1022 Evaluating the mechanism of enhanced responses to the IV STING agonist dazostinag (TAK-676) plus pembrolizumab in neuroendocrine tumors
Year: 2024
Type: conference-abstract
Abstract: Background Neuroendocrine tumors (NETs) are a collection of rare malignancies that generally exhibit an immunologically ‘cold’ tumor microenvironment and share molecular similarities to small cell lung cancer (SCLC). Despite the success of immune checkpoint inhibitors in treating several types of solid tumors, durable responses in NETs are rare, potentially attributable to low MHC-I expression. STimulator INterferon Genes (STING) agonist-mediated anti-tumor activity is driven by immune reprogramming, increased antigen presentation, and myeloid/lymphoid cell activation resulting from induction of type I interferon (IFN) and other proinflammatory cytokines. Dazostinag is a novel, systemic, cyclic dinucleotide STING agonist that, when combined with pembrolizumab, demonstrated durable responses in some NET patients across two clinical studies (NCT04420884, NCT04879849). Therefore, we utilized preclinical models to evaluate potential mechanisms leading to these clinical responses and explore the potential for responses in related tumors. Methods NET patients treated with dazostinag and pembrolizumab were evaluated for STING-mediated biomarker activity by flow cytometry, RNAseq and peripheral cytokine analyses. Real-world patient-derived data (Tempus Labs) from >1700 NET and >1300 SCLC samples was analyzed for key molecular features to identify relevant preclinical models. Selected SCLC/NET cell lines were characterized by Western blot, RNAseq and viability assays to evaluate potential for tumor intrinsic activity following dazostinag treatment in vitro. Immune-mediated impacts on tumor MHC-I and PD-L1 expression following dazostinag and/or pembrolizumab treatment were assessed utilizing relevant co-cultured cell lines and patient-derived tumor cells. Combination treatment was evaluated for efficacy potential and pharmacodynamic responses in vivo using a murine RPP (CRISPR-mediated knockout of Rb1/Trp53/p130) SCLC model. Results Real-world data suggest tumors with neuroendocrine features have low immune cell infiltration and diminished STING expression, which correlate with higher tumor grade. Dazostinag had no tumor intrinsic effect on NET cell lines in vitro. Type I/II IFN mediated upregulation of MHC-I and PD-L1 on NET cell lines and patient-derived lung NETs in a STING-dependent immune-mediated manner. Compared with single agent, dazostinag in combination with anti-PD-1 resulted in enhanced antitumor efficacy in vivo, which correlated with increased T/NK cell infiltration. Preclinical systems recapitulated clinical biomarker observations that were consistent with evidence of STING activation and provide potential mechanistic insight into responses observed in patients. Conclusions Preclinical STING agonism via dazostinag increased immune trafficking and infiltration into the NET/SCLC microenvironment and enhanced antigenicity and immune recognition leading to sensitization to anti-PD-1 therapy. Our results provide rationale for clinical evaluation of STING agonists as part of a combination strategy for immunotherapy-based treatment of NETs.
Institutions: Takeda Oncology (United States), Dana-Farber Cancer Institute
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W4404052745