How Immunotherapy is Making an Impact in Gynecologic Cancers

This year will see an estimated 101,000 women diagnosed with new cases of gynecologic cancers in the United States, and almost 31,000 deaths will be caused by ovarian cancer, cervical cancer, and uterine cancer, which is also known as endometrial cancer.

Recent advances are providing hope that there might soon be better options for these patients, especially those with advanced disease. To that end, for Gynecologic Cancer Awareness Month in September, we spoke with Kunle Odunsi, MD, PhD, the deputy director of the Roswell Park Comprehensive Cancer Center, to learn how immunotherapy is making an impact in these cancers.

Arthur N. Brodsky, PhD:

This past year there were two approvals that apply to people with gynecologic cancers.

First, the approval of pembrolizumab (Keytruda®), a checkpoint immunotherapy that blocks the PD-1 “brake” on T cells and can help sustain their attacks against cancer, for advanced solid cancers that have a high tumor mutational burden (TMB-H). This approval doesn’t apply exclusively to gynecologic cancers, but instead allows anyone whose unresectable or metastatic cancer is TMB-H—defined as greater than or equal to 10 mutations per million DNA bases—to receive this therapy after they have progressed following prior treatment and have no alternative options.

How valuable is this approval for women with gynecologic cancer?

Kunle Odunsi, MD, PhD:

The approval of pembrolizumab for TMB-H tumors has important implications for gynecologic malignancies, especially uterine cancer, which is also known as endometrial cancer. The other types of gynecologic cancers, such as those that affect the ovaries, cervix, and vulva could also benefit from this approval because we see a fraction of those patients with TMB-H tumors, too.

This approval will mostly be applicable for patients whose tumors have high microsatellite instability (MSI-H), a genomic biomarker associated with high numbers of mutations. As a consequence, these tumors are more likely to harbor more mutated markers, known as neo-antigens, that can be targeted by the immune system. They are also more likely to have already been infiltrated by killer T cells, which is associated with checkpoint immunotherapy being more likely to work.

This is an example of where we need go as a field: to come up with biomarkers that can be useful regardless of the organ in which a cancer originates. In other words, whether the cancer is coming from the brain, the lungs, the kidneys, the bladder, or the uterus, it would be very helpful to have a distinguishing molecular feature that gives us better understanding of the biological behavior of cancer and allows us to treat those tumors the same no matter where they came from. High tumor mutational burden is a good example of a biomarker that cuts across multiple tumor types.

Arthur N. Brodsky, PhD:

That’s a very important point you bring up regarding biomarkers, and I do want to come back to them and their role in immunotherapy. But before that I want to turn to the other immunotherapy approval that was specific for endometrial cancer: the combination of pembrolizumab plus lenvatinib.

PD-1 immunotherapies are well‑known for their ability to support activity of cancer-fighting T cells, but what is the rationale behind combining it with lenvatinib, which blocks other pathways that can promote tumor survival?

Kunle Odunsi, MD, PhD:

The approval of this combination is a significant step forward because it takes advantage of the fact that a lot of endometrial cancers have disruption of several tyrosine kinases such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) pathways, many of which inhibit immune responses against tumors. With lenvatinib, you are blocking these pathways and therefore at the same time enhancing the potential effectiveness of the checkpoint immunotherapy,  pembrolizumab.

Clinical trials have shown that this effect is the same regardless patient’s tumor mutation status as well as their expression of PD-L1, which is the protein that binds to PD-1 and shuts down immune cells. Interestingly, there is evidence of responses regardless of any biomarkers. Nevertheless, my thought is that there is probably a subset of patients who will respond better than others and I think we should continue to find out who are these good responders so that we can come up with biomarkers to identify them and potentially give them the maximum benefit.

Arthur N. Brodsky, PhD:

That would definitely be valuable. With those biomarkers, you could determine which patients are likely to benefit from that combination and treat them. Of course, other patients will still be in need of better treatments, many of which are being investigated in clinical trials currently.

