Clinical development of mAbs to block the PD1 pathway as an immunotherapy for cancer.

Tumor antigen-specific T-cell function is regulated by both positive and negative costimulatory signals, which are received in the secondary lymphoid organs and within the tumor microenvironment. Tumor-induced T-cell dysfunction results from a lack of positive costimulatory signals, combined with a predominance of negative immunoregulatory mechanisms. The engagement of the protein programmed death 1 (PD1), expressed on activated T-cells, by programmed death ligand 1 (PD-L1)/B7H1 within tumor cells or other host-derived cells results in the downregulation of T-cell function, and represents an important negative regulatory pathway. Preclinical cancer models suggest that interruption of PD1/PD-L1 interactions leads to improved antitumor T-cell responses and tumor control. mAbs developed against both PD1 and PD-L1/B7H1 are being evaluated in phase I/II clinical trials in patients with a variety of cancers. The uncoupling of negative immune regulatory pathways therefore represents an exciting and potentially highly valuable new modality for cancer immunotherapy.