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May provide better targets for cervical cancer vaccine development

New research sheds light on why cervical precancers disappear in some women and not in others. Scientists at the Johns Hopkins Kimmel Cancer Center report in the July 1 issue of Clinical Cancer Research that the reason many of these lesions persist is an unlikely mix of human papilloma virus (HPV) strain and a woman’s individual immune system.

For decades, scientists have known that HPV causes nearly all cases of cancer in the neck of the womb.  Most sexually active women - some reports say up to 80 percent - are exposed to HPV and more than half of these women are infected with strains of the virus that could likely turn a precancerous lesion to cancer.  But only a small percentage of precancers progress to full-blown cancer, a process that takes years.

To find out why, gynecologic oncologist Cornelia Trimble, M.D., closely monitored 100 women with high-grade, precancerous cervical lesions before standard surgery to remove the abnormal tissue.  Some of the lesions - about 28 percent -- regressed by themselves before surgery within a time period considered within the bounds of care standards.  But among patients whose pre-cancers lingered, Trimble discovered that women were three times less likely to resolve their lesions if they carried a certain immune system gene and did not have HPV16, the most common strain of the virus.

Trimble was particularly interested in these molecular differences because she is using HPV-targeted vaccines in related studies to treat early cervical lesions before they turn into cancer.  “It’s important for us to know the immunologic fingerprint of women who may best benefit from our vaccine,” she says.  “Some lesions are on the brink of resolving, but may need the vaccine to push them over.”

Lesions containing HPV16 alone are the most troublesome and difficult to resolve.  In the subset of 44 patients with HPV16 only, their type of immune system made no impact on whether or not their lesion resolved.  But in 30 women with non-HPV16 lesions, those who carry a gene called HLA*A201 were three times less likely to clear up their lesions than those without the gene (14.3 percent vs. 42.3 percent).  According to Trimble, 40 percent of people carry the HLA*A201 gene, which codes for certain white blood cell proteins.

None of the lesions got worse during the study period, and all unresolved lesions were surgically removed when the observation period ended.  “Since none of the lesions progressed after 15 weeks, we can be reasonably assured that this window of time is safe for vaccine treatments,” she said.

Trimble is studying a larger group of patients to confirm her results and rule out other potentially confounding factors such as age, smoking status, and contraceptive method, which may influence how these lesions clear.  Trimble recently published results linking second-hand cigarette smoke to cervical cancer progression.  She also is looking for additional immune system characteristics that could predict mechanisms of immune responses to HPV.  This may provide more information on which women have lesions more likely to regress and potentially avoid surgery, plus provide the opportunity to treat early-stage disease.

According to the Centers for Disease Control, an estimated 20 million people in the United States are infected with HPV and up to three-quarters of these have viral strains that are linked to cervical, oral and anal cancers. More than 10,000 cases of cervical cancer are diagnosed in the United States annually.

The research was funded by the National Cancer Institute and Cigarette Restitution Fund Program.

Trimble’s research collaborators include Steven Piantadosi, Patti Gravitt, Brigitte Ronnett, Ellen Pizer, Andrea Elko, Barbara Wilgus, William Yutzy, Richard Daniel, Keerti Shah, Shiwen Peng, Chienfu Hung, Richard Roden, T.C. Wu, and Drew Pardoll.

Photo Available: Normal, Low-grade, High-grade Precancerous Lesions compared with Cancerous.

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