Nov. 1, 2017:

Investigator Spotlight

Dr. Zachary Morris is an Assistant Professor in the Department of Human Oncology at the University of Wisconsin School of Medicine and Public Health and is a member of the UW Carbone Cancer Center.

This story is adapted from an earlier version, originally published by UW Health

Teaching the Immune System to Fight Cancer

Vaccines against an infection work by training the immune system at the site of injection and then spreading those educated immune cells throughout the body.

UW Carbone Cancer Center researcher and Big Ten Cancer Research Consortium (Big Ten CRC) Head and Neck Clinical Trial Working Group member Zachary Morris, MD, PhD, thinks that same immunotherapy concept can be applied to fighting cancer, especially metastatic cancers where cells from the initial tumor have spread to other parts of the body. Morris is also working with Big Ten CRC to launch a Sarcoma Clinical Trial Working Group.

“We’re working on vaccinations against metastatic cancer, where we target one of the tumor sites and generate such a robust local anti-tumor immune response that the immune system will then have an effect on the other distant sites,” Morris said. “We think our approach, where one site becomes the higher education center for the immune system, will give us the best chance to improve patient outcomes.”

Calling immunotherapy one of the most exciting areas of oncology over the past several years, Morris pointed to the checkpoint inhibitor drugs being used to effectively improve outcomes for some cancers. Cancer cells often evade destruction at the hand of the immune system by engaging checkpoint receptors on immune system T cells. When engaged, the cancer cell is telling the T cell it is a “self” cell and should be left alone. Checkpoint inhibitors block that interaction, allowing the immune system to recognize the cancer cell for the harmful cell it really is.

“The checkpoint inhibitor drugs tend to work better on cancers that have lots of mutations, such as melanomas, and we think they do not work as well on cancers with lower mutation burdens,” Morris said. “But we think they could, it just may take more training of the immune system. So now we’re trying to look at other types of cancers that haven’t been responding to checkpoint inhibitors.”

Morris and colleagues are adding two treatments, in addition to checkpoint inhibitors, to effectively create an immune system-educating vaccine from the tumor itself. One of these treatments is radiation.

“Radiation kills cancer cells by causing DNA damage, but it also increases the levels of DNA that are found outside of the cell nucleus, in the cytoplasm. Typically a cell is exposed to DNA in the cytoplasm only if it’s been infected by a virus,” Morris said. “Radiation treatment, then, appears to activate pathways in the cell so that it acts as if it’s been virally infected, drawing in the immune system.”

They also inject the irradiated tumor with tumor-specific antibodies and immune-activating proteins called cytokines. The antibodies attach to the surface of cancer cells that express the marker the antibodies specifically recognize, where they then flag down immune cells that know to attack antibody-coated cells; the cytokines boost immune cell performance. When a marked cancer cell is attacked, the immune cell essentially eats it. As the cancer cell is digested, the immune cell surveys the contents for as many abnormal cancerous proteins as it can find.

“The engulfing immune cell shows those proteins to other immune cells, teaching them which proteins to go look for on other cancer cells,” Morris said. “And because the metastatic cells share many mutations with the cells at the treatment site, the immune system should be trained to target even those resistant cells that lack the target of the injected antibody.”

With the immune system boosted and the cancer cells’ defenses weakened, Morris and his team are beginning to see better survival outcomes in mice with metastatic cancers that previously did not respond well to checkpoint inhibitors alone. He expects to see this work translated into human clinical trials in the next few years.

Thought Leader Perspectives

Lisa Barroilhet, MD, is an Assistant Professor in the Department of Medicine at the University of Wisconsin School of Medicine and Public Health, the Dolores A. Buchler, MD Faculty Fellow in Gynecologic Oncology and a member of the UW Carbone Cancer Center.

This article is used by permission. Please see the original post at OncLive.com

PARP Inhibitors Are Changing Diagnostic and Therapeutic Landscape in Ovarian Cancer

Targeted therapy in ovarian cancer is a relatively new field, and one that is rapidly expanding. PARP inhibitors are the most commonly used targeted therapy for patients with recurrent ovarian cancer, and the indications for the use of these drugs have broadened in recent months. Their popularity has increased as newly reported study findings support their efficacy and because of their oral bioavailability and convenient dosing schedule.

PARP inhibitors block the enzyme poly (ADP-ribose) polymerase, causing multiple doublestrand DNA breaks to form in patients who have homologous recombination deficiency (HRD). The best-known HRD pathway proteins are BRCA1 and BRCA2, which are encoded by t u mor – suppr e ssion genes that can harbor germline mutations. BRCA-related ovarian cancers make up about 15% of all ovarian cancers diagnosed in the United States, and the genes are most commonly altered in patients with familial breast and ovarian cancer syndromes. Patients with BRCA mutations have up to a 60% lifetime risk of developing ovarian cancer.

