Feature

Erectile dysfunction medication, flu vaccine combination may reduce postoperative metastasis

The combination of a common erectile dysfunction treatment and the influenza vaccine could reduce postoperative metastasis among patients with cancer, according to study findings published in OncoImmunology.

“Further clinical studies are warranted to investigate the immunotherapeutic role of phosphodiesterase-5 inhibitors in combination with cancer surgery,” Rebecca Auer, MD, MSc, FRCSC, associate professor in the department of surgery and biochemistry at University of Ottawa, and colleagues wrote.

The study by Auer and colleagues investigated sildenafil (Viagra, Pfizer) tadalafil (Cialis, Eli Lilly) and an inactivated influenza vaccine (Agriflu, Novartis) in a mouse model that mimicked the spread of cancer after surgery.

The treatment strategy, which essentially blocks immune suppressors triggered by surgery and allows natural killer cells to do their job, reduced the spread of cancer by more than 90%.

Researchers now are evaluating tadalafil and the flu vaccine in a world-first human clinical trial.

HemOnc Today spoke with Auer about why she and colleagues hypothesized this combination might work, the mechanism of action, and the potential implications of this approach is proven effective and safe.

 

Question: What made you think this combination might work?

Answer: We were investigating how cancer metastases seem to spread more after surgery in animal models. We know there is significant immune suppression after surgery, and we homed in on natural killer cells and the fact that they are defective after surgery. The first thing we tried to do was simply activate natural killer cells. The next thing we did was to try to understand why these natural killer cells were dysfunctional, so that we could prevent it.

 

Q: Can you explain what the mouse model showed?

A: In our animal models, we have shown that major surgery causes immunosuppression of natural killer cells, and this leads to cancer metastases. We knew natural killer cells were highly activated by viruses, but we were reluctant to give patients a live virus around the time of surgery. Instead, we looked at a panel of viral-based vaccines — such as the measles and influenza vaccine — and discovered that the seasonal influenza vaccine was the best at both activating natural killer cells in patients and reducing cancer metastases in our animal model. However, we noticed that even when hyperactivated, natural killer cells still could be suppressed after surgery. When we started to look for the mechanism behind the suppression, we uncovered a population of myeloid cells, which increases after surgery and directly suppressed natural killer cells. These cells are known as myeloid derived suppressor cells (MDSC), and this is where the phosphodiesterase-5 inhibitors come in.

 

Q: Why does this combination work?

A: The influenza vaccine hyperactivates the natural killer cells before surgery and the phosphodiesterase-5 inhibitor prevents natural killer cell suppression after surgery. The combination strategy was able to almost completely prevent cancer metastases.

 

Q: Did the findings surprise you?

A: Based on our prior studies, we predicted that the combination would be more effective, but when we first saw the data, we were extremely excited. We were laughing at the prospect of proposing a clinical trial in which patients receive a drug for erectile dysfunction and the influenza vaccine right before surgery. It seemed like a far-fetched idea, but the more we considered it, the more it actually made sense.

 

Q: Can you provide an overview of the first-in-human trial?

A: Our first-in-human trial is primarily a safety trial. Our primary endpoint is safety and we will have 24 patients total — 12 patients on each arm. Patients in the control group will receive standard-of-care treatment, and those in the interventional arm will receive tadalafil and the influenza vaccine. All patients are required to be undergoing major abdominal surgery for a malignancy with a planned hospital stay of 3 days or more so we can perform the blood work we need.

 

Q: What are the potential implications if this approach is proven effective and safe?

A: The most exciting thing, in terms of efficacy, would be if we see improvements in natural killer cell function after surgery. This would not necessarily mean we will reduce metastases, but it would be an amazing first step toward demonstrating the combination might work. If we prove it to be safe and effective for preventing postoperative immunosuppression, then we would plan to proceed with a larger study of patients with a specific cancer — such as colon cancer — and evaluate the effect of the therapy on cancer recurrence.

 

Q: Is there anything else that you would like to mention?

A: Surgical resection is still the most effective treatment for most localized solid malignancies, but we need to work toward finding out how the immune system is suppressed by surgery and what the implications are for cancer recurrence. We have a real opportunity here, especially with the emergence of many new immunotherapeutic agents, to affect the immune suppression after surgery. – by Jennifer Southall

 

Reference:

Tai LH, et al. Oncoimmunology. 2018;doi:10.1080/2162402X.2018.1431082.

 

For more information:

Rebecca Auer, MD, MSc, FRCSC, can be reached at Ottawa Hospital Research Institute, 501 Smyth Road, Box 134, Ottawa, ON, K1H 8L6; email: rauer@ohri.ca.

