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In Search of a Novel Immune Therapy for Ovarian Cancer

Neff Newitt, Valerie

doi: 10.1097/01.COT.0000557606.85818.72
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Rachael Rowswell-Turner, MD, PhD, is at once a “young investigator” and a trailblazer. A researcher and senior instructor of medicine in the Division of Gynecologic Oncology at Wilmot Cancer Institute, University of Rochester, she is hard at work exploring the troubling implications and impact of human epididymis protein 4 (HE4) in ovarian cancer. As understanding expands, Rowswell-Turner is hopeful of developing a novel immune therapy to enhance existing therapies and possibly, in the long-term view, even cure ovarian cancer.

It is precisely that vision and work in a heretofore underfunded cancer research area that resulted in Rowswell-Turner being named the first-ever recipient of the Bristol-Myers Squibb Endowed Women Who Conquer Cancer Young Investigators Award presented at 2018 ASCO.

The award is intended to empower the next generation of female researchers who can help propel scientific innovation and improve patient care, according to information provided to ASCO by Nicole Dinello, lead of Bristol-Myers Squibb Network of Women. “It feels great that they see merit in our research and want to support it,” Rowswell-Turner told Oncology Times.

Originally from Niagara County, the native New Yorker obtained her PhD and MD credentials at the University of Buffalo through their medical scientist training program, then went to the University of Rochester for her internal medicine residency and oncology fellowship. Now married and the mother of two sons, 2 and 6 years old, her earliest interest in medicine followed a high school “introduction to health care” career program. “I shadowed different health care professionals and really identified medicine as my path at that point,” she recalled.

It was in college that her attention was drawn to immunology. “I was fascinated by the idea that the human body has its own army of cells that can attack infections, cancers. Once I took a cancer immunology class, I realized that was what I loved doing. I committed to it from the start,” Rowswell-Turner explained. There were personal experiences, too—multiple family members and friends who were struck with cancers—that deepened her professional commitment. “It made me aware of how terrible cancer is and how essential it is to find better treatments and cures.”

Though she wanted to care for patients, Rowswell-Turner also was devoted to research that she believed could move the field ahead. “I knew that would require a PhD, particularly to gain research funding. The University of Buffalo's medical scientist training program was a great fit for me. There were renowned researchers in tumor immunology I was interested in working with there, and the university worked hard to get us through the program in a reasonable amount of time, about 8 years.”

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The Call to Ovarian Cancer Research

Seeing patients has been of great importance to help this clinician/researcher carve out her specific niche. “It has given me a unique point of view to see where we have clinical needs. If a particular type of cancer is highly curable and blessed with great treatments, it is not where I need to focus,” Rowswell-Turner said. “I identified ovarian cancer as my research interest because it is highly fatal and it tends to present at advanced stages.

“Other gynecological cancers have symptoms before spreading throughout the body. But ovarian cancer is a very different beast from other cancers. The ovaries are in an area where there is room for them to expand without causing pain or obstruction,” she continued. “They are surrounded by peritoneal fluid which is rich in myeloid cells that are traditionally very immune suppressive. While those cells are important to normal health—you certainly wouldn't want a lot of inflammation inside your belly—ovarian cancer takes advantage of this immune suppressive environment and thus escapes being killed by immune cells.”

Though survival rates have improved for women with metastatic ovarian cancer in recent years, allowing some to live years with the disease, there is still no reliable cure. At some point the cancer returns. “If patients don't respond well to chemotherapy, or if they recur quickly after chemotherapy, it is a sign that their prognosis is likely less than 5 years.”

“The immune aspect of ovarian cancer interests me greatly because it's been known for a long time that CD8 T cells, cytotoxic killer cells, can attack cancer. Having high levels of CD8 T cells tends to predict a longer survival—something we have known for decades. But when we have tried immune checkpoint therapies—successful in other cancers—they really haven't worked well in ovarian cancer,” said Rowswell-Turner.

Asked why there is that fatal disconnect, the investigator said part of the problem could be the presence of a multitude of myeloid cells, in addition to other factors. “Immune checkpoint inhibitors are meant to stimulate CD8 T cells, but there are other things beside immune checkpoints in that environment that could still suppress them. The research is still relatively new in this area, but it appears that just blocking an immune checkpoint doesn't seem to be enough in ovarian cancer. It seems to be a much more suppressive immune environment than is seen with other cancer types.”