Tumors with BRCA mutations are particularly susceptible to double-strand DNA breaks. In the presence of a PARP inhibitor, repair of DNA damage, which is an expected part of any cell cycle, cannot be performed efficiently and tumor cells die (Figure). Normal cells that do not replicate their DNA as frequently as cancer cells do and that lack BRCA abnormalities survive PARP inhibition. This means that some of the most frustrating adverse effects of traditional chemotherapy, such as hair loss, are avoided.

Impact of FDA Approvals

There are 3 PARP inhibitors on the market that are approved for the treatment of patients with ovarian cancer: olaparib (Lynparza), rucaparib (Rubraca), and niraparib (Zejula).

The FDA approved olaparib in December 2014 for use in patients with suspected or confirmed BRCA-mutated advanced ovarian cancer who have been treated with 3 or more prior lines of chemotherapy. A phase III clinical trial accruing at UW Carbone Cancer Center and centers throughout the United States is examining olaparib with and without cediranib, a potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, compared with standard platinum-doublet chemotherapy (NCT02446600). This is the largest multiarm prospective trial examining the efficacy of olaparib paired with other targeted therapy.

Rucaparib was approved in December 2016 for patients with confirmed somatic or germline BRCA mutations who have been treated with 2 or more prior lines of chemotherapy. Testing of tumor tissue in the recurrent setting in order to identify a potential somatic BRCA mutation is now becoming commonplace, while it was rarely performed prior to rucaparib’s approval.

In March 2017, following a report in the New England Journal of Medicine,¹ niraparib was approved for maintenance treatment of patients with recurrent ovarian cancer who meet the common definition of platinum sensitivity. This is the first FDA-approved maintenance therapy for ovarian cancer and has the potential to change standard practice.

In general, PARP inhibitors are well tolerated. Common toxicities include anemia, nausea, and fatigue. Myelodysplastic syndromes are seen in up to 2% of patients treated with these medications, and patients should be appropriately counseled regarding this adverse effect.

Unanswered Questions

PARP inhibition may be beneficial outside of BRCA-positive patients. The study findings that led to niraparib’s FDA approval for all platinum-sensitive patients show improved survival in patients with and without known BRCA mutations. This raises questions about larger implications for other mutations in genes associated with HRD, including PALB2, BRIP1, CHEK2, RAD51C, and RAD51D. Potentially, abnormalities in these genes could be markers for platinum sensitivity.

As we enter this new landscape of precision medicine in ovarian cancer, we must be prepared to offer these therapies to our patients at various points during their treatment course, which often extends over years. We know little about using a different PARP inhibitor after the first has failed. The optimal timing of screening for somatic BRCA mutations has not been defined. One could argue that biopsy at the time of recurrence would be the most accurate; however, many patients do not have disease amenable to core biopsy. Until more is known, many providers rely on tissue from the original cancer debulking surgery.

Further, although the Society of Gynecologic Oncology recommends genetic counseling and genetic testing for all patients with ovarian cancer, only about half of eligible patients have BRCA testing results available at the time of cancer recurrence. There are many opportunities here to enrich the care of patients battling recurrent ovarian cancer. PARP inhibitors have opened the door to the potential of targeted therapy in treating this challenging disease.

About the Big Ten Cancer Research Consortium: The Big Ten Cancer Research Consortium was created in 2013 to transform the conduct of cancer research through collaborative, hypothesis-driven, highly translational oncology trials that leverage the scientific and clinical expertise of Big Ten universities. The goal of the Big Ten Cancer Research Consortium is to create a unique team-research culture to drive science rapidly from ideas to new approaches to cancer treatment. Within this innovative environment, today’s research leaders collaborate with and mentor the research leaders of tomorrow with the unified goal of improving the lives of all patients with cancer.

About the Big Ten Conference: The Big Ten Conference is an association of world-class universities whose member institutions share a common mission of research, graduate, professional and undergraduate teaching and public service. Founded in 1896, the Big Ten has sustained a comprehensive set of shared practices and policies that enforce the priority of academics in the lives of students competing in intercollegiate athletics and emphasize the values of integrity, fairness and competitiveness. The broad-based programs of the 14 Big Ten institutions will provide over $200 million in direct financial support to almost 9,500 students for more than 11,000 participation opportunities on 350 teams in 42 different sports. The Big Ten sponsors 28 official conference sports, 14 for men and 14 for women, including the addition of men’s ice hockey and men’s and women’s lacrosse since 2013. For more information, visit www.bigten.org.