Abstract 5522: Combination of a supramolecular nanotherapeutic targeting MEK and immune checkpoint inhibitor exerts a synergistic antitumor outcome
Authors: Kulkarni Ashish A. , Sabbisetti Venkata , Pandey Prithvi Raj , Sengupta Shiladitya 
Published: August 2015

The use of targeted therapeutics, such as BRAF inhibitors, and breakthrough immunotherapy treatments such as immune checkpoint inhibitors, are two emerging paradigms in treatment of chemotherapy-resistant melanoma. However, the treatment responses with targeted therapies are short lived mainly because the patients develop resistance, and also the treatment leads to severe toxicities. Higher concentrations of drug in tumor and sustained inhibition of the kinase signaling pathway for longer period of time is required to achieve better therapeutic efficacy. Similarly, immunotherapy results in lower response rates and the response takes longer time. We envision a new paradigm where a quick as well as durable objective response could be achieved by novel supramolecular nanotherapeutic that targets MEK, downstream of BRAF, in combination with immune checkpoint inhibitor antibody PD-L1. A supramolecular nanotherapeutic is engineered from self-assembly due to supramolecular interactions of molecular building blocks designed using an in silico model based on large scale all atomistic explicit water molecular dynamic simulations. The molecular building blocks were engineered using selumetinib as a template, and rationally re-engineering these molecules by conjugating it to cholesterol to enable supramolecular nanoassembly. The supramolecular nanostructures were stable for over a month as measured by changes in size and zeta potential at different time points. Drug release kinetics profiles showed sustained activation into selumetinib in cell lysate conditions. In vitro cytotoxicity studies in multiple cell lines including Breast Cancer (MDA-MB-231), Lung Cancer (A549) and Melanoma (B16F10) cells showed that supramolecular nanotherapeutics were as effective as selumetinib, and resulted in a sustained inhibition of the MAPK pathway. In vivo studies using a B16/F10 melanoma model revealed that supramolecular nanotherapeutics alone exerted significant tumor growth inhibition as compared to selumetinib. Furthermore, the combination of supramolecular nanotherapeutics and PD-L1 antibody resulted in superior antitumor efficacy, as well as significantly increased number of tumor infiltrating lymphocytes, compared to selumetinib + PD-L1 antibody or PD-L1 antibody alone treatments. This study shows that a successful strategy to improve chemotherapy outcome could be devised by synergistic combinations of supramolecular nanoparticles that target oncogenic signaling pathway with immune checkpoint inhibitors.

Citation Format: Ashish A. Kulkarni, Venkata Sabbisetti, Prithvi Raj Pandey, Shiladitya Sengupta. Combination of a supramolecular nanotherapeutic targeting MEK and immune checkpoint inhibitor exerts a synergistic antitumor outcome. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5522. doi:10.1158/1538-7445.AM2015-5522