It is this unique immune microenvironment in the peritoneal cavity that has piqued Rowswell-Turner's interest. “Ovarian cancer tends to spread to the peritoneal cavity and omentum, a bit of fatty tissue that sits in the left upper abdomen. In medical school we just pulled it away and really didn't talk much about it. But in relation to ovarian cancer, we now know that it tends to be a good environment for ovarian cancer cells to stick to and grow,” she detailed.

“There are these little milky spots within the omentum that contain immune cells and yet those are specifically the spots where the tumor cells stick and start growing. So, it seems as if these immune cells are even stimulating the cancer cells' ability to seed throughout the abdomen,” she continued. “This is truly unique; we need to understand this to be able to develop an effective immune treatment. What we have in FDA-approved immune therapies doesn't work for ovarian cancer. We need to find a different type of immune therapy or possibly a combination of a few different types.”

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The Lab Work at Hand

Rowswell-Turner and colleagues work in the lab of her mentor, Richard Moore, MD, Director of Gynecologic Oncology at the university medical center. His research has focused on finding new biomarkers for ovarian cancer so that it can be diagnosed at earlier stages.

“Through that he found the HE4 marker, which is highly expressed in the majority of ovarian cancers; it seems to increase the aggressiveness of the cancer and its resistance to chemotherapy,” said Rowswell-Turner. “Related molecules in other cancers have been shown to modulate the immune microenvironment, so I have started to look at HE4's effects on the immune microenvironment surrounding ovarian cancer. We are using animal models where we have transfected ovarian cancer cells to overexpress HE4 in mice or rats.”

After comparing these models to control animals, the investigators believe they are starting to see an important relationship. “It seems that when there is more HE4 present, there are fewer tumor-killing CD8 T cells. So HE4 may be helping cancers grow by evading the immune system. HE4 also seems to cause more suppressive myeloid cells to be in the surrounding ascites fluid or in the area of the tumor,” she explained.

“We are also developing an HE4 ‘knockout mouse’ which lacks that protein in select tissues, such as the ovary. This will allow us to see if the absence of HE4 is actually protective against developing ovarian cancer and if HE4 may be important in the initial steps of tumorigenesis. It might suggest that this could be a preventative strategy in an earlier treatment time frame.”

The team of researchers in the Moore lab is hoping to find a way to counteract any ill effects of HE4. “That's where we are headed,” said Rowswell-Turner. The lab has biologists, clinicians, and chemists working in concert. “That makes us unique. It's wonderful to have such collaboration from different disciplines right within our group. Our chemists have done a large high-throughput screening to try to identify molecules that can inhibit HE4 production. So, we have a few leads to explore and follow-up on.

“We are also working with another group here at the university in hopes of developing a blocking antibody to HE4. We are taking a multi-pronged approach to try to find an answer since we know this protein is such a bad actor in cancer and might drive immune suppression and therapy resistance.”

Indeed, if that answer is found, it could well pave the way toward a less aggressive cancer or one less able to migrate. “We have done some preliminary experiments with HE4 blocking oligonucleotides which prevent or limit a cell's production of HE4 protein. These tumor cells generally seem to be more sensitive to chemotherapy and less aggressive,” added Rowswell-Turner. “It's very exciting and has given validity to our theory that blocking HE4 could be important in the treatment of ovarian cancer.”

The researcher/clinician admitted it could take many more years to identify a drug and get it through clinical trials. “But if our attempts to generate an antibody progress quickly, then things could move a bit faster,” she said.

Asked if there is any mental escape from the medical imperatives and research urgencies surrounding ovarian cancer, Rowswell-Turner said she finds some respite when hiking with her family in the woods of New York State, as well as when she runs. “Senior faculty members advised me never to lose my love for running. They said, ‘Exercise is going to be really important in keeping you sane and getting you through the stressful life you've chosen.’ I still jog and run, and it does help to burn off a little stress. I have also noticed that exercise clears my head and gives me clarity; often an answer I've been struggling with all day will just come to me.”

However, there is never lack of clarity about the importance and objectives of her work and where it could lead. “What we know about HE4 already is that it is highly produced by ovarian cancer cells and it makes them more aggressive and more resistant to treatment,” recapped Rowswell-Turner. “Preliminary work in our lab suggests that HE4 is modulating the tumor immune microenvironment and letting tumor cells escape from CD8 T cell killing.

“Our goal is to find targeted treatments against HE4 to enhance the cancer therapies that we have available, increase survival for patients, and ultimately achieve a cure for ovarian cancer,” she concluded. “Cure is the ultimate goal.”

Valerie Neff Newitt is a contributing writer.

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