Surgical resection is the mainstay of therapy for patients with localized solid malignancies. Despite complete resection, many patients develop a metastatic recurrence and ultimately die of their disease. Pre-clinical work from my laboratory, and others, has demonstrated that the postoperative period is a uniquely susceptible time for the development of metastases. A number of changes that occur following surgery promote tumour growth and the formation of metastases, including dissemination of tumour cells, initiation of coagulation, and suppression of the innate and adaptive immune systems. Despite this, the postoperative period remains a therapeutic window that is largely ignored.

Therapeutics aimed at targeting these mechanisms will reduce recurrences and improve survival in surgical cancer patients when used in the perioperative period. My research program makes use of both preclinical and clinical research to understand the mechanisms responsible for the prometastatic effects of surgery and to develop rational perioperative therapies designed to target them.

The link between surgery, coagulation, natural killer cells and cancer metastases
In the publication Auer et al (2009) J Amer Coll Surg, a surgical database of over 23, 000 patients was used to demonstrate that the incidence of postoperative pulmonary emboli (PE) is increasing. This database allowed us to evaluate cancer survival among cancer patients who have experienced a postoperative venous thromboembolism (VTE) compared to those that did not. In Auer at al. (2011) Ann Surg, we have published that, even when matched for gender, age, cancer type, stage and procedure, patients with VTE have an inferior cancer-specific survival, suggesting that a postoperative VTE is an independent predictor of a poor cancer outcome. I further explored this association in preclinical work from my laboratory, using a murine model of metastatic colon cancer. In the manuscript Seth et al (2013) Ann Surg, we demonstrated that surgery promotes the development of metastases by a coagulation-dependent mechanism that involves natural killer cells. This effect can be abrogated by the administration of perioperative anticoagulation with Low Molecular Weight Heparin (LMWH). This research was awarded the prize for the Best Basic Science Paper at the Canadian Surgical Forum (2010) and at the Society of Surgical Oncology (2012). Based on the above studies, I have designed and initiated a randomized controlled trial evaluating the use of extended perioperative LMWH to improve cancer-free survival following colon Blood, Coagul Fibrin), and I am the co-Principle Investigator (with Dr. Marc Carrier, Clinical Epidemiologist and Haematologist) of the CIHR funded Canadian multicenter trial enrolling 1080 colon surgery patients. The trial is currently open at 8 sites across Canada and actively enrolling.

Targeting metastatic disease with perioperative oncolytic viruses and vaccines
During my MSc, I studied the interaction between the immune system and the oncolytic viruses (OV). My thesis was awarded the Commission on Graduate Studies Award for the best graduate thesis in the sciences (2004). Currently my laboratory is further exploring the immune effects of perioperative OV administration, in particular a genetically engineered vaccinia virus and a novel rhabdovirus. We have established that the immune system is critical for the efficacy of OV (Rintoul et al (2012), Mol Ther, Lemay et al (2012) Mol Ther) and have evaluated this effect in a surgical model (Tai et al (2012) Cancer Res). We have further explored the ability of clinical grade vaccines to attenuate the prometastatic effects of surgery (Tai et al (2013) Clin Cancer Res and Zhang et al (2014) Mol Ther). In view of these findings, I designed and drafted a protocol for a “Phase II clinical trial evaluating neoadjuvant vaccinia (Thymidine Kinase-deleted Vaccinia Virus plus GM-CSF) virus followed by surgery in patients with metastatic colorectal tumors in the liver”. I was the Principle Investigator for this trial funded by the Ontario Institute of Cancer Research, as part of the Ontario Research in Biotherapeutics Program. More recently we have demonstrated that cytotoxic T cells are defective following surgery and that this effect can completely reverse an antigen-specific T cell immune response, allowing postoperative tumour recurrence and metastases (manuscript in preparation). Currently we are exploring combining a personalized oncolytic vaccine, based on tumour-specific mutations, with surgery in order to optimize the benefits of anti-tumour vaccination and minimize the immunosuppressive effects of surgery.