Sarcoma and Melanoma Surgery Team

Immune checkpoint inhibitors in combination with oncolytic virotherapy delivered by isolated limb perfusion as a means of enhancing systemic tumour-specific immunity in extremity sarcoma

Isolated limb perfusion (ILP) with melphalan and tumour necrosis factor α (TNFα) achieves limb salvage rates of up to 90% in patients with advanced extremity sarcoma. However, it is a regional treatment and has no effect on the development and progression of disseminated disease. Oncolytic virotherapy (OV) is able to kill tumour cells directly but also has the potential to prime the immune system to target local and disseminated disease.

The efficacy of OV may be limited by tumour mechanisms of immune evasion. Biological agents targeting immune checkpoints, such as monoclonal antibodies against PD-1/PD-L1, aim to combat adaptive immune resistance in tumours and have shown promising results in clinical trials in other pathologies. Early clinical trials of these agents in sarcoma are currently underway.

Previous work within our group, using an established model of ILP in rodent extremity fibrosarcoma, has demonstrated prolonged local disease control when OV (vaccinia virus) is added to standard ILP combined with tumour excision and adjuvant radiation (Figures 1 & 2). Although local disease control was achieved, disseminated disease developed in some animals, mimicking the clinical picture of extremity sarcoma in humans. When surviving animals were re-implanted with the original tumour cell line, the rate of tumour growth was slower compared to controls suggesting that some degree of anti-tumour immunity had developed.

We hypothesise that the addition of immune-modulatory agents to our established treatment protocol will induce a greater degree of anti-tumour immunity, improving control of local and disseminated disease.

The Sarcoma and Melanoma Surgery Group consists of surgical oncologists who undertake both translational and clinical research in soft tissue sarcoma, melanoma and other rare tumours of the soft tissues.

Within the laboratory, our research focus is on developing new treatments for advanced limb malignancies treated by the technique of isolated limb perfusion that delivers regional chemotherapy to the affected limb. Specifically, Mr Henry Smith is investigating the combination of oncolytic viral therapy and immunotherapy with traditional chemotherapeutic drugs to improve both the local control of tumours and to prevent or treat metastatic disease.

The clinical research interests within our group include retroperitoneal sarcoma surgery. Mr Dirk Strauss is the UK Principal investigator for the EORTC International STRASS Randomised trial, which is investigating the role of pre-operative radiotherapy in improving survival for retroperitoneal sarcoma and has published extensively on clinical and oncological outcomes after retroperitoneal sarcoma surgery.

Mr Myles Smith is leading on the development of robotic surgery and intraoperative imaging in gastrointestinal stromal tumour and intra-abdominal melanoma. The group is also looking at optimising the surgical management of early stage melanoma and Mr Hayes recently published long-term results of an international randomised trial of surgical margins in melanoma.

The whole group is part of an international collaboration of sarcoma units in Europe and North America that have developed treatment guidelines and nomograms predicting outcome for patients with retroperitoneal and limb sarcoma. The group has published and lectured extensively on the surgical management of soft tissue sarcoma melanoma and other rare tumours.