Intratumoral Delivery of a Novel STING Agonist Synergizes with Checkpoint Blockade to Regress Multi-Focal Pancreatic Cancer
Casey Ager1,2, Maria Emilia Di Francesco3, Philip Jones3, Michael A. Curran1,2 1University of Texas MD Anderson UT Health Graduate School of Biomedical Sciences; 2University of Texas MD Anderson Cancer Center, Department of Immunology; 3Institute for Applied Cancer Science
Immunosuppressive myeloid populations potently constrain T cell function in the tumor microenvironment. Dismantling suppressive myeloid networks through local engagement of innate pathogen recognition receptors such as the Stimulator of Interferon Genes (STING) can promote antitumor T cell function and potentiate the therapeutic effects of checkpoint blockade immunotherapy. Using flow cytometric phenotyping and T cell suppression assays, we find that in vitro polarized human M2 macrophages and murine bone marrow-derived myeloid derived suppressor cells (MDSC) can be phenotypically and functionally repolarized by STING-activating cyclic dinucleotides (CDN). These studies show that pro-inflammatory repolarization is proportional to the affinity of the applied STING agonist. Therefore, we developed and characterized IACS-8803, a novel STING-activating CDN with over 10-fold greater potency than ML-RR-S2-CDA, the first-in-class CDN currently in Phase I clinical trials. We next investigated the capacity for intratumoral delivery of IACS-8803 to sensitize murine pancreatic cancer to checkpoint blockade and to mobilize abscopal immunity against disseminated lesions. We utilized mT4-2D, a novel pancreatic cancer cell line derived from Kras+/LSL-G12DTp53+/LSL-R172HPdx1-Cre tumor organoids. Mice bearing 10-day established orthotopic and subcutaneous mT4-Luciferase (mT4-Luc) tumors received standard regimens of αCTLA-4, αPD-1, or combined αCTLA-4/αPD-1 in the presence or absence of IACS-8803 injected into the orthotopic tumor. We find single agent treatment with IACS-8803, αCTLA-4, αPD-1, or αCTLA-4/αPD-1 can cure 40-60% of mice of both orthotopic and subcutaneous tumors in this system; however, combination of IACS-8803 and checkpoint blockade completely eradicates both injected and distal mT4-Luc tumors in all mice. Mechanistic studies suggest critical contributions of both tumor myeloid and T cell activation at both tumor sites. Our findings suggest a potential for local STING agonist delivery to sensitize pancreatic adenocarcinoma to checkpoint blockade immunotherapy.
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