Immunotherapy is changing the lives of patients with advanced cancers. This type of therapy causes a patient’s immune system to attack his or her cancer. Patients with advanced melanoma and lung cancers who respond to immunotherapy can now live for years, rather than dying in less than one year, as was typically the case in the past. Often the immune system already knows that the cancer is there, but the cancer is able to hamper the immune system’s ability to get fight it. Immunotherapy restores the immune system’s ability to attack the cancer. My career goal is to figure out how to make ovarian cancers susceptible to immunotherapy.
Under the mentorship of Drs. Jedd Wolchok and Timothy Chan, our group identified tumor features that lead to immunotherapy responsiveness in melanoma and lung cancers. In patients with advanced melanoma and lung cancers, we found that tumors with more genetic errors, or mutations, were more likely to respond to immunotherapy. These genetic errors generate proteins that the immune system recognizes as foreign; a boost from immunotherapy treatment causes the immune system to switch from “somnolent” to “active” so that it can attack the tumor successfully.
Most melanomas and lung cancers have a large number of genetic errors that the immune system can recognize. Ovarian tumors differ in the type of genetic errors they harbor: there are fewer genetic changes of the sort that are recognized by the immune system. Therefore, even if a patient receives immunotherapy, she is much less likely to respond than if she had melanoma, because her immune system does not realize the cancer is there. This is particularly problematic because ovarian cancer is the most deadly gynecologic cancer, and women desperately need more effective and durable treatments for advanced disease.
In order for immunotherapy to work in ovarian cancers, we must first make sure that the immune system realizes the ovarian cancer is there. One way to do this is to change the genetics of the tumors. Some of the chemotherapy used to treat cancer works by purposely damaging tumor DNA. In the proposed project, we will take the approach of damaging tumor DNA to cause changes that are recognized by the immune system. First, we will look at tumors from patients before and after treatment with chemotherapy, to see whether tumor DNA has been damaged in a manner that will cause it to be recognized by the immune system. Second, we will use a mouse model of ovarian cancer to see if we can use chemotherapy and immunotherapy together to make the immune system recognize and reject previously “hidden” ovarian cancer. If these experiments are successful, they could be used as the basis for a clinical trial in patients to try to “sensitize” ovarian cancer patients’ tumors to immunotherapy.