Abstract IA7: Blockade of immunologic checkpoints in cancer therapy: The B7-H1/PD-1 pathway

Abstract

Abstract Malignant cells display altered surface molecular signatures distinguishing them quantitatively and qualitatively from their normal counterparts. Such modifications may facilitate tumor progression by regulating interactions between cancer cells and immune cells in the tumor microenvironment. Central to the ability of cancer cells to evade immune destruction is the immunoglobulin-like molecule B7-H1 (PD-L1), constitutively expressed by many human cancers including melanoma and lung, kidney, colon and ovarian cancers. Expression of cell surface B7-H1 is upregulated by proinflammatory stimuli such as interferons, and may be influenced by activated oncogenic pathways such as PI3K/AKT. B7-H1 acts as a ligand for the programmed death-1 (PD-1) receptor normally expressed on activated T cells, which delivers an inhibitory signal to suppress immune responses. The mechanisms underlying B7-H1/PD-1-mediated immunosuppression include apoptosis induction, anergy, and exhaustion of recently activated effector or memory T cells. Based on findings of B7-H1 over-expression by human cancers as well as the observation that tumor-infiltrating T cells can express high PD-1 levels in situ, multicenter clinical trials of blocking antibodies against PD-1 or B7-H1 have been undertaken. In the first phase I/II trial of anti-PD-1 (MDX-1106, Bristol-Myers Squibb), 39 patients with treatment-refractory advanced melanoma, NSCLC, RCC, colon cancer or prostate cancer were treated with intermittent (every 1–3 month) escalating doses of antibody. Durable objective tumor regressions including one CR (colon cancer) and 2 PR's (melanoma and RCC) were observed, and 2 additional patients (NSCLC and melanoma) experienced transient lesional tumor regressions. There were no dose-limiting toxicities after a single dose of anti-PD-1, up to the highest planned dose of 10 mg/kg. Based on these results as well as correlative in vitro assays defining the B7-H1/PD-1 axis as a promising target for cancer therapy, a follow-up phase I/II trial of biweekly MDX-1106 administration, and the first-in-human trial of anti-B7-H1 (MDX-1105, BMS), were initiated. Preliminary results from biweekly MDX-1106 administration in patients with advanced metastatic solid tumors have recapitulated clinical activity in melanoma, RCC and NSCLC, with generally manageable toxicities. Objective response rates of ∼30% in melanoma and RCC have been reported. The majority of patients experiencing objective tumor regressions (CR or PR) on MDX-1106 therapy continue in remission, with follow-up up to 3 years. Also of interest, preliminary experience with anti-B7-H1 therapy has shown evidence of clinical activity in advanced melanoma, RCC and NSCLC. Current investigations of pharmacodynamics, tumor biomarkers and intratumoral immune events aim to explore the mechanisms of action of anti-PD-1 and anti-B7-H1 in order to guide future clinical development, including synergistic combinatorial strategies with other targeted agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr IA7.