Clinical experiences with anti-CD137 and anti-PD1 therapeutic antibodies.

Monoclonal antibodies (mAbs) provide a pharmacological platform to block or activate the function of surface receptors. The immune system has evolved receptor-ligand pairs that repress or empower the cellular immune response, which, if tampered with, unleash more potent cellular immunity against tumor antigens. Agonist antibodies directed against CD137 (4-1BB) on the surface of antigen-primed T lymphocytes increase tumor immunity that is curative against some transplantable murine tumors. A fully human IgG4 anti-CD137 antibody is under development with signs of clinical activity and cases of severe liver toxicity that seem to be on-target and dose-dependent effects. Programmed death-1 (PD1) is a surface molecule delivering inhibitory signals important to maintain T-cell functional silence against their cognate antigens. Interference with PD1 or its ligand PD-L1 (B7-H1) increases antitumor immunity. As a result anti-PD1 and anti-PD-L1 human mAbs are under clinical development. Phase I trials with anti-PD1 mAb have yielded encouraging results with durable objective responses and a reasonable safety profile. As new class of drugs in cancer therapy, immunostimulatory mAbs have resulted in redefinition of tumor response criteria and rethinking of the rationale for combining these among each other and with other strategies.