@article{32a12241458942f6a869f050e7ae6aae,
title = "A surgically optimized intraoperative poly(I:C)-releasing hydrogel prevents cancer recurrence",
abstract = "Recurrences frequently occur following surgical removal of primary tumors. In many cancers, adjuvant therapies have limited efficacy. Surgery provides access to the tumor microenvironment, creating an opportunity for local therapy, in particular immunotherapy, which can induce local and systemic anti-cancer effects. Here, we develop a surgically optimized biodegradable hyaluronic acid-based hydrogel for sustained intraoperative delivery of Toll-like receptor 3 agonist poly(I:C) and demonstrate that it significantly reduces tumor recurrence after surgery in multiple mouse models. Mechanistically, poly(I:C) induces a transient interferon alpha (IFNα) response, reshaping the tumor/wound microenvironment by attracting inflammatory monocytes and depleting regulatory T cells. We demonstrate that a pre-existing IFN signature predicts response to the poly(I:C) hydrogel, which sensitizes tumors to immune checkpoint therapy. The safety, immunogenicity, and surgical feasibility are confirmed in a veterinary trial in canine soft tissue tumors. The surgically optimized poly(I:C)-loaded hydrogel provides a safe and effective approach to prevent cancer recurrence.",
keywords = "cancer, drug delivery, hydrogel, immunotherapy, PD-1, poly(I:C), surgical oncology, Toll-like receptor, tumor, wound healing",
author = "Rwandamuriye, {Francois Xavier} and Evans, {Cameron W.} and Ben Wylie and Marck Norret and Breana Vitali and Diwei Ho and Dat Nguyen and Roper, {Ellise A.} and Tao Wang and Hepburn, {Matt S.} and Sanderson, {Rowan W.} and Maren Pfirrmann and Fear, {Vanessa S.} and Forbes, {Catherine A.} and Ken Wyatt and Ryan, {Anne L.} and Johns, {Terrance G.} and Phillips, {Marianne B.} and Rupert Hodder and Connull Leslie and Kennedy, {Brendan F.} and Zemek, {Rachael M.} and Iyer, {Killugudi Swaminathan} and Lesterhuis, {Willem Joost}",
note = "Funding Information: F.X.R. and B.V. are supported by Australian Government PhD scholarships and Abbie Basson PhD top-up scholarships. B.W. is supported by a Cancer Council WA Fellowship. R.Z. is supported by a Forrest Fellowship and a Raine Priming Grant . W.J.L. was supported by fellowships from the Simon Lee Foundation and the National Health and Medical Research Council ( NHMRC ). This work was funded by grant APP1184331 from Cancer Australia /The Kids{\textquoteright} Cancer Project and supported by funding from the Sock it to Sarcoma! Foundation , the Australian and New Zealand Sarcoma Association , Perpetual, and the Children{\textquoteright}s Leukaemia and Cancer Research Foundation . The authors acknowledge the facilities and the scientific and technical assistance offered by Diana Patalwala at the National Imaging Facility at the Centre for Microscopy, Characterization & Analysis, The University of Western Australia, a facility funded by the University, State, and Commonwealth Governments . Icons of mice and dogs were created with BioRender.com . Funding Information: F.X.R. and B.V. are supported by Australian Government PhD scholarships and Abbie Basson PhD top-up scholarships. B.W. is supported by a Cancer Council WA Fellowship. R.Z. is supported by a Forrest Fellowship and a Raine Priming Grant. W.J.L. was supported by fellowships from the Simon Lee Foundation and the National Health and Medical Research Council (NHMRC). This work was funded by grant APP1184331 from Cancer Australia/The Kids{\textquoteright} Cancer Project and supported by funding from the Sock it to Sarcoma! Foundation, the Australian and New Zealand Sarcoma Association, Perpetual, and the Children's Leukaemia and Cancer Research Foundation. The authors acknowledge the facilities and the scientific and technical assistance offered by Diana Patalwala at the National Imaging Facility at the Centre for Microscopy, Characterization & Analysis, The University of Western Australia, a facility funded by the University, State, and Commonwealth Governments. Icons of mice and dogs were created with BioRender.com. Conceptualization, K.S.I. and W.J.L.; methodology, F.X.R. C.W.E. B.W. M.N. M.S.H. B.F.K. R.M.Z. K.S.I. and W.J.L.; formal analysis, F.X.R. C.W.E. B.W. M.S.H. R.M.Z. and V.S.F.; investigation, F.X.R. C.W.E. B.W. M.N. B.V. D.H. D.N. E.A.R. T.W. M.S.H. R.W.S. V.S.F. C.A.F. K.W. and R.M.Z.; resources, M.N. and K.W.; writing – original draft, F.X.R. C.W.E. B.W. K.S.I. and W.J.L.; writing – review & editing, all authors; visualization, F.X.R. B.W. R.M.Z. and W.J.L.; supervision, B.W. R.M.Z. and K.S.I. and W.J.L.; project administration, F.X.R. B.W. K.S.I. and W.J.L.; funding acquisition, K.S.I. and W.J.L. We declare a patent application pertaining to aspects of this work. B.F.K. discloses a financial interest in OncoRes Medical, a company developing QME for use in surgery. W.J.L. declares consultancy for Douglas Pharmaceuticals and MSD and research funding from Douglas Pharmaceuticals, AstraZeneca, and ENA Therapeutics. We support inclusive, diverse, and equitable conduct of research. Funding Information: We declare a patent application pertaining to aspects of this work. B.F.K. discloses a financial interest in OncoRes Medical, a company developing QME for use in surgery. W.J.L. declares consultancy for Douglas Pharmaceuticals and MSD and research funding from Douglas Pharmaceuticals, AstraZeneca, and ENA Therapeutics. Publisher Copyright: {\textcopyright} 2023 The Author(s)",
year = "2023",
month = jul,
day = "18",
doi = "10.1016/j.xcrm.2023.101113",
language = "English",
volume = "4",
journal = "Cell Reports Medicine",
publisher = "Cell Press",
number = "7",
}
