Hold Up, HPV: How Therapeutic Vaccines Can Help Curb Cervical Premalignancies

Since their adoption nearly 20 years ago, preventive human papilloma virus (HPV) vaccines have dramatically reduced the rates of HPV infection and cervical precancers, especially in young women. Despite our progress, almost 14,000 new cases of cervical cancer are still diagnosed each year in the United States, and almost all are linked to HPV. 

However, if we could catch HPV infection in the earliest stages of its malignant transformation of the cervix, perhaps we could halt its spread and even curb the cervical cancers that arise from infection. 

To that end, a new study published in the American Association for Cancer Research (AACR) journal Clinical Cancer Research shows that a therapeutic vaccine might offer protection to those who have already developed precancerous lesions due to HPV infection. In contrast to preventive HPV vaccines given prior to exposure, therapeutic HPV vaccines are designed to target and eliminate HPV-infected cells that have potentially begun their march to malignancy. 

Halting HPV-driven Cervical Oncogenesis  

The progression of cervical tissue toward malignancy is categorized into three stages, based on the extent of the cervical intraepithelial neoplasia (CIN). CIN1 is the least severe, followed by CIN2, and then CIN3, which is the most abnormal precancerous condition that covers severe dysplasia on the verge of malignancy. 

Patients with CIN3 are typically treated with a surgical technique known as loop electrosurgical excision procedures (LEEP), also referred to as large loop excision of the transformation zone (LLETZ). 

“The main purpose of our trial was to investigate whether our therapeutic vaccine—Vvax001—could offer a potential alternative treatment to the standard-of-care loop excision surgery, which is frequently associated with complications,” said Refika Yigit, MD, principal investigator and oncological gynecologist at University Medical Centre Groningen in the Netherlands, who co-led the work with her colleagues Hans W. Nijman, MD, PhD, and Marco de Bruyn, PhD. 

When administered to those with CIN3, the results were remarkable. Lesions shrunk in 17 of the 18 patients, most within a month. More importantly, half had clinical regressions, with three no longer showing any signs of precancer. 

“To the best of our knowledge, this response rate makes Vvax001 one of the most effective therapeutic vaccines for HPV16-associated CIN3 lesions reported to date,” said Yigit. 

And the real rate might be even higher. Biopsies were conducted 19 weeks after vaccination, but of the nine patients whose biopsies showed no regression then, four later had little to no signs of residual disease when they subsequently underwent surgery. 

“If confirmed in a larger trial, our results could mean that at least half of these patients with CIN3 might be able to omit surgery and avoid all its possible side effects and complications,” Yigit declared. 

The team also examined the immune landscape of these patients, finding that most with regression had T cells that were “excluded” and waiting at the perimeter of their lesions prior to vaccination. Due to how well many responded and the lack of lesion at the time of biopsy, deeper analysis of the T cells that infiltrated after vaccination proved hard. In contrast, the lesions that did not regress were immune “deserts” with no substantial T-cell presence even at the periphery of the diseased tissue.  

HPV Clearance and Long-term Protection 

In standard care, HPV clearance is closely linked to a reduced risk of recurrence, and circulating HPV DNA can be used for early detection of cervical cancer relapse. Of the 16 patients evaluated in this regard in the Vvax001 trial, 10 cleared HPV16, including all those whose disease regressed. Intriguingly, two patients whose disease did not regress also cleared HPV16, though their lesions harbored, and were presumably driven by, other HPV strains. 

Half of the Vvax001-treated patients have now been followed for at least 20 months post-vaccination, with no recurrences reported among the 18 participants—a hopeful sign of the vaccine’s durable benefits. 

“To that end, we observed HPV-specific T cells up to 19 weeks after the last immunization,” said Yigit. “In patients where HPV was cleared, we expect the anti-HPV immune response to have resolved and the HPV-specific T cells we observe to represent long-term protective immune cells critical for reducing the likelihood of recurrence. However, longer follow-up will be needed to confirm this hypothesis, ideally in a larger set of patients.” 

By expanding the toolbox of cervical cancer prevention and treatment, researchers are also paving the way for more personalized and less invasive care. Therapeutic vaccines like Vvax001, which target existing infections and promote long-term immune responses, offer new hope to patients while reducing the need for surgical interventions and their associated complications. 

Complementary HPV Vaccine Strategies 

Preventive vaccines like Gardasil cast a wide protective net against several of the most common high-risk HPV strains—the latest version of Gardasil targets nine HPV strains, covering those responsible for around 90% of cervical cancers globally.  

These preventive vaccines are designed to stop infections before they begin, by stopping the virus from entering cells and integrating into a cell’s genome, which enables the virus to make copies of itself. However, once HPV has infected cells, these preventive vaccines are ill-equipped to clear the virus completely. Thus, therapeutic solutions are essential for those who are already infected and at greater risk of disease progression. 

That’s where therapeutic HPV vaccines, several types of which are in clinical trials for a variety of anogenital precancers, come in. They are designed to elicit a more focused immune response against a foe that has already breached cellular defenses. 

Vvax001 uses a modified Semliki Forest virus that cannot replicate but produces the proteins E6 and E7, which are only made by HPV16-infected cells. Notably, two participants also experienced clearance of other HPV strains, suggesting the vaccine’s potential ability to promote antigen spread and broader immune surveillance. 

There is also evidence that prophylactic HPV vaccines can provide even greater protection to patients whose precancerous lesions are surgically removed, according to a recent practice advisory from the American College of Obstetricians and Gynecologists. 

This strategy could be particularly valuable across various patient populations and stages of disease progression. By leveraging the preventive capabilities of vaccines like Gardasil 9 in a post-surgery setting, clinicians can help bolster the immune system’s ability to prevent lingering high-risk HPV strains from gaining a foothold and triggering recurrence. Studies are underway to confirm the long-term benefits of this dual approach, which could continue to transform the current treatment paradigm for HPV-related anogenital diseases. 

Toward a Comprehensive Approach to Cervical Cancer 

With ongoing research, broader implementation, and continued refinement, therapeutic HPV vaccines could redefine the standard-of-care, complementing preventive measures and ultimately offering protection to everyone—from those who are still free of infection to those already facing advanced disease. As these approaches evolve, they underscore the transformative power of science and innovation in the fight against cervical cancer, and are helping to move us closer to a future where deaths from the disease become exceedingly rare.