News

Research team assesses addition of complement inhibitor drug to immunotherapy for ovarian cancer

3 Jul 2023
Research team assesses addition of complement inhibitor drug to immunotherapy for ovarian cancer

Researchers at Roswell Park Comprehensive Cancer Center have launched a phase 2 clinical trial that they hope will improve both survival and quality of life for patients with recurrent ovarian, fallopian-tube or primary peritoneal cancer and malignant effusion, a side effect of the disease that significantly impairs quality of life. 

The study is exclusive to Roswell Park, where it was developed.

The clinical trial will evaluate the safety and effectiveness of pegcetacoplan (APL-2) as a treatment for these patients.

The Food & Drug Administration has already approved the drug, a complement inhibitor, for the treatment of the rare blood disease paroxysmal nocturnal hemoglobinuria, but this marks the first time it has been evaluated for the treatment of cancer.

Emese Zsiros, MD, PhD, FACOG, serves as principal investigator for the new study (NCT04919629), and Brahm Segal, MD, will lead the immune-system studies that are part of the trial.

The clinical trial is supported with a five-year, $3.3 million multiple-principal-investigator Research Project Grant (R01) awarded to Drs. Zsiros and Segal.

“The tumour microenvironment of ovarian cancer strongly suppresses the immune system,” says Dr. Zsiros, who is Chair of the Department of Gynecologic Oncology at Roswell Park. “Understanding how it is able to do that and finding ways to prevent it from happening should improve response to treatment.”

Although the immune system’s complement system helps protect against injury and illness, in the tumor microenvironment (TME) — the area surrounding the tumour — a complement protein called C3 can help cancer cells grow and develop.

Research led by Dr. Segal’s lab has shown that when neutrophils — white blood cells that are part of the immune system — move into the TME, they can disrupt the work of the immune system’s T cells, which help provide long-lasting immunity against the tumor. Dr. Segal and his colleagues have observed that the TME has high levels of complement activation and that suppressing complement weakens the neutrophils’ ability to suppress the cancer-fighting work of the T cells.

This insight led his team to hypothesize that APL-2 could reduce the accumulation of neutrophils in the tumor tissue, enabling T cells to be more effective and boosting the effectiveness of a type of immunotherapy called an immune checkpoint inhibitor.

The new clinical trial will assess that hypothesis using APL-2 in combination with the immune checkpoint inhibitor pembrolizumab (brand name Keytruda) — another first.

“This clinical trial is the result of several years of research conducted in our lab and the work of others in the field, and the steadfast commitment of Dr. Zsiros and our teams to transfer research findings from the lab into the clinic for the first clinical trial of a C3 inhibitor in patients with cancer,” says Dr. Segal, Chair of the Department of Internal Medicine, Chief of Infectious Diseases and Member of the Department of Immunology at Roswell Park.

The team also hopes APL-2 will improve patients’ quality of life by shutting down the generation of anaphylatoxins, which make blood vessels more porous and can lead to malignant ascites and malignant pleural effusion.

Malignant ascites, or fluid buildup, affects nearly 50% of the patients with stage 3 or stage 4 ovarian cancer and is associated with failure to respond to treatment.

The condition can severely impact quality of life, causing pressure and discomfort, shortness of breath, difficulty moving, pain, nausea, fatigue, constipation and other digestive issues.

Standard treatment involves draining the fluid through a needle — a procedure called paracentesis, which usually needs to be repeated on a regular basis.

Treatment also includes bevacizumab (brand name Avastin), either alone or in combination with another drug. Bevacizumab works by preventing the growth of new blood vessels that could “feed” the tumor.

A similar condition, called malignant pleural effusion, affects about a third of ovarian cancer patients during their illness.

It occurs when fluid that contains cancer cells accumulates in the space between the lung and chest wall, causing chest discomfort and breathlessness.

As with malignant ascites, it is treated by draining the fluid on a regular basis.

“We hope that this research can lay the foundation for testing the efficacy of suppressing C3 as a way to enhance cancer immunotherapy,” notes Dr. Zsiros.

“We hope that knowledge gained from this trial may be applicable to other cancers,” adds Dr. Segal.

Source: Roswell Park Comprehensive Cancer Center