Abstract PO-105: Overcoming stromal barriers in PDA with a novel polymeric Toll-like receptor agonist
Authors: DuFort Christopher C. , Lopez Ciana L. , Whittle Martin C. , Vlaskin Vladimir , Vadodkar Aditi , Srinivasan Selvi , Stayton Patrick S. , Hingorani Sunil R. 
Published: November 2021

Abstract
The complex tumor microenvironment (TME) of PDA creates a uniquely immune- and drug-privileged sanctuary that contributes to disease pathogenesis and treatment resistance. The profoundly immunosuppressive microenvironment of PDA includes abundant MDSC, Treg, M2-like TAM and a dearth of cytotoxic T-cells. Recent discoveries of highly expressed Toll-like receptors 7 and 8 (TLR7/8) in the desmoplastic stroma of PDA suggest that TLR7/8 agonists may be an effective immune-targeted therapy. TLR7/8 agonists may inhibit tumor growth by any of several mechanisms including myeloid cell reeducation, depletion of MDSC, and/or depletion of Treg, thereby activating cytotoxic CD8+ T cells. However, the circulatory half-life of most TLR7/8 agonists is relatively short, and elevated systemic levels and prolonged treatment can also cause severe adverse reactions that can limit their use and effectiveness. To address these concerns, we have developed a novel polymeric form of a TLR7/8 agonist that exploits a breakthrough synthetic technology to directly polymerize drugs into nanocarriers with defined architectures. These agents are designed to minimize adverse effects and increase efficacy through more favorable pharmacokinetics and enhanced delivery to desmoplastic tumors with release profiles tailorable over the range of days to weeks. This agent is in development in our murine preclinical trials program (MCTP) which is modeled on human clinical trials and involves randomized, blinded, placebo-controlled studies against the current standard-of-care using the KrasLSL-G12D/+;Trp53LSL-R172H/+;p48Cre/+ (KPC) model as our primary platform of the autochthonous disease. Exploratory experiments were performed to determine optimal dose and treatment schedule. KPC mice with ultrasound-imaging documented disease meeting enrollment criteria were subsequently randomized into one of two arms in 28-day pilot studies: control vehicle-treated and polymeric TLR7/8 (n=5-8 animals per arm). Daily health and behavior checks, serial body weight measurements, and complete blood count (CBC) profiles over the course of the study revealed no adverse health effects or overt toxicities. Mice were euthanized at study completion and all organs harvested for histological analyses; single cell suspensions from blood, spleen, peri-pancreatic lymph nodes and primary tumor were analyzed by FACS and/or CyTOF Helios cytometry (incorporating 30+ specific markers and with a particular focus on identifying specific states and subtypes of CD8+ T cells as well as markers of checkpoint activation to assess innate and adaptive immunity in treated versus untreated and tumor versus normal tissues). Preliminary analyses reveal response associated with increases in T cell activation markers and concomitant changes in inhibitory markers. M1 and M2 macrophage populations also appeared to be profoundly affected, suggesting targeting of specific immune cell types and distinct activation states.
Citation Format: Christopher C. DuFort, Ciana L. Lopez, Martin C. Whittle, Vladimir Vlaskin, Aditi Vadodkar, Selvi Srinivasan, Patrick S. Stayton, Sunil R. Hingorani. Overcoming stromal barriers in PDA with a novel polymeric Toll-like receptor agonist [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-105.