In that regard, I want to talk about an approach being tested in a CRI trial for patients with ovarian cancer and other peritoneal malignancies that you’re helping to lead. This strategy involves a PD-L1 checkpoint immunotherapy in combination with an oncolytic virus. First, what are oncolytic viruses, and second, do you have any results from that trial that you can share?

Kunle Odunsi, MD, PhD:

Oncolytic viruses are viruses that have been specifically designed to attack cancer cells and spare normal cells, and several different types exist. In addition to destroying tumor cells directly, oncolytic viruses can cause tumor cells to release internal markers known as antigens that can be recognized by the immune system. In this way, they’re acting almost as in situ vaccines that would generate anti-cancer immune responses that further lead to tumor destruction.

Furthermore, these oncolytic viruses can be engineered with additional genes so that upon delivery they release a cargo within the tumor. In the case of the oncolytic virus that we’re testing in the CRI trial, which is a modified adenovirus, it has been engineered to release a chemical called GM‑CSF, which stands for granulocyte macrophage colony­‑stimulating factor. And what GM-CSF does is to help recruit different populations of immune cells into the tumor microenvironment, so that the ongoing immune attack against the cancer can be amplified.

So this oncolytic virus is working via several mechanisms. It is directly destroying cancer cells, and this leads to a vaccine-like effect to generate immune responses against the cancer. Finally, it is also reprograming the environment of the tumor, and has been engineered to directly deliver GM-CSF into the tumor, which can lead to recruitment of additional immune cells to help in the ongoing battle.  But there’s still one problem. As those immune cells arrive in the tumor environment they can rapidly become “exhausted,” so it’s important to try and rescue them and prolong their activity. That is why the clinical trial also includes the addition of a checkpoint inhibitor immunotherapy called durvalumab, or Imfinzi™.

This trial is still ongoing, and we remain very hopeful and optimistic about the results.

Arthur N. Brodsky, PhD:

Thank you for that great explanation!

Now I want to turn to vaccines, and specifically the human papilloma virus (HPV) vaccine. When people think of vaccines, they often think of vaccines used to prevent infection as well as cancers associated with infection. In this case, the HPV vaccine can help protect against the development of HPV-related cervical cancer. But recently we also learned that a therapeutic HPV vaccine, in combination with chemotherapy, can be helpful for patients with established, advanced cervical cancer. Could you talk a little bit about this breakthrough and what it might mean for patients in the future?

Kunle Odunsi, MD, PhD:

Therapeutic HPV vaccines for cancer patients had a long history where they didn’t appear to provide significant clinical benefit by themselves for patients with cancer. So it became very clear to us that vaccines will have to be used in combination with other treatments, especially those that can kill cancer cells in a way that also alerts and stimulates the activity of the immune system against the remaining tumor cells.

Another way for combinations to be effective are to disrupt the cancer-supporting immune cells, known as myeloid-derived suppressor cells or MDSCs, that can suppress immune responses against tumors. And this is the approach that was shown to be effective in the recent study you mentioned, which was led by Dr. Kees Melief in the Netherlands. His group has also demonstrated promising results in a phase 2 trial with the combination of HPV vaccination and PD-1 checkpoint immunotherapy in patients with otherwise incurable HPV-16–positive cancers.

In addition to vaccines, another way to go after these HPV-related cancers is with HPV-targeting T cells. These can be isolated from patients and then expanded in the lab to generate cells for adoptive cell immunotherapy against HPV‑related malignancies. That’s exactly what some groups are doing now in clinical trials. We’re currently collaborating with investigators from the National Institutes of Health (NIH) on a trial in which patients with HPV‑related malignancies—not just cervical cancer, but other types of HPV‑related malignancies, too—are receiving T cells targeting the HPV E7 protein.

Arthur N. Brodsky, PhD:

Hopefully some of those will prove useful and become more widely available for patients soon. Are there any other promising immunotherapy combinations in clinical trials that might be valuable for gynecologic cancer patients to know about?

