Combined Therapy of PD-1 and 4-1BB

Introduction of PD-1 and 4-1BB

Activated T cells and other immune cells both express the inhibitory receptor known as programmed death 1 (PD-1). Both enhanced effector T-cell responses and induced T-cell-mediated tumor rejection have been demonstrated by antibody blocking of PD-1. Numerous tumor types have significantly shrunk after receiving immunotherapies that target PD-1. For larger populations to benefit from cancer immunotherapy, however, strong and secure combination medicines are still required. A subset of immune cells, such as T cells and natural killer cells, are normally required for the activation of 4-1BB (also known as CD137 and TNFRSF9), a member of the TNF receptor superfamily. Combinations of anti-4-1BB and anti-PD-1 have been shown to have synergistic anticancer effects, blocking the immune checkpoint and exhibiting promising anti-tumor activity.

Case 1: Combined Therapy Causes Pronounced Melanoma Inhibition

Inhibiting the growth of the B16F10 tumor with anti-4-1BB or anti-PD-1 alone is inconsistent. When anti-4-1BB and anti-PD-1 antibodies are given to tumor animals simultaneously, a striking efficacy of 85% tumor growth reduction as compared to the isotype control is observed, which is eliminated in the IFNγ-deficient mouse model. Combination therapy-mediated tumor suppression is also totally abolished when anti-CD8 antibody is used to eliminate CD8⁺ T cells in tumor-bearing animals. Additionally, the combination therapy clearly raises the proportions of CD8⁺/CD4⁺ and CD8⁺/Treg in tumor-infiltrating lymphocytes, which is thought to encourage an anti-cancer immune response in the tumor microenvironment. Taken together, IFNγ and CD8⁺ T cells are required for the anti-4-1BB/anti-PD-1 combo to be effective.

Fig.1 The combination of anti-4-1BB and anti-PD-1 can reduce the tumor volume in an IFNγ- and CD8⁺ T cells-dependent manner.¹

Case 2: Combination of Anti-4-1BB and Anti-PD-1 Inhibits Subcutaneous Tumor

In a subcutaneous colorectal cancer mouse model generated by CT26 cell injection, the combination of anti-4-1BB and anti-PD-1 shows the best antitumor response without overt toxicity. The number of CD8⁺ T cells, CD8⁺/IFN⁺ T cells, and AH1-specific CD8⁺ T cells is considerably enhanced in the spleen in mice receiving combination therapy. Additionally, the percentage of tumor-infiltrating CD3⁺ cells of the combination therapy-treated group dramatically increased on days 17 and 24 detected by pathological analysis.

Fig.2 The combined therapy of anti-4-1BB and anti-PD-1 shows significant anti-tumor activity.²

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References

1. Chen, Shihao, et al. "Combination of 4-1BB agonist and PD-1 antagonist promotes antitumor effector/memory CD8 T cells in a poorly immunogenic tumor model." Cancer immunology research 3.2 (2015): 149-160.
2. Shindo, Yoshitaro, et al. "Combination immunotherapy with 4-1BB activation and PD-1 blockade enhances antitumor efficacy in a mouse model of subcutaneous tumor." Anticancer research 35.1 (2015): 129-136.

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