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Table 2. Immunomodulatory mAb and immunoconjugate trials in pediatric brain tumors
Trial/therapy Description NCT/reference
Agonistic CD40 mAb, APX005M Phase I trial for children with recurrent malignant brain tumors and NCT03389802
newly diagnosed diffuse intrinsic pontine glioma [60]
B7-H3 directed radioisotope, 124I-8H9 Phase I trial for children with diffuse intrinsic pontine glioma NCT01502917
[71]

[66]
tive in preclinical pediatric brain tumor models but has not reached the clinic . Immunoconjugates bearing
a pseudomonal exotoxin that the IL-4 receptor , IL-13 receptor , or tumor growth factor alpha (TGFα)
[69]
[67]
[68]
were safe following direct administration into the tumor and intermittently effective in early-phase studies
but have not been evaluated in children.
Immunoconjugates can also induce tumor death and anti-tumor immunity using radioisotopes, referred to
as radioimmunotherapy. To date, only one radioisotope immunoconjugate has been used to treat primary
pediatric brain tumors. I-8H9 contains a scFv recognizing the B7-H3 antigen, expressed on glial tumors
124
[70] 124
but not healthy cells, coupled to a radioactive iodine isotope . I-8H9 is being evaluated as a phase I trial
[71]
for children with diffuse intrinsic pontine glioma and is administered intratumorally .
Lastly, immunoconjugates incorporating an immune-activating ligand, also called bispecific antibodies, are
being explored. Blinatunomab is a bispecific molecule that recognizes CD19, expressed on immature B cells,
and CD3, which engages T cells. This T cell-engaging molecule induces remission in relapsed, immature B-
[72]
lineage leukemia and is FDA approved for this disease . Investigators at Duke developed a fully human,
bispecific antibody (hEGFRvIII-CD3 bi-scFv) that redirects human T cells to kill EGFRvIII-positive malig-
[73]
nant glioma cells . This product is being evaluated in adults but is less useful for children with malignant
glioma, as less than 5% of malignant glioma in children expresses EGFRvIII . Table 2 lists current immu-
[74]
nomodulatory mAb and immunoconjugate trials in pediatric brain tumors.

IMMUNE CHECKPOINT INHIBITORS
Initial clinical evaluation of PD-1 and PD-L1 monoclonal antibodies demonstrated response rates of around
25% in adults with relapsed/refractory solid tumors [75,76] . Patients rarely had complete or sustained responses,
but these encouraging results prompted evaluation checkpoint inhibitors in brain tumors. Unfortunately,
[77]
these agents have been largely ineffective for most patients with brain tumors .

A growing number of immune checkpoints are being targeted clinically, but mAbs targeting the PD-1/PD-
L1 immune checkpoint remain the most widely used. Activated T cells express PD-1, a member of the CD28
[78]
family which impairs T cell activation and promotes T cell anergy and apoptosis . PD-L1, which is ex-
pressed ubiquitously on solid tumors and also on regulatory immune cells within the tumor bed, binds PD-1
to dampen an anti-tumor T cell response [79,80] . Blocking this interaction using a mAb binding either PD-1 or
PD-L1 can promote anti-tumor T cell activity.

In order for checkpoint inhibition to be optimally effective, the tumor must be immunologically hot, with
T cell infiltration and tumor antigens that can be recognized by T cells. Tumor mutational load and T cell
infiltration within the tumor are highly predictive for response with checkpoint inhibitors [81,82] . In melanoma
and lung cancer, tumor mutational burden, which impacts the number of neoantigens and T-cell immuno-
genicity, correlate with response to checkpoint blockade [8,83] .

Hypermutant pediatric GBM, while rare, responds to anti-PD-1 checkpoint blockade. Two children with
[13]
biallelic mismatch repair deficiency and hypermutated recurrent GBM responded to nivolumab . These
data are similar to those reported in adults with hypermutated colorectal carcinoma who received pembroli-
[84]
zumab, a PD-1 checkpoint inhibitor .