumor bed or immune cells isolated from peripheral blood or lymph nodes. Following collection,
autologous lymphocytes were stimulated with cytokines or tumor antigen and infused back into patients.
Overall, ACT using TILs or peripheral lymphocytes was well-tolerated but clinically ineffective, although
immune activation and some responses were reported [108,109] . Natural killer T cells, which are specialized,
CD1d-restricted T cells, recognize lipid antigens and have been tested in melanoma, but not brain tumors [110] .

By far, the most prominent type of adoptive cellular therapy involves cytotoxic T cells that are genetically
modified to express a chimeric antigen receptor (CAR). CARs are synthetic receptors containing an antigen-
binding domain, typically derived from the short chain variable fragment (scFv) of an antibody, coupled to
the zeta chain and cytolytic machinery of a T cell receptor. Using retroviral vectors, primary human T cells