Combined Therapy of PD-L1 and 4-1BB

Numerous cancers have shown promise for PD-1/PD-L1 blockade immunotherapy, but its clinical efficacy is constrained in part because of the lack of tumoral effector cytotoxic T lymphocyte invasion. Costimulatory receptor 4-1BB is expressed on activated CD4⁺ and CD8⁺ T cells, NK cells, DCs, macrophages, and Tregs, which also serves as a useful surrogate marker for tumor-reactive T-cell subsets in the tumor microenvironment. Anti-4-1BB mAb (also known as anti-CD137) treatment increases antibody-dependent cell-mediated cytotoxicity, drives anti-tumor immune responses, and promotes T-cell proliferation and cytokine secretion. Combining PD-L1 inhibition and 4-1BB agonism can result in an increase in tumor-infiltrating CD8⁺T cells and speed up tumor remission than treated alone.

Case 1: Synergistic Anti-tumor Activity Between Anti-4-1BB and Anti-PD-L1

Individual tumor growth curves in the 4T1.2 breast cancer mouse model reveal that 4T1.2 tumors are only moderately rejected by anti-PD-L1 or anti-4-1BB mAb, with pronounced tumor delay in the combination therapy. Additionally, lung metastasis is significantly reduced in mice treated with the combination of anti-PD-L1 and anti-4-1BB. Administration of anti-PD-L1 mAb or anti-4-1BB mAb alone has little to no impact on the quantity of tumor-infiltrating lymphocytes, whereas the number of infiltrating CD8⁺ T cells increases significantly in the combinatorial treatment, including the CD103⁺CD8⁺ T cells with higher cytolytic activity. This is the same as the result that cytotoxic T cell influx is not enough with a single PD-1/PD-L1 inhibition.

Fig.1 Combined treatments of anti-PD-L1 and anti-4-1BB obviously delay the tumor growth and enhance the CD8⁺ T cell infiltration.¹

Case 2: Virus-based Combination Treatment Shows Tumor Suppression

Immune checkpoint inhibition caused by monoclonal antibodies frequently has negative side effects when administered systemically. Expression of antibodies using viral vectors like Semliki Forest virus (SFV) can prevent this toxicity. The combination of intratumorally injection of anti-PD-L1-expressing SFV and intraperitoneal administration of anti-4-1BB antibody (anti-CD137) in mice with subcutaneous tumors exhibits much greater tumor inhibition than either treatment alone, as well as a higher survival rate. This broadens the range of immune checkpoint treatment techniques.

Fig.2 Anti-PD-L1-expressing SFV plus anti-CD137 highly decreases tumor growth and improves survival rate.²

Creative Biolabs, which was founded by distinguished scientists, is committed to giving you a thorough grasp of your project about immune checkpoint therapy. Don't hesitate to contact us for more details.

References

1. Qu, Qiu-xia, et al. "4-1BB agonism combined with PD-L1 blockade increases the number of tissue-resident CD8⁺ T cells and facilitates tumor abrogation." Frontiers in Immunology 11 (2020): 577.
2. Ballesteros-Briones, Maria Cristina, et al. "Short-term local expression of a PD-L1 blocking antibody from a self-replicating RNA vector induces potent antitumor responses." Molecular Therapy 27.11 (2019): 1892-1905.

All listed customized services & products are for research use only, not intended for pharmaceutical, diagnostic, therapeutic, or any in vivo human use.