Combined Therapy of PD-L1 and B7-H3

Background

The immune system can identify and eliminate cancer cells via immune checkpoint molecules including the most effective one, programmed death-1 (PD-1). Immunotherapy targeting PD-1 and its ligand PD-L1 reaches notable tumor regression in the majority of cancers, but its efficiency is limited since certain malignant cells are immune-suppressed. Alternative techniques are necessary for the tumor types that are resistant to anti-PD-1/PD-L1 treatment. B7 homolog 3 protein (B7-H3, also known as CD276) is abundantly expressed in several cancer cell types, particularly those that are fundamentally resistant to anti-PD-L1 treatment. A new and promising therapeutic option for B7-H3-expressing NSCLC is combined PD-L1 and B7-H3 signaling blocking therapy, which has been shown to give potential therapies for various malignant illnesses in recent research.

Case 1: Anti-PD-L1 Enhances the Tumor Regression When B3-H7 is Knock-out

After the inoculation of luciferase-expressing ID8 ovarian cancer cells with or without B7-H3 KO, anti-PD-L1 antibodies or solvent are injected intraperitoneally for 4 weeks. The tumor progression is obviously inhibited after anti-PD-L1 treatment, which is monitored by in vivo bioluminescence imaging after substrate delivery. Besides, the combination of B3-H7 knock-out and anti-PD-L1 achieves the most significant anti-tumor activity, reflected in the reduced fluorescence and prolonged survival rate. These uncover the promising combined immune checkpoint therapy between B3-H7 and PD-L1.

Fig.1 B7-H3 knock-out mice show additive effects in tumor inhibition when treated with anti-PD-L1.¹

Case 2: Synergistic Anti-tumor Effect of Anti-B7-H3 and Anti-PD-L1

B7-H3 is also highly expressed in the pancreatic ductal adenocarcinoma cell line, which provides the opportunity for combined immune checkpoint therapy based on anti-B7-H3 and anti-PD-L1. In mice subcutaneously implanted with adenocarcinoma cells, peritoneal injection of antibody combination causes the most remarkable tumor volume reduction and survival rate increase than each single antibody therapy, which demonstrates a good synergistic effect between B3-H7 and PD-L1. Moreover, FACS analysis indicates that elevated CD8⁺ T cell infiltration exists in the combined therapy-treated mouse tumor, one of the key conditions of anti-tumor ability.

Fig.2 Combo of anti-B7-H3 and anti-PD-L1 leads to the best tumor regression.²

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References

1. Huang, Mingyan, et al. "Deficiency of tumor-expressed B7-H3 augments anti-tumor efficacy of anti-PD-L1 monotherapy rather than the combined chemoimmunotherapy in ovarian cancer." Pharmacological Research 186 (2022): 106512.
2. Yonesaka, Kimio, et al. "B7-H3 negatively modulates CTL-mediated cancer immunity." Clinical Cancer Research 24.11 (2018): 2653-2664.

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