Human Clinical Trials Begin For Cervical Cancer Vaccines

Efforts are under way to develop a vaccine against one of the world's deadliest illnesses, cervical cancer. Along with a number of university research laboratories, at least a half-dozen biotechnology and pharmaceutical companies are beginning clinical trials or are in preclinical development of such drugs. Efficacy in humans remains to be firmly established, but if the vaccines progress to later-phase trials, challenging jobs for immunologists, microbiologists, and biochemists will multiply. "This is an area of enormous potential," says Michael Steller, chief of the gynocologic oncology surgery branch at the National Cancer Institute (NCI). "I can't emphasize enough the opportunity that exists-for cervical cancer as much as any cancer I can think of-to develop an anticancer vaccine." About 15,800 cervical cancers are detected and almost 5,000 fatalities recorded each year in the United States, according to NCI. Worldwide, reported deaths number about 44,000 per year. The annual cost of managing the disease domestically is $6 billion, according to consultants KPMG Peat Marwick Strategic Health Solutions of Cambridge, Mass. None of the current treatments, including radiotherapy and surgery, is completely effective, and the mortality rate from the disease is 60 percent. More than 90 percent of all cervical malignancies are associated with any of a dozen types of sexually transmitted human papillomavirus (HPV). The two most prevalent strains, HPV-16 and HPV-18, are classed as "high risk" for both sexes, having been linked with cancers that develop in the anus or on the genitalia. There are more than 70 types of HPV. Vaccines for types associated with cervical cancer could be either prophylactic or therapeutic. Prophylactics, administered to healthy people, are thought to spur B cells of the humoral immune system to produce antibodies that neutralize an HPV virus before it can infect a host cell. Therapeutics, for HPV-infected or cancerous patients, apparently prompt cytotoxic T cells and other components of the cellular immune system to attack malignant tissue. Both approaches have hurdles to overcome, not least of which is to demonstrate in clinical trials that the vaccines can prevent or cure either HPV infection or cervical cancer in humans. EXCITING PROSPECTS : Much has been achieved and the potential for further advances in cervical cancer vaccines is enormous, NCI's Michael Steller thinks. MedImmune Inc., a publicly held biotechnology company in Gaithersburg, Md., is developing preventive vaccines for various HPV types. "Our overall goal would be the development of a multivalent vaccine," says molecular biologist Julie Adamou, MedImmune's investor and media relations associate. However, she adds that cross-reactivity, in which a single vaccine is effective against different strains-particularly those associated with cervical cancer and with genital warts-has not yet been established in trials. MedImmune's self-financed Phase I trials of two HPV vaccines to prevent cervical cancer in healthy patients are scheduled for 1998. Corporate partnership is being sought. MedImmune's vaccines contain an HPV structural protein that self-assembles as the viral shell. Called a virus-like particle (VLP), it structurally imitates the virus but is noninfectious. VLPs in the body will stimulate an immune response. For animal tests, MedImmune derived VLPs from a canine oral papillomavirus (COPV) that occurs on mucosal surfaces, as in humans. The VLPs generated antibodies that protected healthy dogs against subsequent high doses of infectious COPV (J. Suzich et al., Proceedings of the National Academy of Sciences, 92 :11553-7, 1995). Although COPV does not progress to malignancy, it nevertheless is a step toward a workable animal model, the lack of which has plagued researchers. GROWING STRAINS : Craig Myers, whose Penn State team produced infectious HPV viruses in tissue culture, now wants more life cycle studies on the virus. Problems in culturing infectious HPV associated with cervical cancer constituted another difficulty, overcome recently by researchers at Penn State University's Milton S. Hershey Medical Center. "We were able to transfect the viral DNA into normal keratinocytes [epidermal cells]," says Craig Meyers, an assistant professor of microbiology and immunology at Penn State, "and we produced enough virus to reinfect other cells. So, if you have the viral DNA, you should be able to make the virus." The significance of this achievement is that HPV vaccines now can be tested in vitro. The existence of HPV in cervical cancer cells presents an excellent target for vaccine developers. One firm engaged in such work, the publicly owned Cantab Pharmaceuticals plc of Cambridge, England, has Phase II trials now under way in Europe for a vaccine to treat early-stage cervical cancer. In America, Cantab is completing recruitment for Phase I trials at NCI of a similar vaccine for late-stage patients. A vaccine to treat cervical dysplasia, the abnormal growth that often leads to cancer, is in preclinical development. The vaccines encode genes E6 and E7 of the HPV types 16 and 18. These oncogenic genes are known to possess transforming ability and have been shown to interfere with cellular "tumor suppressor" proteins. This interference leads to mutations of the cell and to malignancy. Eventually, the rest of the viral genotype is absorbed into the host cell's chromosomal DNA, but E6 and E7 remain as intact antigens, identifying the cell as cancerous. PERFECT TARGET : The E6 and E7 genes of HPV control the tumor phenotype and therefore are excellent gene therapy targets, says Cantab's John Shields. "These proteins are ideal targets," enthuses immunologist John Shields, Cantab's senior vice president of research. "For many of our immune targets [in other drug development], the actual