Abstract 5022: Peptide therapeutic inhibiting PD1 immune checkpoint ligands: Potential for greater anti-tumor immune response and better management of immune-related adverse events

Abstract

Abstract Antibodies to immune checkpoint receptors have revolutionized the outlook of cancer therapy by achieving highly durable clinical responses. However, along with impressive clinical activity (response rate of ∼25% with either anti-CTLA4 or anti-PD1 as single agent, but > 50% with a combination), severe immune-related adverse events (irAEs) due to the breaking of immune self- tolerance (25-30% with anti-CTLA4 and up to 15-17% with anti-PD1) are becoming increasingly evident. Sustained target inhibition as a result of a long half-life (>15-20 days) and >70% target occupancy for months are likely contributing to severe irAEs observed in the clinic with antibodies targeting immune checkpoint proteins. The antibodies targeting PD-1 signaling pathway are either based on receptor (PD-1) or its ligands (PD-L1 & PDL2). It has also been reported that PDL1 also interacts with B7-1(CD80) resulting in negative T-cell regulation. Our efforts are therefore focused on (a) developing a first in class peptide therapeutic inhibiting all three reported interaction of PD-1 pathway to improve the anti-tumor immune response (b) developing immune checkpoint blockers with potent anti-tumor activity but with a shorter pharmacokinetic profile as a strategy to better manage severe irAEs. Peptide antagonist AUR-012, constructed with elements from human PD-1 receptor, displayed equipotent antagonism towards PD-L1 and PD-L2 with potent activity in rescue of lymphocyte proliferation and effector functions. Additionally crosslinking study to evaluate the effect of AUR-12 on B7.1 - PDL-1 interaction supports the finding that AUR-012 prevents the interaction of B7.1 with PD-L1. Rescue of proliferation of immune cells analyzed upon stimulation with anti-CD3/anti-CD-28 indicated a complete rescue of CD4+ and CD8+ T cells and 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. In models of melanoma, breast, kidney and colon cancers, AUR-012 showed efficacy in inhibition of both primary tumor growth and metastasis. Additionally, anti-tumor 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 14-day repeated dose toxicity studies, AUR -012 was well tolerated at 100x of the efficacious doses. These findings demonstrating inhibition of all PD-1/ PD-1 ligands mediated co-inhibitory signaling pathway and the observed correlation between anti-tumor activities with the modulation of specific T-cell populations support further development of AUR-012 in the clinic. Citation Format: Murali Ramachandra, Pottayil G. Sasikumar, Rajeev K. Shrimali, Sreenivas Adurthi, Raghuvir Ramachandra, Leena K. Satyam, Amit A. Dhudashia, Samiulla Dhodheri, K B. Sunilkumar. Peptide therapeutic inhibiting PD1 immune checkpoint ligands: Potential for greater anti-tumor immune response and better management of immune-related adverse events. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5022. doi:10.1158/1538-7445.AM2014-5022