Molecular Pathways: Targeting B7-H3 (CD276) for Human Cancer Immunotherapy

Abstract

B7-H3 (CD276) is an important immune checkpoint member of the B7 and CD28 families. Induced on antigen-presenting cells, B7-H3 plays an important role in the inhibition of T-cell function. Importantly, B7-H3 is highly overexpressed on a wide range of human solid cancers and often correlates with both negative prognosis and poor clinical outcome in patients. Challenges remain to identify the receptor(s) of B7-H3 and thus better elucidate the role of the B7-H3 pathway in immune responses and tumor evasion. With a preferential expression on tumor cells, B7-H3 is an attractive target for cancer immunotherapy. Based on the clinical success of inhibitory immune checkpoint blockade (CTLA-4, PD-1, and PD-L1), mAbs against B7-H3 appear to be a promising therapeutic strategy worthy of development. An unconventional mAb against B7-H3 with antibody-dependent cell-mediated cytotoxicity is currently being evaluated in a phase I clinical trial and has shown encouraging preliminary results. Additional therapeutic approaches in targeting B7-H3, such as blocking mAbs, bispecific mAbs, chimeric antigen receptor T cells, small-molecule inhibitors, and combination therapies, should be evaluated, as these technologies have already shown positive results in various cancer settings. A better understanding of the B7-H3 pathway in humans will surely help to further optimize associated cancer immunotherapies. Clin Cancer Res; 22(14); 3425-31. ©2016 AACR.

Figure 1. Human cancer immunotherapy strategies targeting B7-H3

(A) Blockade of B7-H3 with blocking monoclonal antibodies (mAbs) neutralize inhibitory signaling in its’ unidentified receptor(s) in T cells, NK cells and other immune cells enabling effector function. (B) B7-H3 specific antibody-dependent cell-mediated cytotoxicity (ADCC) initiated by Fc receptor engagement of NK cells and other immune cells induces death of tumor cells. Antibody drug conjugates (ADC) bind to B7-H3 expressed by tumor cells and are internalized and generate cytotoxicy to tumor cells. (C) CD3/B7-H3 bispecific antibodies bind to tumor-expressed B7-H3 and crosslink the CD3 portion of the TCR complex, activating T cells in the tumor microenvironment for tumor cell death. (D) Small molecule inhibitors may bind to specific regions of B7-H3, such as the FG loop of the IgV domain, inhibiting the ligand-receptor interaction between tumor cells and immune cells, thus blocking receptor signaling and restoring effector function of immune cells. (E) Engineered chimeric antigen receptor (CAR) T cells recognize membrane B7-H3 and directly kill tumor cells. (F) Blocking mAbs against B7-H3 in combination with radiation, chemotherapy, targeted therapy, or other immune checkpoint inhibitors blockade synergize to generate more effective anti-tumor immune responses.