Feature

Vaccine shows potential against cervical precancer, HPV infection

Harper_Diane_80x106
Diane M. Harper

An investigational therapeutic vaccine eliminated high-grade cervical intraepithelial neoplasia and underlying HPV infection among one-third of women in a phase 2 trial, according to study results.

The vaccine includes a specific protein that triggers an immune system response to attack high-risk HPV types that have already caused severe CIN.

“There are very few products trying to cure women who already have an HPV infection,” Diane M. Harper, MD, MPH, MS, professor of family medicine and obstetrics and gynecology at University of Michigan, said in a press release. “This is the first time we have seen something with this success rate that is relatively easy to implement.”

Researchers randomly assigned 192 women with CIN grade 2 or CIN grade 3 lesions to receive the vaccine (n = 129) or placebo (n = 63).

Compared with women in the placebo group, those in the vaccine group achieved more than twice the rate of complete resolution of CIN grade 2 and CIN grade 3 (10% vs. 24%; P < .05), regardless of HPV infection type. Moreover, researchers observed higher viral DNA clearance with the vaccine when compared with placebo (P < .01).

HemOnc Today spoke with Harper about what makes this vaccine unique, the safety and efficacy observed so far, and what still must be confirmed in subsequent research.

Question: How does the vaccine work?

Answer: The vaccine is made up of a carrier virus that has been deactivated and is no longer pathogenic. We insert three different genes into the virus —a human cytokine gene that causes inflammation and activation of the immune system, and the HPV16 E7 protein and HPV16 E6 protein, which are no longer oncogenic. This virus is then injected subcutaneously into the woman’s thigh at 1-week intervals for a total of 3 weeks. The vaccine primes T cells to be able to fight the HPV-infected cells. This vaccine is unique because it not only destroys the abnormal cells, but also the HPV infection, which is a very different mode of action than currently exists for women with precancerous disease.

Q: How did you conduct the study?

A: We invited women aged 18 years and older who had either a CIN grade 2 or CIN grade 3 lesion to participate in the study. We screened to check which HPV type was associated with their lesions so that they could be enrolled in the appropriate arm of the trial. We overenrolled women in the HPV16 group and stratified enrollment for other HPV types. This allowed us to investigate post-hoc whether it was important that the E6 protein and E7 protein were HPV16-related. Women were enrolled in a 2:1 ratio and followed for 2.5 years after vaccination. Six months later, all women were treated with standard surgical procedures for CIN grade 2 and CIN grade 3 lesions, and the removed tissue was examined.

Q: What did you find?

A: We observed quicker clearance of the virus, regardless of HPV type, which was maintained for 2.5 years. We observed complete resolution of CIN grade 3 in 36% of one group of women, whereas the placebo arm had 0% complete resolution. Post-hoc, we found that it was not important that the E6 protein and E7 protein came from HPV16. Thus, we have something that is novel and exciting for women.

In addition, although our original hypothesis set the bar at 60% CIN grade 2 and CIN grade 3 complete histologic resolution for HPV16 at twice the placebo clearance rate for HPV16, we found post-hoc that all CIN grade 3 lesions, regardless of HPV type, completely cleared at more than twice the rate of placebo for the same infection group. We reached a 36% complete clearance rate of CIN grade 3 and complete viral clearance in these women, which is amazing. The vaccine was well-tolerated, with the most common adverse events being injection site reactions.

The 36% complete clearance rate could offer women an option of therapy that is not surgical. We know that loop electrosurgical excision procedure or conization is associated with preterm birth, cesarean sections and low-birth weight infants, as well as scarring and inability to identify the transformation zone in subsequent surveillance. In addition, the surgical procedure does not treat the HPV infection. We are hearing from women that they would like an option that is twice as good as placebo as a first step toward viral clearance and lesion treatment. If it fails, then they will go to the surgical intervention.

Q: What would having a vaccine like this mean for clinical practice?

A: This means that we are able to not only identify women with a precancerous lesion through screening systems, but also to provide treatment to women who have an HPV infection that caused a precancerous lesion without the use of surgery. This means that primary care physicians in the U.S. and western Europe, as well as health care workers in developing countries, have a nonsurgical method that could reduce the burden of cervical cancer. This could allow surgeons more capacity to treat the more advanced cancers that escape prevention.

Q: What still needs to be confirmed in subsequent research?

A: We would like to test this compound further or look into changing the E6 and E7 proteins of the virus particle. We may be able to tweak these proteins so that they can be more immunogenic to a greater proportion of women. The positive results of this trial can help inform what we put into the carrier virus the next time around.

Q: How soon before we see this in practice?

A: We are not yet at a phase 3 trial, so we still have to figure out whether or not we will take this vaccine forward. Regardless, I think that these results are incredibly encouraging. – by Jennifer Southall

Reference:

Harper DM, et al. Gynecol Oncol. 2019;doi:10.1016/j.ygyno.2019.03.250.

