Efforts Continue to Increase Immunotherapy Impact in Gynecologic Cancers

John A. Glaspy, MD

Immunotherapy has demonstrated efficacy in a number of solid and liquid tumors, and although responses in ovarian cancer have yet to mirror those in other malignancies, John A. Glaspy, MD, explained that, though limited, immunotherapy is not completely inactive.

There are many routes to triggering immunogenicity in ovarian cancer, such as vaccines, epigenetic therapies, and combination strategies, said Glaspy, adding, “Sorting through them is going to be the challenge.”

OncLive: How has immunotherapy impacted the field of ovarian cancer, if at all?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Ovarian Cancer, Glaspy, professor of medicine, Jonsson Comprehensive Cancer Center (JCCC), director, JCCC Clinical Research Unit and Women's Cancer Research Program, University of California, Los Angeles, discussed challenges and progress with immunotherapy in gynecologic cancers.Glaspy: Immunotherapy has been an exploding field over the last few years. It's revolutionized the treatment of some cancers, especially melanoma and other skin cancers, lung cancer, bladder cancer, and others. It has not been nearly as effective in the treatment of [patients with] breast cancer and colon cancer. It has been disappointing but not totally inactive in ovarian cancer. The question is, “Is there a way to make it work as well in ovarian cancer as it does in, say, melanoma? If that is possible, what is the path to that?”

We know that the best predictor of immunotherapy’s efficacy is the extent of the mutation in the individual tumor type. If the immune system is going to recognize a cancer as unique, that cancer needs to express an antigen that isn’t expressed on normal cells, called a neoantigen. The chances of any one mutation leading to a neoantigen that will work is very small. You need thousands and thousands of mutations to have a chance of getting some neoantigens. That is probably why the mutational burden of tumors is predictive of response to these agents.

There isn't a way that I'm aware of, or that will be available anytime soon, to make a patient’s tumor have more mutations. The question is, if we think tumor mutational burden (TMB) is the problem with ovarian cancer—which it may be—“How do we make those tumors more immunogenic? How do we introduce neoantigens into them?”

There are a variety of possibilities, including vaccines. Vaccines can be directly injected into tumors, causing them to express cytokines and rendering them more immunogenic. There is a school of thought that radiating a tumor will cause it to break down and make it more likely to find an antigen that will work.

Where does immunotherapy's future lie?

Is there a rationale for triplets?

What has immunotherapy’s impact been in endometrial cancer?

How do you find that patients tolerate immunotherapy?

Are there combination immunotherapy studies being done in the endometrial space?

What clinical trials are you looking forward to reading out?

We're working on epigenetics and the ability of epigenetic therapies to make ovarian tumors express genes that are more likely to be attacked by T cells. There are hundreds of other possibilities out there.It's unlikely that it lies with VEGF or PARP inhibitors. Nonetheless, those agents have a future in ovarian cancer. Once you get immunotherapy to work, then you can integrate it with treatments, including PARP inhibitors and VEGF-targeted drugs. I don't think these agents are going to be the key to get immunotherapy to the table. Immunotherapy is going to have to get there with combinatorial therapies that enhance its efficacy.We're already doing triplets, but they're triplet immunotherapy agents. When you look at all of the potential targets on dendritic cells and T cells, you realize that just doing 2-drug combinations is going to take hundreds of clinical trials. Doing 3-drug combinations is going to take more clinical trials because of the factorial nature of adding additional agents. We already have 3-drug combinations in clinical trials for melanoma. What works in melanoma will need to be tested elsewhere. It has had a huge impact because endometrial cancer is one of the cancers that patients with Lynch syndrome get. It's not separate from uterine cancer. Endometrial cancers are going to need to have the same sort of combinatorial trials and TMB analyses because they tend to be on the low end, as in ovarian cancer. It may be that the clear-cell subset would be a good place to focus because those patients have a higher TMB. Most patients tolerate it very well because monoclonal antibodies have relatively little toxicity—that is if we're talking about checkpoint inhibitors. Patients may develop mild autoimmunity or have a rash that requires some thyroid replacement. However, it can be really serious. Bad hepatitis or pancreatitis [can manifest in patients on immunotherapy], although that is the minority of patients. Most patients tolerate immunotherapy wonderfully. Yes. There are trials that are open to all tumor types, and patients with endometrial cancer are enrolled in them. There are also trials that are specifically asking for patients with endometrial cancer.I’m interested in a trial that is looking at chemotherapy combined with a checkpoint inhibitor. I don't know that it's likely to be positive, but it’s clearly a question that needs to be addressed and answered. I'm very anxious to see what happens with epigenetics and checkpoint inhibitors. The LAG-3 plus checkpoint inhibitor trials are of particular interest to me.