target doesn't control the tumor phenotype, so you lose all the antigens. But you need E6 and E7 to be a cancer cell." Cantab's vector is the same vaccinia virus used against smallpox. Although a viral vector is currently the most-used way to express the antigens, it also elicits a cellular immune response, in which antibodies attack the pox vaccinia. A question yet to be fully answered is, what effect might even a weakened virus have on patients whose immune systems already are compromised? That problem has confronted researchers at the Johns Hopkins Oncology Center in Baltimore. Drew Pardoll, an associate professor of oncology at Johns Hopkins, says he isn't sure when clinical trials will begin by French vaccine maker Pasteur Mérieux Connaught, mainly because the Johns Hopkins viral vector "has a little bit more danger for humans than do somewhat more attenuated versions." He anticipates that a vaccinia similar to Cantab's may be developed by the French company. The key to the Johns Hopkins technology is a "molecular tag" attached to the E7 antigen, creating a fusion protein called a chimera. The molecular tag is the sorting signal of a specific membrane protein that directs the chimera to a cellular compartment called the lysosome, where the chimera is broken down. The resultant antigen peptide is then expressed in association with a cell-surface molecule of the major histocompatability complex (MHC), enabling cytotoxic T cells to recognize the foreign invader. "We're actually attaching an address to the antigen," Pardoll explains. VITAL DATA : Mark Philip says Pangaea has assembled a database of more than 400 self-epitopes that could become "the next genomics." Yet another approach, incorporating three interrelated technologies, has been created by Pangaea Pharmaceuticals Inc. of Cambridge, Mass. The company's lead product is a nonviral, plasmid DNA for patients infected with anogenital HPV types who have developed cervical dysplasia. Phase I and IIa clinical trials will begin in early 1998 at Brigham and Women's Hospital in Boston. Pangaea does not yet have a backer for later trials, but negotiations with several major partners are in final stages, says president and chief executive officer Mark Philip. "We can create a plasmid DNA which encodes the [specific] small peptide that can be engineered to replicate in the cell, as if the cell had digested a cancerous protein and was loading it up on the MHC molecule. It's a minigene, if you like," Philip explains. "So, a full-blown immune response is generated." A second technology predetermines the precise disease-related antigens, called epitopes, bound by MHC molecules that will generate a cellular immune response. Using advanced microchemistry and high-throughput mass spectrometry, Pangaea has assembled a database of more than 400 such "natural," or self, epitopes. "It will be, we think, the next genomics," Philip predicts. The third innovation is Pangaea's delivery system, "a way to package the DNA material and deliver it to the professional antigen-presenting cells (APCs) internally," he says. This proprietary formulation increases the drug's potency by targeting APCs. NCI's Steller sees a promising future for prophylactics in particular. "I think this may drastically decrease the incidence of cervical cancer," he says, "but not in our lifetime." He explains that the mean age in America for development of cervical cancer is 53, and most such patients would have been HPV-infected through sexual contact many years earlier. Cancer Group Institute-Cervical Cancer http://www.cancergroup.com Johns Hopkins Oncology Center http://www.med.jhu.edu/cancerctr MedImmune Inc. http://www.medimmune.com National Cancer Institute http://www.nci.nih.gov University of Pennsylvania Cancer Center http://oncolink.upenn.edu/ He thinks therapeutic vaccines ultimately may be best suited either to preinvasive cancers or following first-line treatment. Therapeutics face the difficulty that tumors can mutate and clone in various ways, he notes, helping them to avoid expressing the viral antigens. "The big picture is, does the treatment work?" he asks of current therapeutic vaccines. "The resounding answer is, 'No.' So far, no one has demonstrated a response in which the tumor shrinks and people get better." At NCI, Steller recently completed a Phase I clinical trial of a vaccine that links an HPV-16 E7 peptide epitope to a lipid moiety that aids absorption into the cell and to a "helper" epitope that elicits improved T cell function. Unlike the gene therapy approaches, Steller is not driving a gene that encodes the peptides into the APCs. Instead, he uses a modified peptide itself to stimulate a specific HPV cellular immune response, with the assistance of the helper epitope. He argues that this approach may have several practical advantages compared to gene delivery methods. "Enormous progress has been made in the last decade, and that's something in which the medical community can take immense satisfaction," Steller believes. "But I think drug companies are assuming a cautious posture. The business end of it is developing a popular and successful vaccine that is useful to patients."

Human Clinical Trials Begin For Cervical Cancer Vaccines

Become a Member of

Meet the Author

Steve Bunk

Published In

October 1997

Related Research Resources

How Do Embryos Know How Fast to Develop

Research Resources

Podcasts

Webinars

Videos

Infographics

eBooks

The Advent of Automated and AI-Driven Benchwork

Become a PCR Pro

Genetic Insights Break Infectious Pathogen Barriers

Navigating Cold Storage Solutions

Products

Product News

BRAND® Dispensette® S Bottle Top Dispensers for Precise and Safe Reagent Dispensing

Sapio Sciences Makes AI-Native Drug Discovery Seamless with NVIDIA BioNeMo

New DeNovix Helium Nano Volume Spectrophotometer

Olink® Reveal: Accessible NGS-based proteomics for every lab