Abstract 4711: Immunomodulatory effects of an EphA2-targeted docetaxel antibody-directed nanotherapeutic and synergistic combination with PD-1 inhibitor
Authors: Sawyer Andrew J. , Dugast Anne-Sophie , Luus Lia , Huang Zhaohua Richard , Tipparaju Suresh K. , Kirpotin Dmitri B. , Drummond Daryl C. , Kamoun Walid S. 
Published: July 2017

The efficacy of the current class of PD-1/PD-L1 antagonists can be limited by the immunogenicity of the tumor microenvironment. Studies showed that some chemotherapeutic agents including taxanes and anthracyclines can increase immunogenicity, resulting in therapeutic synergy with immune checkpoint inhibitors. In particular, treatment with a taxane has been shown to increase the recruitment of CTLs and decrease immunosuppressive cells such as MDSCs and T-regs. Additionally, the immune-modulatory activity of paclitaxel has been shown to increase with prolonged exposure of the taxane at the tumor level, achieved through metronomic dosing. MM-310 is an Ephrin Receptor A2 (EphA2)-targeted antibody-directed nanotherapeutic (ADN) that encapsulates a docetaxel prodrug. Preclinically, MM-310 leads to prolonged exposure of docetaxel at the tumor level, while lowering systemic exposure to bioavailable docetaxel, and thus decreasing not only dose-limiting neutropenia but also the killing of circulating lymphocytes potentially critical to anti-PD1/PDL1 activity relative to free docetaxel. Taken together, we hypothesize that MM-310 can synergistically combine with anti-PD-1 therapy. In this study, we evaluated the potential combination of MM-310 and a murine anti-PD-1 Ab in the treatment of several syngeneic mouse tumor models. The tumor lines EMT-6, CT-26, and LLC were selected to provide a range of sensitivity to both docetaxel and anti-PD-1. In vivo activity studies and immune-phenotype studies were performed comparing MM-310+anti-PD-1 combination to the monotherapies. MM-310 administration was initiated two days prior to anti-PD-1 therapy and consisted of four weekly doses, while anti-PD-1 was dosed twice weekly for four weeks. The response to MM-310 or anti-PD-1 as monotherapies varied between the models. LLC was unresponsive to anti-PD-1 and poorly responsive to MM-310, CT-26 was poorly responsive to both anti-PD-1 and MM-310, while EMT-6 responded moderately to anti-PD-1 with tumor stasis and well to MM-310, achieving tumor regression. In all models, however, MM-310 given in combination with anti-PD-1 outperformed controls and both monotherapy arms in terms of growth inhibition and tumor regression rate. In the EMT-6 model, combination treatment resulted in durable complete regressions in 6/10 mice when compared to 2/10 and 0/10 for MM-310 and anti-PD-1 monotherapies respectively. In MM-310 and MM-310+anti-PD-1 groups, re-challenge of mice with the same tumor cells, at 10 weeks post treatment interruption, did not lead to tumor growth, suggesting that treatment with anti-PD1+MM-310 promotes the development of a memory response against the tumor antigen. In conclusion, the novel combination of MM-310, an EphA2-targeted docetaxel ADN with an anti-PD-1 antibody, is highly active in syngeneic tumor models, and represents a promising strategy for the treatment of cancer.

Citation Format: Andrew J. Sawyer, Anne-Sophie Dugast, Lia Luus, Zhaohua Richard Huang, Suresh K. Tipparaju, Dmitri B. Kirpotin, Daryl C. Drummond, Walid S. Kamoun. Immunomodulatory effects of an EphA2-targeted docetaxel antibody-directed nanotherapeutic and synergistic combination with PD-1 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4711. doi:10.1158/1538-7445.AM2017-4711