The initial evidence that anti-4-1BB agonistic mAbs may have strong antitumor effects emerged from studies on the highly tumorigenic P815 mastocytoma and poorly immunogenic Ag104A sarcoma. Administration of anti-4-1BB mAb eradicated established tumors in both models and generated increased numbers of tumor-specific cytotoxic T cells. Importantly, anti-4-1BB mAb therapy appeared to trigger an immunologic memory response: Mice that had been cured of P815 cancer were challenged 3 months later with P815 cells and, after a period of transient growth, all tumors regressed. The antitumor capacity of 4-1BB-targeted mAb has since been replicated in a variety of cancer models, including lymphoma, hepatocellular carcinoma, and colon cancer. The mechanism of action underpinning 4-1BB-mediated cancer regression consists of multiple, complimentary antitumor immune pathways. Primarily, 4-1BB agonism induces a potent, cytotoxic T-cell population that can infiltrate and lyse tumors. In addition to direct tumor lysis, 4-1BB stimulation promotes the secretion of type 1 cytokines, creating an inflammatory, immunogenic cytokine milieu within the tumor microenvironment (TME). Finally, 4-1BB ligation increases the secretion of perforin and granzyme and activation of the Fas ligand (FasL) effector system by both CD8+ T cells and NK cells.
Chester C, Ambulkar S, Kohrt HE. 4-1BB agonism: adding the accelerator to cancer immunotherapy. Cancer Immunology, Immunotherapy. 2016;65(10):1243-1248.