A woman coming of age in a country with modern health carestandards becomes acquainted with two regular chores that she'll facefor the rest of her life.
* One is a periodic mammogram, intended to spot breast tumorswhen they're still small enough to treat with the prospect of totaleradication.
* The other is a pap smear, which scrapes cervical cells from the tipof her uterus, and examines them for signs of precanceroustransformation.
Cervical carcinoma accounts for 15 percent of all deaths from cancer.Around the world, 465,000 new cases are diagnosed each year,14,000 in the U.S. alone. Deaths in this country amount to 5,000annually; in the U.K., 2,000.
Once cervical cells cross the line from normal to premalignant, ittakes about eight years for invasive cancer of the cervix to develop. Ifcaught in time, hysterectomy _ surgical removal of the uterus _followed by chemotherapy, can often thwart or forestall tumorrecurrence and death.
At the University of Wales in Cardiff, viral immunologist BorisBorysiewicz is head of medicine. He and his colleagues joined forceswith scientists at Cantab Pharmaceuticals in Cambridge, U.K., tocreate a vaccine that would treat cancer of the cervix.
This malignancy, more than most, offers a clear-cut bull's-eye forsuch an immunological strategy. That target is the ubiquitous,iniquitous human papillomavirus (HPV).
This single-stranded DNA virus exists in 70 strains, of which the firstdiscovered answers only for the misdemeanor of causing childhoodwarts on the hand. (Nineteenth-century reports in literature prescribedas therapy swinging a dead cat by the tail in a cemetery at midnight.)
Now it's known that at least two strains of HPV, 16 and 18, are guiltyof the high crime of cervical carcinoma. Four years ago, Borysiewiczrecalled, researchers reported that in parts of the world "as widelyscattered as Mali, the Philippines, Colombia and Spain, 94 percent ofall cervical tumors contained DNA from papilloma types."
He added: "Wherever you are in the world, HPV 16 and 18 are thedominant two strains associated with cancer."
So in constructing their vaccine, together with Cantab, Borysiewicztold BioWorld Today, "what we did was to take the two HPV geneproducts, E6 and E7 from both the 16 and 18 strains. Theseoncogenes are the virus' transforming proteins. From them we madea vaccine construct, TA-HPV, containing all four antigens," insertedin a vaccinia virus vector.
Vaccinia Vector Delivers Four Oncogenes
Cantab, which identified, isolated and cloned the four genes, holdsthe rights to the TA-HPV vaccine, which is one of its lead products indevelopment (see BioWorld Today, April 21, 1995, p. 1). TA standsfor therapeutic antigen.
Borysiewicz is first author of a paper in Saturday's Lancet, datedJune 1, 1996. Its title: "A recombinant vaccinia virus encodinghuman papillomavirus types 16 and 18, E6 and E7 proteins asimmunotherapy for cervical cancer." Cantab's vice president ofmolecular sciences, Stephen Inglis, is senior author.
Their article reports what the company's medical director, JohnRoberts, described to BioWorld Today as "the first published trial ofa vaccine for cervical cancer. Nobody else has a vaccinia constructfor it that I'm aware of."
Eight women with late-stage cancer of the cervix took part in thePhase I/II clinical trial in Wales. Each was vaccinated in July 1994by a small skin scarification on the upper arm, just as in the long-gone vaccination against smallpox _ which also employed thevaccinia virus.
"In Europe, unlike the U.S., Borysiewicz explained, "there have beenno other recombinant vaccinia studies done at all. We therefore hadto do it under considerable isolation conditions, to show that in theeight patients the vaccine was safe, it didn't spread unduly into theenvironment and caused no major side effects.
"Interestingly," he observed, "it induced immune responses to theinserted genes, regardless of whether the patients had been previouslyvaccinated in the smallpox eradication campaign [in the 1970s]."
The eight volunteer subjects ranged in age from 39 to 72. By the endof 1995, all but two had died of their disease and its complications.One of the two, still alive and tumor-free today, had had ahysterectomy, which the clinicians suggest may itself have been life-saving.
The other woman who survives without tumor, despite recurringbouts of cancer flare-up before her vaccination, displays not onlyantibodies to the viral antigens, but cytotoxic T lymphocytes (CTL)as well. But a commentary accompanying the Lancet paper suggestedthat "the association may be due to chance."
What the co-authors will do now, Borysiewicz said, "is take the fourgenes and insert them into an adenovirus construct to restimulatethese CTLs in the test tube. Eventually growing up enough of thesecell-killing cells for ex vivo therapy of cervical cancer is somethingwe have in the pipeline, but that is some way off."
U.S. Trial Vaccinates Outpatients
Meanwhile, in the here and now, Cantab has launched a Phase I/IItrial of its TA-HPV vaccine in the U.S., under the aegis of theNational Cancer Institute's outpost in Frederick, Md. This clinicalstudy is being managed by immuno-oncologist Gary Gause, of theNCI's clinical research branch.
"We started with two patients two months ago," Gauze toldBioWorld, "and intend to treat 14 patients initially. If there is anyfavorable response, we would go on to 30 subjects."
One salient difference from the U.K. trial: The NCI study is beingconducted on an outpatient basis, rather than in isolation units. Thisbecame possible because the initial U.K. study showed noenvironmental spread of the recombinant vaccine components.
Cantab now is arranging with the Amsterdam-based EuropeanOrganization for Research and Treatment of Cancer to set up anumber of Phase II trials. "We intend to start, the second half of thisyear, in the Netherlands and Belgium," Roberts said, "and thenextend to other European countries as we obtain approval."
In this program, the subjects will have early stage rather than late-stage cervical cancer, he added. "We believe the vaccine is designedfor optimum effect in early stage disease, when women are fertile andimmunocompetent, and have a smaller tumor burden." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.