Immunotherapy has revolutionized the treatment of many types of cancer and is now undergoing testing in ovarian cancer. Clinical trials of drugs known as immune checkpoint inhibitors, which can unleash a potent immune system attack on cancer cells, have produced remissions in about 10-15 percent of patients with advanced and recurrent ovarian cancer – somewhat of a respectable figure, but given these modest response rates, the side effects of these agents, and the sometimes short remission periods, new approaches for the use of these agents need to be explored.
Perhaps one of the keys to achieving greater success with these agents is using them in combination with other therapies. Laboratory studies have provided an abundance of evidence that combinations of immunotherapy agents plus other biologic therapies may prove significantly more effective in ovarian cancer than immune checkpoint inhibitors alone.
Immune Checkpoint Inhibitors
Ovarian cancer is a heterogenous disease, firstly meaning that several different types, or “histologies,” exist, each with its own unique genetic make-up. It also means that within an individual patient, different sites of cancer are likely comprised of several, genetically distinct, subtypes of cancer cells. This is one reason why it can be so difficult to treat with chemotherapy or targeted therapies: while the drugs are lethal to some cancer cell subtypes, they may leave others largely untouched, allowing the surviving cells to grow and proliferate. Immune checkpoint inhibitors, by contrast, have the potential to eliminate a broader range of tumor cell subtypes, sharply reducing the potential for drug resistance.
One of the advantages of combination regimens is that the second drug has the potential to make tumor cells more vulnerable to the immune checkpoint inhibitor. Before such approaches can become standard therapy, however, a variety of questions need to be answered: Which combinations work best in individual tumors? Are combinations more effective as front-line or follow-up treatment? Is it possible to pre-select patients based on the specific genetic profile identified in the cancer, the number of prior therapies, the histology of the cancer, etc.? The number of potential combinations of checkpoint inhibitors and other treatments is rather large, so sorting out these questions will inevitably take time. But we’ve already made a great start.
Immunotherapy Clinical Trials
Recognizing the exceptional promise of immunotherapies for ovarian cancer, my colleagues and I in the Gynecology Oncology Program at Dana-Farber have made a concerted effort to lead and participate in clinical trials of immunotherapies in combination with other types of drugs. These drugs include targeted therapies, which block cancer-related proteins in tumor cells; PARP inhibitors, which interfere with tumor cells’ ability to repair certain types of DNA damage; standard chemotherapy agents; and anti-angiogenic drugs, which pinch off tumors’ access to circulating blood. More than half a dozen such trials are now open or are about to open. Most of these are phase 1 trials, small-enrollment trials that are primarily concerned with the safety of potential new treatments, but which also track their effectiveness. One of the trials is a phase 3 study, the final stage before a therapy can be submitted to the Food and Drug Administration for consideration as a standard therapy.
An array of other immunotherapy trials for ovarian cancer is in the planning stages in the Gynecologic Oncology Program. These include a trial of a “neoantigen vaccine,” a treatment designed to spur a powerful, very precise immune system attack on tumor cells, in patients already treated with chemotherapy. Another will investigate a combination of the checkpoint inhibitors tremelimumab, durvalumab, and radiation therapy.
In addition, several immunotherapy trials led by researchers within the Center for Immuno-Oncology at Dana-Farber are also open to patients with ovarian cancer and other gynecologic cancers. A full list of ovarian cancer treatment trials is available on the Dana-Farber website.
This is a very exciting time in research into immunotherapy for ovarian cancer. There’s every reason to expect that immunotherapy will prove as effective in the treatment of this disease as it already has in cancers such a melanoma, Hodgkin lymphoma, lung cancer, kidney cancer, and others. Today’s clinical trials are where the revolution in treatment will take place.
By Ursula Matulonis, MD, Director, Gynecologic Oncology, Susan F. Smith Center for Women’s Cancers.