Abstract B294: Antitumor efficacy of AUR-012, a peptide antagonist of the PD1 immune checkpoint pathway, correlates well with the modulation of specific T-cell populations.

Abstract

Abstract Recent breakthroughs in achieving highly durable clinical responses via immunotherapy to inhibit immune checkpoint proteins including CTLA4 and PD1 have revolutionized the outlook for cancer therapy. However, along with impressive clinical activity (response rate of ∼25% with either anti-CTLA4 or anti-PD1 as single agent, but more than 50% with a combination), immune-related toxicities due to the breaking of immune self-tolerance (25-30% with anti-CTLA4 and up to 15-17% with anti-PD1) are becoming increasingly visible. Sustained inhibition of the signaling as a result of a very long half-life (>15-20 days) and >70% target occupancy for months are likely contributing to severe adverse effects observed in clinical trials with antibodies targeting immune checkpoint proteins. Our efforts are therefore focused towards developing novel immune checkpoint blockers with potent antitumor activity but with a shorter pharmacokinetic profile as a strategy to better manage severe adverse effects. Herein we report our findings from the pharmacodynamic characterization of a novel peptide inhibitor of the PD1 signaling that displays desired pharmacokinetic and efficacy profile. Peptide antagonist AUR-012, constructed with elements from human PD-1 ectodomain, displayed equipotent antagonism towards PD-L1 and PD-L2 with potent activity in rescue of lymphocyte proliferation and effector functions. Rescue of proliferation of immune cell subset populations analyzed in vitro using anti-CD3/anti CD-28 stimulation indicated that the functional capacity of T-cells has been reinvigorated by AUR-012 resulting in a complete rescue of CD4+ and CD8+ T cell proliferation in the presence of PD-L1. Similar effect in the rescue of proliferation was also observed for B-cells and NK cells. Interestingly, the proliferation of CD4+, FOxP3+ T cells was completely abolished with AUR-012 treatment indicating a complete suppression of regulatory T cells. Sustained activation of circulatory immune cells and their ability to secrete IFN-γ up to 72 h indicate that pharmacodynamic effects persist even after the clearance of AUR-012 in animal models, thus supporting a dosing interval of up to 3 days irrespective of the short half-life of the peptide. In preclinical models of melanoma, breast, kidney and colon cancers, AUR-012 showed superior showed superior efficacy compared to therapeutic agents currently used in the clinic in inhibition of both primary tumor growth and metastasis. Additionally, antitumor activity of AUR-012 in a pre-established CT26 model correlated well with pharmacodynamic effects as indicated by intratumoral recruitment of CD4+ and CD8+ T cells, and a reduction in PD1+ T cells (both CD4+ & CD8+) in tumor and blood. In conclusion, the observed correlation between antitumor activities with the modulation of specific T-cell populations supports the use of immunophenotyping as a potential therapeutic biomarker strategy in the planned clinical studies with AUR-012. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B294. Citation Format: Murali Ramachandra, Pottayil G. Sasikumar, Rajeev K. Shrimali, Sreenivas Adurthi, Raghuveer Ramachandra, Leena K. Satyam, Amit A. Dhudashiya, Dodheri S. Samiulla, K B Sunilkumar. Antitumor efficacy of AUR-012, a peptide antagonist of the PD1 immune checkpoint pathway, correlates well with the modulation of specific T-cell populations. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B294.