Exploring the potential of Vaccinia Virus to target and kill tumour cells
By: Yekta Dowlati
Dr. Andrea McCart is an associate professor in the Department of Surgery at the University of Toronto (UofT) and a scientist at the Toronto General Hospital Research Institute (TGHRI). She completed her medical degree and surgical residency at the University of Western Ontario. While completing her Master’s degree in pathology—looking specifically at mutations in the p53 gene, which acts to suppress tumor formation—Dr. McCart became interested in gene therapy and surgical oncology. To pursue her dreams, she did a fellowship with Dr. David Bartlett at the National Cancer Institute in the United States to investigate gene therapy with a type of virus called “vaccinia virus”. Over the course of her fellowship, they discovered that the vaccinia virus played a greater role as an anticancer therapeutic than the gene therapy itself. After completing her residency and surgical oncology fellowship, she came to the UofT because she considered it the most ideal institute to combine both her research interests and surgical career.
Oncolytic viruses have been investigated in a broad range of preclinical models, and some have also reached the clinical trial stage, showing promising results. For example, the herpes virus has been approved as a therapy for melanoma. The viruses are unique as they are tumor selective, and this selectivity depends on the type of the virus.
Vaccinia virus has been the continued focus of Dr. McCart’s research with oncolytic viruses. She considers her most significant research accomplishment to date to be the development of a novel vaccinia virus with Dr. Bartlett, which is now in clinical trials. They refer to the virus as “doubled-deleted virus” because it is missing two different genes. This is considered a landmark trial of one of the early viruses, showed thus far to be safe in patients. She currently uses it as her gold standard virus to compare with new viruses candidates. The new viruses are required to be better than the double-deleted virus before they are investigated further.
The vaccinia virus can infect any kind of cancer cell; however, with the mutations made—such as in the double deleted virus model—the virus is dependent only on dividing cells. In addition, vaccinia is a large virus that can only escape the bloodstream in tissue with leaky vasculature, such as tumor vasculature. These combined characteristics allow vaccinia to effectively target tumor cells. From an experimental viewpoint, Dr. McCart’s lab focuses on animal models of abdominal cancers—such as mesothelioma, colon, and ovarian cancer—and tries to cure the animals with these viruses. Upon successful results, the viruses may then progress to clinical trials.
Dr. McCart’s research group is currently conducting two main projects. The first project aims to develop novel vaccinia viruses that are simultaneously better at targeting tumor cells and are safer in animal models. These aims are accomplished by engineering novel gene mutations into the parental virus. The new viruses are then tested in vitro and in animal models to determine if they are better at killing cancer cells and if they are as safe, or safer, than the gold standard double-deleted virus. The second project involves enhancing vaccinia and other viruses’ abilities to kill tumors by manipulating the tumor microenvironment. In animal models, they are modulating various aspects of the tumor microenvironment to study the effects on the viruses’ ability to spread, kill cancer cells, and lead to an anti-tumor immune response. In the future, these manipulations can be used to enhance the viruses’ effects in cancer patients.
In Dr. McCart’s opinion, it is still too early to know whether this type of intervention can improve survival rate and treatment outcomes in patients with abdominal cancers, as studies are still at the preclinical level. Nevertheless, early clinical trials have shown both safety and therapeutic responses for oncolytic viruses in general. Patients are somewhat apprehensive about receiving a virus as their treatment. To date, patients may acquire flu-like symptoms but typically experience no major side effects. It is probably too early to confirm the efficacy of vaccinia virus, as no phase three trials have been conducted yet. For instance, herpes virus has been demonstrated as efficacious for melanoma based on large clinical trials and is in the line of other immunotherapies for melanoma. No clinical studies are far enough along to show how effective the vaccinia virus may be for abdominal cancers in patients.
Aside from working on vaccinia virus, Dr. McCart performs hyperthermic intraperitoneal chemotherapy (HIPEC), a technique that she imported to Mount Sinai after her surgical oncology fellowship at the National Cancer Institute in Bethesda. For patients with peritoneal cancers specifically derived from colon cancer, appendix cancer, or peritoneal mesothelioma, a long surgery is initially performed to remove all the tumors. Then, heated chemotherapy solution is delivered into their abdominal cavity to penetrate and eradicate all of the remaining invisible cancer cells. After this procedure, the patient may not need any other therapy and the cancer will be gone. This is currently a standard treatment, but only select patients qualify for it because the disease must be confined to their abdomen and be surgically removable. As a result, only approximately 20% of patients qualify. Overall, this procedure has been performed around the world and has improved survival. In an ideal world, down the road, Dr. McCart would like to combine HIPEC with the virus therapy—however, this may be years away.
Dr. McCart hopes that in the near future they can run a clinical trial using these viruses in abdominal cancer patients, optimistically even in combination with surgeries. In her opinion, this intervention can either be given ahead of time to eradicate some of the tumors or after the surgery for the microscopic disease. Even though survival has improved even up to 50% in some, the other 50% of patients require attention. “Patients are the biggest motivation for my work. Some I can help through surgery, but for the ones that don’t qualify or recur, obviously I’d like to find better treatments,” says Dr. McCart.