By STEPHANIE GALL ’14
Ovarian cancer, pancreatic cancer and mesothelioma aren’t generally diagnosed until late in the disease, making them some of the most difficult cancers to survive. They also all have abnormally high expressions of mesothelin, a protein, on the surfaces of their tumor cells. Researchers at Massachusetts General Hospital have now developed an immunotherapy that triggers an immune response against mesothelin and other antigens, proteins on the surface of cells that set off an immune response, on the tumor cell surface. The vaccine significantly increased the length of survival of mice with ovarian cancer and mesothelioma. It has the potential to be used as a second line of therapy for patients struggling with these cancers after they have gone through the usual treatment options, like chemotherapy.
“For ovarian cancer, there is a significant unmet need for new therapies. That unmet need is now, not in ten years,” said Dr. Mark Poznansky, the lead author of the study and director of Massachusetts General Hospital’s and Harvard Medical School’s Vaccine and Immunotherapy Center. Recognizing the need for treatment, Poznansky and his team set out to develop a vaccine that could reach clinical trials in two to three years.
Immunotherapy involves treating a disease by stimulating the patient’s immune system. Previous approaches to cancer immunotherapy, like the prostate cancer treatment Provenge, involve complicated and time-consuming procedures. First, a sample of the patient’s blood is extracted, then immune cells from the sample are collected and combined with an immune response-inducing protein. Finally, the cells along with the protein are returned to the patient’s body. Poznansky’s approach greatly improves upon this method. Rather than having to extract anyone’s blood, the vaccine can be administered directly to the individual, making for a less expensive and faster process where the immune response occurs within the patient.
The team’s immunotherapy activates the immune system by way of dendritic cells. Dendritic cells, not to be confused with dendrites in the nervous system, are responsible for detecting antigens, proteins on the surface of cells that set off an immune response. After the dendritic cell has detected an antigen, it stimulates and directs the body’s immune response through the immune system’s T and B cells. The protein that Poznansky and his team engineered has two major parts. One end of the researchers’ protein consists of an antibody for mesothelin and the other end contains a single protein from the bacteria that causes tuberculosis. Knowing that the body automatically makes antibodies in response to tuberculosis, the tuberculosis protein’s role is to instigate the immune system. As Poznansky described it, the protein takes “a two pronged approach” to function, and both parts are necessary for the vaccine to have its desired effect. The antibody end of the protein binds to mesothelin on the tumor cells while the body detects the tuberculosis protein on the opposite end and stimulates the immune system through the dendritic cells. Consequently, the immune system generates activated T cells which attack the tumor cells.
Studies in mice models showed that the mice with ovarian cancer and mesothelioma that received the researcher’s vaccine survived longer and had tumors that grew more slowly than the mice that did not receive the vaccine. Moreover, the researchers didn’t detect any inflammation in other areas of the body as a result of receiving the immunotherapy. This new immunotherapy has great promise as a future treatment for cancers in advanced stages.
With this vaccine, patients could have more options for treatment if the initial therapy approaches fail. “The vaccine is currently intended for second line therapy, after standard disease reduction and chemotherapy have been given,” Poznansky said. Patients would receive standard of care treatments before moving on to newer therapy options.
Now, Poznansky and his colleagues have begun enhancing the vaccine so that as much of it binds to mesothelin as possible. They are also investigating how the vaccine treatment works in conjunction with other immunotherapies. Their method could potentially be used to target other types of cancers in addition to mesothelioma and ovarian cancer and illustrates a low-cost, practical method of cancer immunotherapy.