(Oct. 4, 2017) — For more than three decades, Richard Schlegel, MD, PhD, has largely been focused on one goal: decreasing the incidence of cervical cancer, the second leading cause of cancer deaths in women globally.
As a co-inventor, nearly two decades ago, of the Georgetown-owned technology that led to a human papillomavirus (HPV) vaccine, Schlegel, chair of Georgetown University School of Medicine’s pathology department, has helped prevent millions of women from becoming infected with a virus that can lead to cervical cancer.
While the HPV vaccine has been a game changer, Schlegel’s recent research may lead to another advance by treating women already infected with HPV and a precancerous condition that often leads to the development of cervical cancer.
It involves a novel treatment delivery system with a repurposed anti-malarial drug.
Revolutionizing cervical dysplasia treatment
If human trials are successful — and one is now underway — testing and treating women with cervical dysplasia (abnormal, precancerous cells that precede cervical cancer) wouldn’t even require a health clinic visit. That’s a huge advantage for women in developing countries, where 80 percent of cervical cancer cases occur.
Women who have not received the HPV vaccine have an 80 percent chance of becoming infected with the virus sometime during their lives, though for most women, HPV goes away on its own. However, for at least 500,000 women annually, the virus leads to cervical cancer, which kills about 300,000 women each year.
In the U.S., about 50,000 women receive a diagnosis of cervical dysplasia annually. About 13,000 women will develop invasive cervical cancer and more than 4,000 will die from the disease.
Currently, a commonly recommended treatment for women diagnosed with HPV-related cervical dysplasia, a precancerous condition, is to have a surgical biopsy that removes a substantial portion of the cervix, making it potentially difficult for women to become pregnant. Schlegel’s treatment method would revolutionize the treatment by preventing women from developing cervical cancer without compromising their fertility.
Schlegel’s invention for cervical precancer
Schlegel, in collaboration with fellow Georgetown scientist Dan Paul Hartmann, PhD, discovered that a derivative of the anti-malarial drug artesunate may be an effective new treatment for cervical dysplasia.
Artesunate, a derivative of artemisinin, is made by the plant Artemisia annua, or sweet wormwood — a staple of traditional Chinese medicine. The discovery of artemisinin’s anti-malarial properties led to a Nobel Prize and the development of artesunate.
Schlegel says researchers elsewhere are working to develop a simple swab that women can use in their home to collect cells from their cervix. The sample would be sealed and sent to a central clinic for testing.
A woman whose sample was positive for cervical dysplasia caused by HPV, might then receive a kit with Schlegel’s invention. It would include five cervical suppositories embedded with artesunate. Every day for five days, the woman would insert the suppository with a standard tampon that places it against the cervix.
From experimental evidence, it is hypothesized that within three weeks, the artesunate released from the suppositories would kill abnormal cervical cells. Schlegel says the drug works by targeting cells with an abnormal amount of iron — a condition of both malarial parasites that populate a patient’s blood and cervical dysplasia caused by HPV.
“We thought this would be a great drug to treat the cervix because it is non-toxic and so could be applied topically in high concentrations,” Schlegel says. “We tried it in our tissue culture system and it had a very dramatic effect.”
Frantz Viral Therapeutics, LLC., licensed the use of artemisinin to treat cervical dysplasia from Georgetown and is working with Cornelia Liu Trimble, MD, director of the Johns Hopkins’ Cervical Dysplasia Center, to test the therapy in women diagnosed with high-grade cervical dysplasia. Schlegel also plans to work with an Irish company to develop a vaginal ring that could deliver artemisinin to treat cervical dysplasia.
The path to the HPV vaccine
Schlegel recognizes that it takes a diverse ensemble of investigators to develop the science behind any medical advancement. He also gives credit for the development of the HPV vaccine to several others, including German professor Harald zur Hausen, MD, who, in 1984, found the link between HPV and cervical cancer. This discovery, which launched a race for development of a vaccine, was later recognized in 2008 with a Nobel Prize.
In addition to his own group, Schlegel cites the work of investigators at the University of Queensland, Australia, the National Institutes of Health and the University of Rochester.
In 1991, Ian Frazer, MD, and his research group at Queensland’s Diamantina Institute, reported that they could make HPV16 particles from two proteins, L1 and L2, on the virus’s outer coat. (Although there are about 100 different strains of HPV, HPV16 and HPV18 cause about 70 percent of cervical cancer cases.) He believed that mimicking the virus with these “virus-like particles” (VLPs) could induce a natural antibody-based immune response and so could be the basis of a vaccine. The technology for making VLPs on a large scale was just then emerging.
The following year, the group at Georgetown Lombardi Comprehensive Cancer Center, led by Schlegel and A. Bennet Jenson, MD, along with Shin-je Ghim, PhD, published two seminal papers. The first showed that expression of the human L1 gene alone produced protein that reacted with monoclonal antibodies specific for native HPV structure. This finding meant that the structure of L1 resembled the virus enough to function as an effective vaccine. In a second paper, they demonstrated that L1 particles assembled into VLPs that completely protected dogs against HPV infection. These findings were critical to the development of a vaccine for which a number of international patents were issued to Georgetown.
Among other advances, the NIH group identified and corrected a mutation in L1 for HPV16 that had previously made it difficult to make VLPs. The National Cancer Institute began a series of clinical trials that demonstrated the efficacy of the vaccine. Earlier this year, the 2017 Lasker-DeBakey Clinical Medical Research Award was awarded to the NIH scientists Douglas R. Lowy, MD, and John T. Schiller, PhD.
The Rochester team showed that L1 from HPV11, another cancer-inducing viral strain, also self-assembled into VLPs and could induce neutralizing antibodies.
“As is usual in the development of new medical therapy backed by bench science, there were step-wise additions by multiple groups. Nobody did it all. And alone, the vaccine is not attributable to one group,” says Schlegel.
And now again, as Schlegel continues his quest to find a treatment for women who did not benefit from a protective HPV vaccine, he muses about ways to finally, permanently, limit the burden of cervical cancer — a pursuit he has devoted 35 years to, and as he affirms, he’s not done yet.
Disclosure: Georgetown University owns technology on which HPV vaccines were developed. Schlegel, Jenson and Ghim are listed as co-inventors. Georgetown University also owns technology related to the use of artemisinin for the treatment of cancer. Georgetown has several issued patents and pending patent applications in the U.S. and internationally related to this technology. The inventors on the IP are Schlegel, Hartmann and Astrid Baege.