Combined Therapy of PD-1 and B7-H3

Background

The co-inhibitory molecules, such as programmed death 1 (PD-1) and its ligand PD-L1, are thought to be present in tumor microenvironments and aid tumor cells in avoiding immune system elimination, according to increasing evidence. Through adjustment of cytokine production, PD-L1 blockade can reduce tumor immunity suppression caused by myeloid dendritic cells (DCs). One of the B7 superfamily molecules, the B7-H3 checkpoint (CD276), is constitutively expressed in antigen-presenting cells, whose anti-tumor immunity is dependent on CD8⁺ T cells and natural killer cells to inhibit tumor growth. A variety of solid tumors have been identified to co-express B7-H3 and PD-L1, combining PD-1 and B7-H3 blockades further improves the therapeutic control of malignancies with a better targeting capacity.

Case 1: PD-1 Blockade Enhances Anti-B7-H3-based Tumor Inhibition

Both B7-H3 mRNA and corresponding protein are highly expressed in the DCs and tumor cell lines cultured in vitro. Compared to the mice treated with rat IgG, the number of tumor foci formed in anti-B7-H3-treated mice is less when challenged intravenously with B16-F10 melanoma cells. Given that B7-H3 and PD-L1 are co-expressed in the subcutaneously E.G7-transplanted lymphoma model, the immune checkpoint therapy of the combination of anti-B7-H3 and anti-PD-1 antibodies significantly reduces the tumor volume and weight and shows synergistic effects.

Fig.1 Anti-B7H3 shows anti-tumor activity and synergistic effects combined with anti-PD1.¹

Case 2: Advanced Anti-tumor Efficiency of Anti-B7-H3 Plus Anti-PD-1

Intravenously administered single or combination of anti-B7-H3 or anti-PD-1 antibodies are given ten days following the 4T1 breast cancer cell implant. The treatment with anti-B7-H3 or anti-PD-1 alone has no discernible anti-tumor effects from the results of the living bioluminescence image. However, the combination treatment decreased both the tumor size and metastasis. Comparing animals given isotype control antibody injections to those treated with combination therapy, lower vascular density is also seen. While this is happening, more CD8⁺ T cells colocalize with these declining CD31⁺ vessels, pointing to T cell infiltration. This combination immune checkpoint treatment is thought to have anti-tumor efficacy by inhibiting tumor angiogenesis and increasing T-cell invasion.

Fig.2 Combo of anti-B7-H3 plus anti-PD-1 reduces tumor growth, metastasis, and angiogenesis but enhances T-cell invasion.²

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References

1. Lee, Young-hee, et al. "Inhibition of the B7-H3 immune checkpoint limits tumor growth by enhancing cytotoxic lymphocyte function." Cell research 27.8 (2017): 1034-1045.
2. Cheng, Nan, et al. "B7-H3 augments the pro-angiogenic function of tumor-associated macrophages and acts as a novel adjuvant target for triple-negative breast cancer therapy." Biochemical Pharmacology 183 (2021): 114298.

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