Article Text

Download PDFPDF

1149 Sensitizing aggressive murine pancreatic cancer to immune checkpoint blockade using a tumor-targeted, STING agonist ‘payloaded’ antibody
  1. Akash Boda1,
  2. Shweta Hegde1,
  3. Sean Smith2 and
  4. Michael Curran1
  1. 1The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  2. 2Silverback Therapeutics, Seattle, WA, USA
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


Background Previously we have shown that intratumoral injection of IACS8803, a potent synthetic agonist of the Stimulator of Interferon Genes (STING) innate immune sensor, can act as an ‘in-situ vaccine’ that orchestrates a proinflammatory rewiring of the immunosuppressive myeloid stroma thereby driving robust T cell activation and infiltration into otherwise ‘cold’ tumors. While this approach promotes cure of numerous murine models, clinical application of STING agonists has been limited by IR-guided direct injection into single tumor lesions, an invasive practice with limited potential for re-administration which has failed to significantly benefit metastatic cancer patients. Immune-Stimulating Antibody Conjugates (ISACs) leverage the specificity and safety of traditional antibody-drug conjugates but carry immuno-stimulatory payloads rather than cytotoxic warheads.

Methods With ImmunoGenesis and Silverback, Inc. we developed an ISAC using our highly potent STING agonist IACS8803 conjugated to the Her2/neu antibody trastuzumab. We characterized the specificity and uptake of this ISAC by Her2-expressing tumor cells, and the capacity of associated PBMC for downstream STING activation using ELISA or a THP1-dual reporter assay. Next, in the MT4-LA orthotopic Kras+/LSL-G12D; Trp53+/LSL-R172H; Pdx-Cre (‘KPC’) derived model of pancreatic ductal adenocarcinoma (PDAC), we compared the ability of intratumorally-administered IACS-8803 to intraperitoneally administered Her2-IACS8803 to sensitise PDAC to checkpoint blockade using bioluminescent in vivo imaging and multi-parameter flow cytometry of tumor stroma post-therapy. We also assessed their toxicity and tolerability with multiple low-dose treatments.

Results In mT4-LA cells expressing Her2 protein, fluorophore-conjugated Her2-IACS8803 ISAC was taken up readily using receptor-mediated endocytosis across a concentration gradient. In tumor and human PBMC coculture assays we observed an elevated expression of downstream STING pathway targets such as type I IFNs and cytokines such as CXCL10, TNFα etc. Next, in the multi-focal mT4-LA PDAC tumor model (orthotopic and flank tumors), we found that systemic administration of a low concentration of the Her2-IACS8803 ISAC could provide equivalent tumor control and survival extension to multiple intra-tumoral injections of the STING agonist in combination with immune checkpoint blockade. Finally, TIL analyses of multiparameter flow cytometry data show a proinflammatory remodeling of the myeloid stroma and enhanced T cell function as salient features of synthetic agonists in orchestrating the in vivo therapeutic benefit, an effect that mirrors intratumoral IACS-8803 delivery.

Conclusions These preclinical studies demonstrate the potential of STING agonist ‘payloaded’, tumor-targeted antibodies non-invasively administered to provide better control of aggressive and multifocal PDAC in combination with immune checkpoint blockade.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.