From an early age, medical oncologist Paul Sabbatini has had a keen interest in analyzing symptoms and diagnosing problems. Now a specialist in treating gynecologic cancers, he leads a Memorial Sloan Kettering Cancer Center clinical research program seeking to improve treatments for ovarian cancer by harnessing the power of the immune system.
Growing up, I worked in my family’s business — an automotive repair shop in Greenville, Mississippi — and realized I enjoyed diagnosing problems and was curious about how things worked. That inquisitiveness stuck with me over the years. When I began college at the University of Mississippi in 1981, I majored in biology with an eye toward teaching and conducting research. But I realized the missing piece was an interaction with people, and becoming a doctor began to hold great appeal.
I continued at the University of Mississippi for medical school. During the summers I worked as an aide in a Greenville hospital, which allowed me to interact with patients directly. I also saw older physicians who had great relationships with their patients — something I really valued. After receiving my MD degree in 1989, I went to Vanderbilt University for my residency in internal medicine. Several Vanderbilt physicians served as wonderful role models. They were very compassionate, renowned for their hands-on patient care, yet also conducted clinical research. It showed me that you could retain the old-fashioned attributes of a caring physician while advancing academic medicine.
When I needed to find a research focus, oncology seemed the perfect fit. You could have close and important relationships with patients, but it was wide open in terms of opportunities to make much-needed differences in outcome. After coming to Memorial Sloan Kettering in 1994 for an oncology fellowship, I worked first with the Genitourinary Service and became involved in immunological and other approaches to treating prostate cancer. I then migrated to the Gynecologic Service because the immunological targets we were evaluating were well suited for patients with ovarian cancer.
Today, ovarian cancer is often treatable, but in many patients the illness is chronic. We can treat patients with surgery and chemotherapy and the majority will go into remission. In fact, when the cancer recurs we may be able to put women into second and even third remissions — but over time the tumor becomes resistant to treatment and difficult to control.
Due to the limited effectiveness of standard chemotherapy, and the disappointing activity to date of some of the newer targeted approaches, we have increased our focus on immunotherapy as one potentially effective strategy for patients with ovarian cancer. There is evidence to suggest that the immune system plays an important role in ovarian cancer surveillance, meaning that it has the capacity to prevent the disease from developing or recurring. Our hypothesis is that if we could manipulate the immune system — which has obviously failed our patients in its responsibility to stop the cancer — it could recognize those cells as abnormal and prevent them from returning.
We have developed a clinical program based on work done over the years by our immunology group led by Alan Houghton [former Chief of the Clinical Immunology Service in the Department of Medicine] and Philip Livingston [Head of the Laboratory of Tumor Vaccinology]. Ovarian cancer specimens were analyzed to identify the most common antigens [molecules that trigger an immune response], and initial human trials demonstrated that vaccines targeting these antigens were safe and that they generated an immune response.
Meanwhile, studies in preclinical models suggested the immune responses could prevent tumor growth in mice, and that a vaccine combining multiple antigens would be more effective than a vaccine that targets only one. Our immunologists assembled a vaccine containing five antigens that is now being tested in a randomized, national phase II trial that I am leading. If the therapy works, it could enter into the standard of care for patients with ovarian cancer.
A combination vaccine is difficult to build because it involves putting multiple pieces together, with each antigen separately attached to a carrier protein in the presence of a general immune stimulant. So [Memorial Sloan Kettering chemist] Samuel Danishefsky, in a brilliant feat of biochemistry, created a structure consisting of a single backbone that allows you to plug in multiple antigens and is easy to manufacture. This innovation allows for the targeting of many antigens in many different tumor types and has potential applications beyond ovarian cancer.
However we’ve learned that the bar is high with these immune strategies and others have not been successful to date. Vaccination alone is not likely sufficient — we will need to add agents that can modify the immune response, such as ipilimumab. Ipilimumab blocks a brake that the immune system uses to prevent itself from attacking normal tissue. By temporarily taking the brakes off, ipilimumab allows the immune system to become more robustly activated than it would otherwise be and potentially attack the cancer. It has recently proved effective against melanoma.
Going forward, we are evolving a more personalized immunotherapy program for ovarian cancer patients. We will screen tumors for one of three antigens and then immunize patients who are in remission with the appropriate vaccine. Other areas of treatment for women with ovarian cancer remain a high priority. [Memorial Sloan Kettering gynecologic oncologist] Douglas Levine and others, for example, are investigating the notion that ovarian cancer may actually begin in the fallopian tube, which is adjacent to the ovary. It might be possible to sample this accessible site and look for a molecular signature that predicts the development of cancer — a major advance for early detection, which is our most urgent need for treating this disease.
We are also continuing to explore multiple other targeted approaches. Much work at the Center and elsewhere is directed at identifying mutations that drive tumor growth and that can be blocked with newer agents under development. Our efforts are all multidisciplinary and illustrate how a clinical researcher such as myself can interact with various scientists at the Center and together can move novel treatments developed in a laboratory into the clinic to evaluate their effectiveness.