Disclosure: Auer reports no relevant financial disclosures.

The combination of a common erectile dysfunction treatment and the influenza vaccine could reduce postoperative metastasis among patients with cancer, according to study findings published in OncoImmunology.

“Further clinical studies are warranted to investigate the immunotherapeutic role of phosphodiesterase-5 inhibitors in combination with cancer surgery,” Rebecca Auer, MD, MSc, FRCSC, associate professor in the department of surgery and biochemistry at University of Ottawa, and colleagues wrote.

The study by Auer and colleagues investigated sildenafil (Viagra, Pfizer) tadalafil (Cialis, Eli Lilly) and an inactivated influenza vaccine (Agriflu, Novartis) in a mouse model that mimicked the spread of cancer after surgery.

The treatment strategy, which essentially blocks immune suppressors triggered by surgery and allows natural killer cells to do their job, reduced the spread of cancer by more than 90%.

Researchers now are evaluating tadalafil and the flu vaccine in a world-first human clinical trial.

HemOnc Today spoke with Auer about why she and colleagues hypothesized this combination might work, the mechanism of action, and the potential implications of this approach is proven effective and safe.

 

Question: What made you think this combination might work?

Answer: We were investigating how cancer metastases seem to spread more after surgery in animal models. We know there is significant immune suppression after surgery, and we homed in on natural killer cells and the fact that they are defective after surgery. The first thing we tried to do was simply activate natural killer cells. The next thing we did was to try to understand why these natural killer cells were dysfunctional, so that we could prevent it.

 

Q: Can you explain what the mouse model showed?

A: In our animal models, we have shown that major surgery causes immunosuppression of natural killer cells, and this leads to cancer metastases. We knew natural killer cells were highly activated by viruses, but we were reluctant to give patients a live virus around the time of surgery. Instead, we looked at a panel of viral-based vaccines — such as the measles and influenza vaccine — and discovered that the seasonal influenza vaccine was the best at both activating natural killer cells in patients and reducing cancer metastases in our animal model. However, we noticed that even when hyperactivated, natural killer cells still could be suppressed after surgery. When we started to look for the mechanism behind the suppression, we uncovered a population of myeloid cells, which increases after surgery and directly suppressed natural killer cells. These cells are known as myeloid derived suppressor cells (MDSC), and this is where the phosphodiesterase-5 inhibitors come in.

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Q: Why does this combination work?

A: The influenza vaccine hyperactivates the natural killer cells before surgery and the phosphodiesterase-5 inhibitor prevents natural killer cell suppression after surgery. The combination strategy was able to almost completely prevent cancer metastases.

 

Q: Did the findings surprise you?

A: Based on our prior studies, we predicted that the combination would be more effective, but when we first saw the data, we were extremely excited. We were laughing at the prospect of proposing a clinical trial in which patients receive a drug for erectile dysfunction and the influenza vaccine right before surgery. It seemed like a far-fetched idea, but the more we considered it, the more it actually made sense.

 

Q: Can you provide an overview of the first-in-human trial?

A: Our first-in-human trial is primarily a safety trial. Our primary endpoint is safety and we will have 24 patients total — 12 patients on each arm. Patients in the control group will receive standard-of-care treatment, and those in the interventional arm will receive tadalafil and the influenza vaccine. All patients are required to be undergoing major abdominal surgery for a malignancy with a planned hospital stay of 3 days or more so we can perform the blood work we need.

 

Q: What are the potential implications if this approach is proven effective and safe?

A: The most exciting thing, in terms of efficacy, would be if we see improvements in natural killer cell function after surgery. This would not necessarily mean we will reduce metastases, but it would be an amazing first step toward demonstrating the combination might work. If we prove it to be safe and effective for preventing postoperative immunosuppression, then we would plan to proceed with a larger study of patients with a specific cancer — such as colon cancer — and evaluate the effect of the therapy on cancer recurrence.

 

Q: Is there anything else that you would like to mention?

A: Surgical resection is still the most effective treatment for most localized solid malignancies, but we need to work toward finding out how the immune system is suppressed by surgery and what the implications are for cancer recurrence. We have a real opportunity here, especially with the emergence of many new immunotherapeutic agents, to affect the immune suppression after surgery. – by Jennifer Southall

 

Reference:

Tai LH, et al. Oncoimmunology. 2018;doi:10.1080/2162402X.2018.1431082.

 

For more information:

Rebecca Auer, MD, MSc, FRCSC, can be reached at Ottawa Hospital Research Institute, 501 Smyth Road, Box 134, Ottawa, ON, K1H 8L6; email: rauer@ohri.ca.

Disclosure: Auer reports no relevant financial disclosures.

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