Targeting B7-H3—A Novel Strategy for the Design of Anticancer Agents for Extracranial Pediatric Solid Tumors Treatment

Abstract

Recent scientific data recognize the B7-H3 checkpoint molecule as a potential target for immunotherapy of pediatric solid tumors (PSTs). B7-H3 is highly expressed in extracranial PSTs such as neuroblastoma, rhabdomyosarcoma, nephroblastoma, osteosarcoma, and Ewing sarcoma, whereas its expression is absent or very low in normal tissues and organs. The influence of B7-H3 on the biological behavior of malignant solid neoplasms of childhood is expressed through different molecular mechanisms, including stimulation of immune evasion and tumor invasion, and cell-cycle disruption. It has been shown that B7-H3 knockdown decreased tumor cell proliferation and migration, suppressed tumor growth, and enhanced anti-tumor immune response in some pediatric solid cancers. Antibody-drug conjugates targeting B7-H3 exhibited profound anti-tumor effects against preclinical models of pediatric solid malignancies. Moreover, B7-H3-targeting chimeric antigen receptor (CAR)-T cells demonstrated significant in vivo activity against different xenograft models of neuroblastoma, Ewing sarcoma, and osteosarcoma. Finally, clinical studies demonstrated the potent anti-tumor activity of B7-H3-targeting antibody-radioimmunoconjugates in metastatic neuroblastoma. This review summarizes the established data from various PST-related studies, including in vitro, in vivo, and clinical research, and explains all the benefits and potential obstacles of targeting B7-H3 by novel immunotherapeutic agents designed to treat malignant extracranial solid tumors of childhood.

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).…”

CAR T cells redirected to B7-H3 for pediatric solid tumors: Current status and future perspectives

“…1 ). Variations of B7-H3-CAR T cells are undergoing translational development, with many groups exploring additional enhancements to improve CAR T cell function [ 48 ].…”

“…Costimulatory molecules of the immunoglobulin superfamily including CD28 are associated with potent initial antitumor activity, while costimulatory molecules of the tumor necrosis factor receptor superfamily including 4–1BB and OX40 are associated with improved CAR T cell persistence [ 91 ]. Both classes of costimulatory molecules are being evaluated in B7-H3-CAR T cell constructs, in addition to third generation CARs which incorporate multiple costimulatory domains [ 48 ]. When incorporating multiple costimulatory domains, the route of costimulation can affect function [ 21 , 91 ].…”

B7-H3 in Pediatric Tumors: Far beyond Neuroblastoma

“…A huge number of tumors have been shown to express B7-H3 at the cell surface. In children, besides the above-mentioned pathologies, the targeting of B7-H3 is considered a promising immunotherapeutic approach for the treatment of many other intracranial and extracranial cancers ( Table 1 ) [ 58 ]; these also include rare diseases that more frequently lack consolidated and effective therapeutic protocols. Pediatric tumors include those affecting CNS or peripheral nerves, desmoplastic small round cell tumors, soft tissue sarcomas, growing in the abdomen and pelvic area of the body, germ cell cancers originating from reproductive cells and most frequently occurring in the testicles or ovaries, gastric and lung cancers, melanoma and retinoblastoma, an intraocular malignancy with primitive neuroendocrine origins primarily affecting young children.…”