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Table 3. Notable past and ongoing active immunization trials for pediatric brain tumors
Trial/therapy Description Reference
Monocyte-derived DCs loaded Phase I trial evaluating DCs pulsed with tumor RNA in children with brain tumors [93]
with tumor RNA
Monocyte-derived DC loaded Phase I trial evaluating DCs pulsed with whole tumor lysate in children and adults [94]
with whole tumor lysate with relapsed malignant glioma
Monocyte-derived DC loaded Phase I trial with DC pulsed with tumor lysate for children with newly diagnosed or [95]
with whole tumor lysate recurrent high-grade gliomas
Monocyte-derived DC loaded Phase I trial with postoperative DC loaded with tumor lysate for children and adults [96]
with whole tumor lysate with recurrent GBM
Peptide vaccine targeting Phase I trial evaluating peptide vaccine targeting H3.K27M neoantigen for HLA-A2+ NCT02960230
H3.K27M children with H3K27M mutated glioma [101]
Peptide vaccine targeting CMV Phase I trial evaluating peptide vaccine targeting CMV pp65 and glycoprotein B for NCT03299309
epitopes pp65 and glycoprotein B children with recurrent malignant glioma and medulloblastoma [102]
Peptide vaccine targeting glioma Phase I peptide trial using glioma-associated antigens for HLA-A2+ children with NCT01130077
antigens malignant brainstem and non-brainstem gliomas, including low-grade glioma [103]

are genetically modified to express the CAR molecule, which is designed to bind a tumor-restricted antigen
and cause tumor cell death.

The CD19 CAR, which is effective against B-lineage lymphoid malignancies [111,112] , is FDA approved and
induces remission in most patients with relapsed CD19-positive leukemia. CAR T cells targeting HER2 [113] ,
IL13rα2 [114] , EGFRvIII [115] , and EphA2 [116] have been used to treat adults with GBM. A trial involving CMV-
specific cytotoxic T lymphocytes expressing a HER2 CAR treated seven children with GBM. There were
no serious adverse events or instances of cytokine release syndrome, and at least one child had a partial
response [113] . Transient responses following adoptive CAR T cell therapy are not infrequent, but almost all
patients ultimately suffer disease progression.

There are multiple reasons the success of the CD19 CAR for B-lymphoblastic leukemia has not been dupli-
cated by CAR T cells for brain tumors. The CD19 CAR targets an antigen that is ubiquitous and expressed
solely on tumor cells or non-essential B cells without a strongly immunosuppressive tumor bed. Additional-
ly, the CD19 single chain variable fragment (scFv) that guides the CAR T cell imparts an optimal activation
profile and supports continued T cell killing [117] . This characteristic of the scFv is a key and unique distinc-
tion in this T cell product. ScFvs for other CAR T cells cause tonic signaling, which can cause T cell exhaus-
tion and limits anti-tumor activity in patients following adoptive transfer [117] .

Antigen escape, tumor heterogeneity, and a harshly immunosuppressive immune microenvironment also
contribute to treatment failure by CAR T cells. In a recently completed phase I trial for adults with recurrent
GBM, EGFRvIII CAR T cells reliably reached the tumor bed following peripheral administration. However,
ex vivo analyses from resected tumor showed dramatic adaptive resistance, with markedly increased PD-
L1 expression and an influx of regulatory T cells, as well as decreased expression of the targeted EGFRvIII
antigen [115] .

CONCLUSIONS
Immunotherapy holds tremendous promise for improving outcomes for children with brain tumors. While
checkpoint inhibitors and CAR T cells are well suited for hypermutated, immunologically hot tumors and
B-cell malignancies, respectively, these modalities are less of a fit for pediatric brain tumors. Rather, immu-
notherapy approaches that induce inflammation and an innate immune response may be a better starting
point, on which checkpoint agents and other T cell-directed agents can build.

While we are optimistic about immunotherapy in pediatric neuro-oncology, it is important to recognize that
conventional chemotherapy and radiation will likely retain a role in treatment, particularly as both of these