B7-H3 in Pediatric Tumors: Far beyond Neuroblastoma

Abstract

B7-H3 is a 4Ig transmembrane protein that emerged as a tumor-associated antigen in neuroblastoma. It belongs to the B7 family, shows an immunoregulatory role toward NK and T cells, and, therefore, has been included in the growing family of immune checkpoints. Besides neuroblastoma, B7-H3 is expressed by many pediatric cancers including tumors of the central nervous system, sarcomas, and acute myeloid leukemia. In children, particularly those affected by solid tumors, the therapeutic protocols are aggressive and cause important life-threatening side effects. Moreover, despite the improved survival observed in the last decade, a relevant number of patients show therapy resistance and fatal relapses. Immunotherapy represents a new frontier in the cure of cancer patients and the targeting of tumor antigens or immune checkpoints blockade showed exciting results in adults. In this encouraging scenario, researchers and clinicians are exploring the possibility to use immunotherapeutics targeting B7-H3; these include mAbs and chimeric antigen receptor T-cells (CAR-T). These tools are rapidly evolving to improve the efficacy and decrease the unwanted side effects; drug-conjugated mAbs, bi–tri-specific mAbs or CAR-T, and, very recently, NK cell engagers (NKCE), tetra-specific molecules engaging a tumor-associated antigen and NK cells, have been generated. Preclinical data are promising, and clinical trials are ongoing. Hopefully, the B7-H3 targeting will provide important benefits to cancer patients.

Transforming Growth Factor Beta 2 (TGFB2) mRNA Levels, in Conjunction with Interferon-Gamma Receptor Activation of Interferon Regulatory Factor 5 (IRF5) and Expression of CD276/B7-H3, Are Therapeutically Targetable Negative Prognostic Markers in Low-Grade Gliomas

“…This protein has been identified as a tumor-associated antigen in neuroblastoma, playing a crucial role in regulating immune responses towards natural killer and T cells. B7-H3 has been shown to be expressed in several types of pediatric cancers, such as tumors of the central nervous system, sarcomas, and acute myeloid leukemia [ 66 , 67 , 68 , 69 , 70 , 71 ]. Focusing on Gliomas: NCT01502917, a phase 1 clinical trial tested the safety and efficacy of 124 I-omburtamab, a monoclonal antibody labeled with 124 I targeting CD276 delivered by convection-enhanced delivery (CED) in patients with diffuse intrinsic pontine glioma (DIPG).…”

Generation of B7‐H3 isoform regulated by ANXA2/NSUN2/YBX1 axis in human glioma

“…For example, it has been suggested that 4Ig rather than 2Ig can form dimers, 26 and increase the activation of AKT, JAK/STAT, HIF1α, NF‐κβ for cell proliferation 27 . The CAR‐T targets currently in use are also designed for 4Ig 28,29 . Although 4Ig is dominant in glioma tissues of the few glioma specimens we collected, 2Ig is specially expressed in glioma patients with malignant grade, hinting that designing CAR‐T targets for 2Ig may be a new strategy for high‐malignant glioma.…”

Hybrid epithelial-mesenchymal status of lung cancer dictates metastatic success through differential interaction with NK cells

“…However, its crucial role in supporting H-CIC escape properties opens new promising perspectives to apply B7-H3-based therapies to control metastatic spread in selected NSCLC patient cohorts. [52][53][54] Author affiliations Acknowledgements We thank Professor Claudia Cantoni for the kind gift of NKp46-Fc and NKp44-Fc chimeric molecules. We thank Dr Eloisa Jantus Lewintre for kindly providing us NSCLC cell lines.…”