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Drawbacks Concerning Cancer Surgery

Surgical resection of solid primary malignancies is a mainstay of therapy for cancer patients. Despite being the most effective treatment for these tumors, cancer surgery has been associated with impaired metastatic clearance due to immunosuppression. In preclinical surgery models and human cancer patients, we and others have demonstrated a profound suppression of both natural killer (NK) and T cell function in the postoperative period, which has been found to play a major role concerning the enhanced development of metastases following surgery. 

"...OV infection results in a profound inflammatory reaction within the tumour, initiating innate and adaptive immune responses against it... (OV) administered immediately before surgery restored NK cell activity and reduced metastic disease."

"...inactivated oncolytic Maraba virus demostrated comparable immune boosting activity as live replicating virus when used at a high enough dose."

"...surgical stress abrogates tumour antigen-specific CD8+ T-cell function... tumour antigen expressing oncolytic Maraba virus can rescue T-cell function and prolong tumour-free survival"

"OV appears to be an ideal targeted therapy... novel and clinically relevant... to activate NK and T cells... and prevent the development of metastases immediately following surgery"

"Despite being the most effective treatment (for solid tumours) ... cancer surgery has been associated with ... a profound suppression of both natural killer (NK) and T cell function..."

"...this plays a major role in the enhanced development of metastases following surgery."

Prospective Solutions The Auer Lab is Exploring

1. Natural Killer Cells

Most solid tumours are treated with surgery before they spread to other organs. Dr. Auer and others have shown that surgery itself can increase the spread of cancer to distant sites (metastasis) but despite this very few treatments are given around the time of surgery because they might be toxic to a recovering patient. Surgery suppresses many cells of the immune system, in particular Natural Killer (NK) cells. NK cells play a key role in preventing cancer cells from spreading and therefore suppression, secondary to surgery, is one reason why patients get metastases. In preliminary studies, using an animal model of surgery and cancer, Dr. Auer has demonstrated that surgery helps cancer cells to spread by suppressing NK cells. She has also demonstrated that this inhibition of NK cells can be reversed by specific anti-cancer treatments, such as oncolytic viruses (OV)

Most patients with solid tumours, like breast, colon or lung cancer, have an operation to remove the tumour, but for a number of patients the cancer will come back, often spreading to distant organs. Many patients get toxic treatments, like chemotherapy, many weeks after surgery to try and prevent this. Dr. Auer’s research is focused on trying to understand how Natural Killer (NK) cells are involved in the spread of tumour cells after surgery so that more effective and less toxic treatments can be given to patients around the time of their operation. Specifically she is interested in studying the ability of a new class of anti-cancer therapies, oncolytic viruses, to stimulate NK cells and prevent metastases when given around the time of surgery. Cancer treatments that are specifically aimed at preventing the recurrence of cancer following surgery will improve survival in all cancer patients undergoing surgery to remove their tumour.

2. Proposing a Perioperative Survivin Clinical Trial

Surgery suppresses many cells of the immune system, in particular T-cells. T-cells play a key role in preventing cancer cells from spreading and their dysfunction following surgery may be one of the reasons why some patients get metastases after their cancer has been surgically removed. T- cells can be stimulated to fight cancer by immunizing patients with a cancer vaccine combined with non-specific stimulators of the immune system. In preclinical studies in mice immunized with a cancer vaccine, Dr. Auer demonstrated that surgery helps cancer cells to grow and spread by suppressing T-cells but that this inhibition of T-cells can be reversed with non-specific immune stimulators, including interleukin-2 (IL2). Dr. Auer, and the team of co-investigators, are proposing a clinical trial to study this effect in patients undergoing surgery for colorectal cancer liver metastases, immunized around the time of surgery with a cancer vaccine, called DPX-Survivac. DPX-Survivac targets a protein called survivin, that is abnormally expressed in cancer cells and not normal cells. Studies of this vaccine in ovarian cancer patients suggests it is very effective at stimulating the immune system to recognize and attack cells that express this protein. The study will demonstrate the safety of using a cancer vaccine +/- IL-2 given before surgery as compared to after surgery and compare the ability of the cancer vaccine to stimulate the immune system to attack survivin-expressing cells. The results of this work could lead to more effective therapies that lower the risk of post-operative metastases in all cancer surgery. 

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