Kunle Odunsi, MD, PhD:

Yes, there are now several promising combinations with regard to ovarian cancer, where we’ve recognized that DNA damage repair mechanisms are disrupted in many advanced ovarian cancers.

The classic genes for these pathways are the BRCA1 and BRCA2 genes, and one of the ways we now treat patients with these genetic alterations is with PARP inhibitors, such as olaparib. These are active because they are lethal to cancer cells through their effects on DNA repair, and they also activate a pathway called STING within the cancer cells, and this provides a signal to the tumor environment that makes it more supportive of anti-cancer immune activity.

A number of clinical studies have been completed or are on-going that combine PARP inhibitors with checkpoint immunotherapies. It’s not quite a homerun but the results are encouraging. Keep in mind that ovarian cancers have not been very responsive to checkpoint immunotherapy by itself, so the combination with a PARP inhibitor seems to be an important step forward, but we obviously have ways to go.

Other trials are combining checkpoint immunotherapies with anti-angiogenesis drugs, which target tumor blood vessel growth. In one study that we recently completed here at Roswell Park, the combination of pembrolizumab, bevacizumab, and low dose chemotherapy led to very high rates of disease control.  Approximately 70 to 75 percent of patients had prolonged disease stabilization, meaning their tumors stopped progressing, and some patients had regression of their tumors.

Above all, for ovarian cancer we’re going to need multipronged approaches that combine different strategies, not only to generate immune activity against the cancer but also to overcome some of the immunosuppressive mechanisms within the ovarian tumor environment.

Arthur N. Brodsky, PhD:

Now, I want to return to the concept of biomarkers, and how they can help doctors figure out what’s going on within tumors, so that doctors can figure out the best approaches for individual patients.

What are some of the most important outstanding questions and challenges in this area?

Kunle Odunsi, MD, PhD:

Finding useful biomarkers is one of the next frontiers that we need to seriously address as a field because it has become increasingly clear that while some patients will respond very well to our current immunotherapies, most will not. So, we need to come up with a strategy to understand and identify who is going to respond so that those patients can receive the appropriate therapy for their disease. This also would allow us to spare certain patients from the potential side effects of an immunotherapy that is unlikely to be beneficial for them. For those who are unlikely to respond, we then can ask ‘what might be the best approach for them?’

So, biomarkers are going to be critical moving forward as a field, and when it comes to identifying new biomarkers, we need to carefully consider how we design our clinical trials. We must—and are starting to—conduct them in way that ensures that we are obtaining appropriate samples from patients that can teach us more about the underlying cancer and immune biology as well as the best markers that will predict response. Only by doing this can we really move forward in the field.

Fortunately, we now have an unprecedented number of tools that were unimaginable only ten years ago. Tools that allow us to ask deep questions at the genetic, molecular, and cellular levels, and thereby identify biomarkers of responsiveness or non‑responsiveness. The technologies have become so sophisticated that you can analyze multiple patients within a relatively short period of time. You can even know the metabolic status of these cells—how are they using glucose, protein, fat. So many questions that we had no way to ask just ten short years ago, now we can ask at a very deep level.

Along with this improved interrogation ability comes the challenge of big data.

Many groups are amassing huge amounts of information, and we need to figure out the best possible way to use the information, to enable groups to work together to rapidly identify the important signals in the data.

Overall, I am optimistic. A lot of clinical trialists in the immunotherapy field are paying more and more attention to these considerations and advancements now, and I envision that in the future most clinical trials will be biomarker‑driven studies. We’re not just going to say one-shoe-fits-all. We’re going to enroll patients into trials based on what their biomarkers are telling us. In the end, this added precision should translate into our day-to-day practice for all patients, so that their treatment is driven by their biomarkers.

Dr. Kunle Odunsi is speaking at the upcoming CRI Virtual Immunotherapy Patient Summit on October 2-3, 2020. Register today for free and ask your questions about new advances in immunotherapy for ovarian cancer.