Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer

Abstract

The immune suppressive molecule programmed death-1 (PD-1) is upregulated in activated T lymphocytes and inhibits T-cell function upon binding to its ligands B7-H1 (PD-L1, CD274) and B7-DC (PD-L2, CD273). Substantial experimental data from in vitro cell culture systems and animal models, and more recently from clinical trials, indicate that PD-1/PD-1-ligand interactions are a major mechanism of immune suppression within the tumor microenvironment. Initial clinical studies of antibodies directed against PD-1 and B7-H1 showed both an encouraging safety profile and remarkable antitumor activity in subsets of patients with metastatic disease, including malignancies--such as lung cancer--which were previously thought to be unresponsive to immunotherapy. Preliminary data have suggested a correlation between tumor membrane B7-H1 expression and clinical response to anti-PD-1 antibodies. Several key challenges remain to optimize development of PD-1/B7-H1 pathway blockade, including defining the biologic significance of all potential ligand-receptor interactions in the tumor microenvironment, developing more accurate predictive biomarkers of response, determining the breadth of activity in human malignancies, and developing rational combinations of therapy that address key mechanisms involved in positive and negative regulation of antitumor immune responses.

Figure 1. PD-1 signaling in inflamed tissue

Ligation of T-cell PD-1 by B7-H1 on APC leads to the formation of PD-1/TCR microclusters and the subsequent recruitment of SHP2 phosphatases, which dephosphorylate multiple members of the TCR signaling pathway. This abrogates downstream effects of T-cell activation, including cytokine production, cell-cycle progression, and the expression of survival proteins. By preventing T-cell activation, PD-1 signaling contributes to the maintenance of tolerance to self-antigens and prevents immune-mediated damage of healthy tissue during the resolution of infection and other inflammatory responses.

Figure 2. PD-1 and cancer

A) Ligation of T-cell PD-1 by tumor B7-H1 results in the downregulation of T-cell effector functions that destroy tumor tissue. B) Blockade of this pathway by anti-PD-1 antibodies prevents this downregulation, and allows T cells to maintain their antitumor functionality and ability to mediate tumor cell death.

Figure 3. B7-H1 expression and inflammation: implications for mechanisms and therapy

I. B7-H1- tumor without TILs II. B7-H1⁺ melanoma with TILs at advancing edge III. B7-H1- tumor with TILs present IV. B7-H1+ tumor without TILs