B7-H3, a potential therapeutic target, is expressed in diffuse intrinsic pontine glioma

Abstract

Diffuse intrinsic pontine glioma (DIPG) is a brain cancer with a median survival of only 1 year. Lack of molecular characterization of this tumor impedes the development of novel therapies. Membrane protein B7-H3, aka CD276, involved in interactions with host defenses in certain cancers, has been shown to be over-expressed in the majority of malignant neuroectodermal tumors including adult high-grade glioma. Targeting B7-H3 with a monoclonal antibody has demonstrated safety and efficacy in the salvage treatment of stage IV childhood neuroblastoma, another neuroectodermal tumor. It thus stands to reason that B7-H3 might serve as a therapeutic target in DIPG. B7-H3 immunoreactivity was determined in DIPG and non-diffuse brainstem glioma specimens with immunohistochemistry. In addition, B7-H3 mRNA expression was evaluated with microarrays in another set of specimens. All of the nine (100 %) DIPG specimens were shown to be B7-H3 immunoreactive. In the non-diffuse brainstem glioma group, none of the eight WHO grade I specimens showed B7-H3 immunoreactivity and nine of the 24 WHO grade II specimens (37.5 %) showed B7-H3 immunoreactivity. The association between histological grade and B7-H3 immunoreactivity was statistically highly significant. B7-H3 mRNA expression was also significantly higher in DIPG samples than in normal brain and juvenile pilocytic astrocytoma (WHO grade I) specimens. In summary, B7-H3 is over-expressed in DIPG. Given the need for novel treatment in this disease, antibody-based immunotherapy against B7-H3 in DIPG warrants further investigation.

Genomic Insights into Diffuse Intrinsic Pontine Glioma

“…For example, a currently open phase I trial is exploring the administration of a radioactively labeled antibody known as 124 I-8H9 for DIPG patients ( Identifier: NCT01502917). 124 I-8H9 is a chimeric toxin with demonstrated specificity toward B7-H3, a membrane protein that has been recognized as tumor selective in DIPG (50, 59). Conjugation of 124 I to the anchoring antibody will allow the therapeutic effects of the radionucleotide against glioma cells to extend beyond B7-H3 tumor expressing cells (59).…”

“…124 I-8H9 is a chimeric toxin with demonstrated specificity toward B7-H3, a membrane protein that has been recognized as tumor selective in DIPG (50, 59). Conjugation of 124 I to the anchoring antibody will allow the therapeutic effects of the radionucleotide against glioma cells to extend beyond B7-H3 tumor expressing cells (59). While the feasibility of CED has been established, ongoing studies are helping to improve the instrumentation to determine optimal flow levels and maximize safety and efficacy (50, 56).…”

B7 family checkpoint regulators in immune regulation and disease

“…When conjugated to a radioactive isotype, it appeared to show safety and efficacy in patients with neuroblastoma that metastasized to the central nervous system [68]. There is also interest to further expand this study to patients with diffuse intrinsic pontine glioma, another aggressive brain cancer, as B7-H3 expression has been detected on some patient samples and there are very limited treatment options for this disease [69]. …”

Humanized Affinity-matured Monoclonal Antibody 8H9 Has Potent Antitumor Activity and Binds to FG Loop of Tumor Antigen B7-H3

“…In early phase human clinical trials, 131 I-8H9 prolongs survival among high risk patients with solid tumors suffering from central nervous system (CNS) metastasis (44 -46). It is a promising target for radioimmunotherapy of leptomeningeal metastases (NCT00089245) (46), diffuse intrinsic pontine glioma (NCT01502917) (34), and peritoneal metastases (NCT01099644). The only other antibody in phase I trial is MGA271, a humanized IgG1 mAb (NCT0139114) (47).…”