Human papillomavirus (HPV)-induced cervical cancer is on the cusp of turning from one of the deadliest cancers affecting women worldwide into a triumph of public health initiatives.
The first of these initiatives was the preventative HPV vaccines, now available, which protect women and men from HPV infection. The second assault on HPV may begin with the first therapeutic HPV vaccine that Wistar has just licensed for development. This vaccine will directly attack HPV-related cancer.
In May 2012, The Wistar Institute signed an agreement that will allow the large-scale production of the first therapeutic HPV cancer vaccine. The vaccine, created through the efforts of Wistar’s Vaccine Center and its Director, Hildegund C. J. Ertl, M.D., may vastly improve the prognosis for the majority of women diagnosed with cervical cancer.
The agreement allows Tianjin Bioroc Pharmaceutical & Biotech Co., Ltd., to license and develop the Wistar HPV vaccine. Bioroc (pronounced “Bye-ORock”) is closely affiliated with Tianjin Medical University Cancer Institute and Hospital (TMUCIH), where clinical trials for the new vaccine will take place. For over 50 years, TMUCIH has been the premier cancer hospital in China, and is in the process of building the largest state-of-the-art cancer hospital in all of Asia, if not the world.
This agreement with Bioroc would enable Wistar’s vaccine to reach what is possibly the biggest single pool of cancer patients on the planet. “An advantage of conducting clinical trials in China, especially at TMUCIH, is that, if we do pursue licensing in the United States, we can present an attractive set of clinical data from China,” Ertl said.
[At right: Hildegund C. J. Ertl, M.D., (second from right) and her laboratory’s project manager, Emily Liu (right), visiting with officials in Tianjin, China, in December of 2011.]
THE HPV-CANCER CONNECTION
While the HPV vaccines currently on the market are designed to prevent cancer by building immunity to HPV, the Wistar vaccine was developed to treat cervical cancer itself. Over 90 percent of all cases of cervical cancer are thought to arise from HPV infection. Although they are considered successful, the preventative HPV vaccines on the market are still not widely used and are of no benefit to women already infected with the virus.
“The idea is to use the human immune system to go after cervical cancer cells that originate due to human papillomavirus,” said Ertl. “Women who show signs of cervical cancer, such as through an irregular Pap smear — or even more advanced cancers — can be treated with a vaccine that directs tumor-killing immune cells toward cancer cells that exhibit HPV proteins.”
According to the American Cancer Society, over 12,000 women will be diagnosed with cervical cancer in 2012 and over 4,000 will die from the disease. Worldwide, cervical cancer is the fifth most deadly cancer in women.
HPV causes cancer when the virus takes up long-term residence in the people it infects, remaining within cells and using their molecular machinery to make viral proteins and replicate copies of viral DNA. In this act of residency, they can transform cells into precancerous lesions that can exhibit viral proteins on their surface. According to Ertl, this makes HPV-induced cancer a prime target for vaccination efforts.
There are a number of other HPV treatment vaccines in development, Ertl says, but most have faced problems invoking the proper immune response. With a glut of potential vaccines hitting the same roadblock, further development of the vaccines seems to have stalled. To avoid this problem, the Ertl laboratory took a different approach to creating a vaccine.
The Wistar HPV vaccine seeks to induce responses against three viral proteins called E7, E6 and E5, produced by HPV-16, the most common variety of the virus. Unlike any other vaccines, the Ertl laboratory fused the three HPV proteins to a protein from another virus, herpes simplex virus (HSV)-1. The difference, Ertl says, is that the HSV protein effectively antagonizes the molecular pathways that prevent white blood cells from acting. The vaccine, therefore, simultaneously delivers both the HPV antigen for the immune system to react to as well as a means of augmenting the response.
In animal model trials — a necessary step before clinical research in humans is possible — the Wistar vaccine stimulates a potent response from tumor-killing white blood cells to theE7 protein. In studies published last year in the journal Molecular Therapy, the vaccine showed it was capable of initially reducing the size of large tumor masses in mice, with sustained regression in more than half of them. In addition, when Ertl provided a booster immunization to these mice, she saw a profound decrease in tumors. All these experiments were done in an animal model that mimics the slowly progressing tumor microenvironment and represents a much more stringent challenge model than those used in other HPV vaccines in development.
“While chemotherapy and radiation therapy are effective, the side effects are well understood,” Ertl said. “In combination with existing therapies or alone, our vaccine may prove away to treat cervical cancer while reducing harmful side effects.”
This article appears in the Fall 2012 issue of Focus magazine, online soon.