Poster Presentation Asia-Pacific Vaccine and Immunotherapy Congress 2023

A surgically optimised intraoperative poly(I:C) releasing hydrogel prevents cancer recurrence (#119)

Francois X Rwandamuriye 1 , Cameron CW Evans 2 , Ben Wylie 1 , Marck Norret 2 , Breana Vitali 1 , Diwei Ho 2 , Dat Nguyen 1 , Ellise Roper 1 , Tao Wang 1 , Matt S Hepburn 3 , Rowan W Sanderson 3 , Maren Pfirrmann 1 , Vanessa S Fear 1 , Catherine A Forbes 1 , Ken Wyatt 4 , Annie L Ryan 5 , Terrance G Johns 1 , Marianne M Phillips 5 , Rupert Hodder 6 , Connull Leslie 7 , Brendan F Kennedy 3 , Rachael M Zemek 1 , Iyer K Swaminathan 2 , Joost W Lesterhuis 1
  1. Telethon Kids Institute, Nedlands, WA, Australia
  2. School of Molecular Sciences, The University of Western Australia, Perth, WA, Australia
  3. BRITElab, Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, WA, Australia
  4. Perth Veternary Specialists, Osborne Park, WA, Australia
  5. Department of Oncology, Haematology and Tissue & Cellular Therapies, Perth Children's Hospital, Perth, WA, Australia
  6. Department of Surgery, Sir Charles Gairdner Hospital, Nedlands, WA, Australia
  7. Department of Anatomical Pathology, PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, WA, Australia

Introduction. Surgery remains the main treatment option for most solid cancers. However, recurrences are common and associated with a poor prognosis.  Systemic immunotherapy, especially with checkpoint inhibitors, has provided improvements in survival, but only in selected cancers and a proportion of patients. 

Methods. We developed a surgically optimised hyaluronic acid-based hydrogel formulation for sustained local delivery of innate immune agonists and mapped its in-vivo degradation kinetic. We assessed the safety, dose, and scheduling of low dose, local innate immune agonists and demonstrated the efficacy of hydrogel-loaded immunotherapy using our established mouse models of incomplete tumour resection. The underlying immunological mechanisms were characterised using cytokine blocking studies, flow cytometry, and RNA sequencing. Finally, we assessed the safety and feasibility of the hydrogel delivery platform in a veterinary clinical trial for canines undergoing surgical removal of soft tissue sarcoma. 

Results. The surgically optimised hydrogel could be feasibly applied in the wound bed after cancer surgery. We identified the optimal immunotherapy to be used in the hydrogel, the TLR3 agonist poly(I:C), which not only resulted in local and systemic anti-tumour immunity but also improved surgical wound healing. The poly(I:C) hydrogel, placed in the tumour resection site, prevented tumour recurrence in multiple mouse models. Mechanistically, poly(I:C) induced a transient IFNα response that reshaped the tumour microenvironment (TME) by attracting inflammatory immune cells and depleting Tregs from the TME. In addition, RNAseq data showed that a pre-existing IFN gene signature predicted response to the poly(I:C)-loaded hydrogel, which sensitised tumours to subsequent anti-PD-1 checkpoint blockade. Finally, the hydrogel delivery platform was safe for use in canine cancer patients, and easy to use for the surgeon, while the immunotherapy induced a measurable systemic immune response. 

Conclusions. The hydrogel provides a safe and effective drug delivery approach to prevent recurrence of solid tumours following surgery.