麻豆传媒

A therapeutic vaccine eradicated human papillomavirus (HPV) in a fourth of women with precancerous cervical lesions, a placebo-controlled clinical trial showed.

Overall, the subcutaneously administered vaccine led to clearance of precancerous cervical lesions in 24% of women who tested positive for one or more HPV strains, as compared with 10% in patients who received placebo injections. Subgroup analyses consistently showed clearance rates two to three times higher with the vaccine, irrespective of HPV type or lesion severity, reported Diane Harper, MD, of Michigan Medicine in Ann Arbor, and colleagues.

The results represent a step forward in efforts to prevent progression of HPV-positive cervical lesions to cervical cancer and to reduce the treatment burden for the lesions, they noted in .

"There are very few products trying to cure women who already have an HPV infection," Harper told 麻豆传媒. "It's very exciting. This is the first time we've seen something with this success rate that is relatively easy to implement."

The vaccine could have a role in several clinical settings with respect to reducing the risk of HPV-related cervical cancer, she added.

"Women who are afraid of having any kind of surgery, who haven't had any children yet, who don't want to have a surgical procedure, would be very excited about an option of having three shots, getting rid of their disease, and then not having to have surgery," said Harper. "In countries where it's hard to have electricity and have the kind of surgery that we have in the United States, being able to provide a drug to treat the infection would allow us to get rid of HPV and prevent its transmission. Another potential role would be to allow primary care physicians and advanced practice nurses to be able to give it -- just like we do regular immunizations -- for therapy."

HPV infection has emerged as a major focus for development of immunotherapeutic vaccines. Persistent infection with the virus causes at least six cancers or cancer precursors, with cervical cancer accounting for 80% of the worldwide burden of HPV-related cancers, Harper and colleagues noted.

Surgery, which has a high cure rate, remains the cornerstone of therapy for cervical cancer but is associated with a risk of reproductive morbidity. A clear need exists for nonsurgical, nonablative therapeutic options to treat HPV-associated diseases, the authors continued. Current screening strategies for HPV-associated diseases do not have any therapeutic option for women with persistent infection, which carries an unknown risk of progressing to cancer.

Harper and colleagues reported findings from a phase II randomized trial of tipapkinogen sovacivec (TS), which consists of a modified vaccinia virus vector carrying a payload of human interleukin-2 and nononcogenic forms of HPV 16 E6 and E7 proteins. After subcutaneous injection, TS infects the surrounding cells, which express E6 and E7 peptides that eventually migrate to the draining lymph node and integrate into T cells to initiate a targeted cell-mediated immune response.

Preclinical and preliminary clinical studies that TS caused resolution of grade 2/3 cervical intraepithelial neoplasia (CIN2/3) by inducing a cell-mediated immune response. The research led to an international, randomized, placebo-controlled clinical evaluation of TS in ≥18 with pathology-confirmed HPV-positive CIN2/3. Women who had received prophylactic HPV vaccine were excluded.

Investigators randomized 192 women 2:1 to TS or placebo. The trial protocol stipulated three injections of the vaccine, or placebo, administered at one-week intervals.

Follow-up visits occurred at 3 and 6 months for cytology and HPV testing. Treating physicians had the discretion to perform cervical biopsies at 3 months. Definitive treatment occurred at 6 months (loop electrosurgical excision procedure or conization), along with HPV typing. Follow-up continued at 6-month intervals to month 30, with repeat cytology, HPV testing, and adverse-event assessment, as well as colposcopy and biopsy, if indicated.

The trial had a primary efficacy endpoint of histologic resolution 6 months after the first vaccine injection in patients with HPV 16 monoinfection and histologically confirmed CIN 2 or 3 at baseline. Exploratory endpoints included complete histologic resolution or partial response (downgrade to CIN1) at 6 months, irrespective of HPV type infection or CIN status.

The study population comprised 82 patients with HPV 16 infection only and 110 with infection by more than one HPV strain. The results showed that 18% of patients with HPV 16 monoinfection had complete resolution of CIN2/3 at 6 months as compared with 4% of the placebo group.

Among patients with HPV 16 and one or more other high-risk HPV types, 18% had clearance of CIN2/3 at 6 months with the vaccine compared with 8% of patients randomized to placebo. An analysis of patients with CIN2/3 and infection with any HPV type except 16 showed lesion clearance in 35% of patients versus 17% with placebo, including 35% of CIN3 lesions in the vaccine group versus none in the placebo group.

For all HPV types combined, clearance of CIN2/3 lesions occurred in 24% of the vaccine group and 10% of the placebo group, including a 21% clearance rate for CIN3 lesions versus none in the placebo group.

Harper said she hopes vaccine owner Transgene will move forward with a phase III trial of TS, as a step toward commercialization. Trials of the vaccine in other HPV-related cancers also are under consideration.

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