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Abstract
Background Surgery is the main treatment option for many solid cancers, including soft tissue sarcomas. However, local relapse remains a leading cause of cancer-related mortality, with recurrent tumours often being more aggressive and therapy-resistant. Adjuvant chemo- or radiotherapy only increase survival in a limited population of patients and are associated with high risk of treatment related toxicities. To address these issues, we developed a surgically optimised biomaterial hydrogel that could be loaded with immunotherapeutics for sustained local release thereby utilising the ‘window of opportunity’ created by tumour resection surgery to deliver intraoperative immunotherapy targeting residual tumour.
Methods We first determined the optimal dose and schedule for local immunotherapy using a double-stranded RNA adjuvant delivered locally, by intratumoral injection, following an incomplete surgical resection in the WEHI-164 fibrosarcoma model. Next, we tuned the biophysical characteristics of the hydrogel to achieve a drug release kinetic matching this optimised schedule. We evaluated the efficacy of hydrogel-delivered intraoperative immunotherapy against multiple preclinical cancer models and studied the underlying immunological mechanisms using in vivo studies, flow cytometry and RNA sequencing. Finally, we assessed the safety and feasibility of this approach with a Phase I trial in canine veterinary patients undergoing surgical removal of a soft tissue tumour.
Results The surgically optimised hydrogel was easily applied to the wound bed during surgery and provided prolonged release of immune adjuvants resulting in local and systemic anti-tumour responses, without adversely affecting wound healing (figure 1). Intra-operative immunotherapy reduced the rate of recurrence following incomplete resection, as monotherapy, and further sensitized tumours to systemic immune checkpoint blockade. Local therapy with RNA adjuvants remodelled the tumour/immune microenvironment to better support anti-tumour immunity by altering the phenotype of tumour associated myeloid populations. Twelve canine patients were treated with increasing doses of a hydrogel-delivered RNA adjuvant, without serious side effects, proving the safety and surgical feasibility of this approach.
Conclusions Our hydrogel provides a safe, effective drug delivery platform to deliver intraoperative immunotherapy and reduce recurrence of solid tumours following surgery.
Acknowledgements We would like to thank Dr. Ken Wyatt and Dr. Albert Thomas our veterinary collaborators who recruited canine patients and administered the clinical trial. We would also like to thank Professor Rupert Hodder, Professor Marianne Phillips and Dr. Annie Ryan for their input on the design of the biomaterial hydrogel specifically for surgical application.
Ethics Approval The preclinical mouse studies were approved by the Harry Perkins Institute for Medical Research Animal Ethics Committee; approval numbers AE161/191/220. The canine clinical trial was approved by the Murdoch University Animal Ethics Committee; Protocol ID: 871, Permit No. R3340/21.
(A) The hydrogel. (B) In vivo imaging showing prolonged drug release from the gel. (C) Preclinical model of surgery and hydrogel-immunotherapy. (D) Prevention of cancer recurrence with hydrogel-immunotherapy. (E) Immune signature indicating response to therapy.
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