麻豆传媒

An investigational therapeutic vaccine showed clinical effectiveness in patients with human papillomavirus (HPV)16-positive cervical intraepithelial neoplasia grade 3 (CIN3), according to results from a small phase II study.

Treatment with Vvax001 -- comprised of replication-deficient recombinant Semliki Forest virus particles encoding a fusion protein of the oncogenic proteins and tumor-specific antigens E6 and E7 of HPV16 -- resulted in a reduction in CIN3 lesion size in 17 of 18 patients, with reductions evident as soon as 3 weeks after last immunization, reported Refika Yigit, MD, of the University Medical Centre Groningen in the Netherlands, and colleagues.

Furthermore, a histopathological complete response (regression to CIN1 or no dysplasia) was seen in nine patients, with three having complete regression (no dysplasia) and six having regression to CIN1.

"To the best of our knowledge, Vvax001 is one of the most effective therapeutic vaccines for HPV16-associated CIN3 lesions thus far," wrote Yigit and colleagues in .

The regression rate of 50% "far exceeds the spontaneous regression rates reported for CIN3, ranging from 1.3%-30% within 2 to 24 months after the initial biopsy," they added.

Prior studies of therapeutic immunizations targeting E6 and E7 proteins in high-grade CIN patients resulted in regression rates ranging from 22% to 52% within a time frame of 1 to 6 months, the authors noted. They pointed out that a majority of those trials included both CIN2 and CIN3 patients, with the spontaneous regression rate of CIN3 significantly lower compared to that of CIN2.

Yigit and colleagues also reported that 10 of 16 patients (eight with regression and eight non-regressors) exhibited HPV16 clearance 19 weeks after the last vaccination, including all eight patients with histopathologic regression, as well as two non-regressors.

HPV clearance "plays a crucial role in the effectiveness of CIN3 management," they observed. "In our cohort, all the evaluable regressors and 25% of the evaluable non-regressors showed HPV16 clearance. Therefore, by eliminating HPV16, our vaccine not only has the potential to prevent recurrence among regressors, but also among non-responders."

The current standard of care for CIN3 is large loop excision of the transformation zone. This invasive procedure is associated with a higher risk of adverse obstetric outcomes, cervical stenosis, and postoperative complications including bleeding, vaginal discharge, and infection.

The E6 and E7 proteins are key oncogenes in the development of HPV-associated tumors, and therapeutic vaccines targeting HPV16 E6 and E7 tumor-specific antigens -- such as Vvax001 -- "represent an attractive, non-invasive alternative to the current invasive treatment of CIN lesions," Yigit and team explained.

This open-label study was conducted at the University Medical Centre Groningen and enrolled patients between March 2021 and August 2023. Median age was 32.5 years, and 12 of 18 patients had a single HPV16 infection at baseline. Two-thirds of patients were non-smokers, and 50% had a history of CIN1-2 for which active surveillance was indicated without treatment.

Patients received three immunizations of Vvax001 at 3-week intervals. It was administered as two injections -- one intramuscular injection of 1 mL into each upper leg. Patients were monitored for regression of CIN3 by colposcopy for up to 19 weeks after the last immunization. A colposcopy-guided biopsy was taken at the last visit and large loop excision was performed only in case of remaining CIN2/3.

Immunizations were safe and well tolerated, with no reported grade >3 treatment-related adverse events. Besides local injection site reactions, swollen lymph nodes in groins, malaise/fatigue, and myalgia were observed, with all treatment-related adverse events resolved without intervention within a median of 3 days.

Comment