For more information:

Diane M. Harper, MD, MPH, MS, can be reached at University of Michigan, 1018 Fuller St., Ann Arbor, MI 48102; email: harperdi@med.umich.edu.

Disclosure: Harper reports no relevant financial disclosures.

Harper_Diane_80x106
Diane M. Harper

An investigational therapeutic vaccine eliminated high-grade cervical intraepithelial neoplasia and underlying HPV infection among one-third of women in a phase 2 trial, according to study results.

The vaccine includes a specific protein that triggers an immune system response to attack high-risk HPV types that have already caused severe CIN.

“There are very few products trying to cure women who already have an HPV infection,” Diane M. Harper, MD, MPH, MS, professor of family medicine and obstetrics and gynecology at University of Michigan, said in a press release. “This is the first time we have seen something with this success rate that is relatively easy to implement.”

Researchers randomly assigned 192 women with CIN grade 2 or CIN grade 3 lesions to receive the vaccine (n = 129) or placebo (n = 63).

Compared with women in the placebo group, those in the vaccine group achieved more than twice the rate of complete resolution of CIN grade 2 and CIN grade 3 (10% vs. 24%; P < .05), regardless of HPV infection type. Moreover, researchers observed higher viral DNA clearance with the vaccine when compared with placebo (P < .01).

HemOnc Today spoke with Harper about what makes this vaccine unique, the safety and efficacy observed so far, and what still must be confirmed in subsequent research.

Question: How does the vaccine work?

Answer: The vaccine is made up of a carrier virus that has been deactivated and is no longer pathogenic. We insert three different genes into the virus —a human cytokine gene that causes inflammation and activation of the immune system, and the HPV16 E7 protein and HPV16 E6 protein, which are no longer oncogenic. This virus is then injected subcutaneously into the woman’s thigh at 1-week intervals for a total of 3 weeks. The vaccine primes T cells to be able to fight the HPV-infected cells. This vaccine is unique because it not only destroys the abnormal cells, but also the HPV infection, which is a very different mode of action than currently exists for women with precancerous disease.

Q: How did you conduct the study?

A: We invited women aged 18 years and older who had either a CIN grade 2 or CIN grade 3 lesion to participate in the study. We screened to check which HPV type was associated with their lesions so that they could be enrolled in the appropriate arm of the trial. We overenrolled women in the HPV16 group and stratified enrollment for other HPV types. This allowed us to investigate post-hoc whether it was important that the E6 protein and E7 protein were HPV16-related. Women were enrolled in a 2:1 ratio and followed for 2.5 years after vaccination. Six months later, all women were treated with standard surgical procedures for CIN grade 2 and CIN grade 3 lesions, and the removed tissue was examined.

PAGE BREAK

Q: What did you find?

A: We observed quicker clearance of the virus, regardless of HPV type, which was maintained for 2.5 years. We observed complete resolution of CIN grade 3 in 36% of one group of women, whereas the placebo arm had 0% complete resolution. Post-hoc, we found that it was not important that the E6 protein and E7 protein came from HPV16. Thus, we have something that is novel and exciting for women.

In addition, although our original hypothesis set the bar at 60% CIN grade 2 and CIN grade 3 complete histologic resolution for HPV16 at twice the placebo clearance rate for HPV16, we found post-hoc that all CIN grade 3 lesions, regardless of HPV type, completely cleared at more than twice the rate of placebo for the same infection group. We reached a 36% complete clearance rate of CIN grade 3 and complete viral clearance in these women, which is amazing. The vaccine was well-tolerated, with the most common adverse events being injection site reactions.

The 36% complete clearance rate could offer women an option of therapy that is not surgical. We know that loop electrosurgical excision procedure or conization is associated with preterm birth, cesarean sections and low-birth weight infants, as well as scarring and inability to identify the transformation zone in subsequent surveillance. In addition, the surgical procedure does not treat the HPV infection. We are hearing from women that they would like an option that is twice as good as placebo as a first step toward viral clearance and lesion treatment. If it fails, then they will go to the surgical intervention.

Q: What would having a vaccine like this mean for clinical practice?

A: This means that we are able to not only identify women with a precancerous lesion through screening systems, but also to provide treatment to women who have an HPV infection that caused a precancerous lesion without the use of surgery. This means that primary care physicians in the U.S. and western Europe, as well as health care workers in developing countries, have a nonsurgical method that could reduce the burden of cervical cancer. This could allow surgeons more capacity to treat the more advanced cancers that escape prevention.

Q: What still needs to be confirmed in subsequent research?

A: We would like to test this compound further or look into changing the E6 and E7 proteins of the virus particle. We may be able to tweak these proteins so that they can be more immunogenic to a greater proportion of women. The positive results of this trial can help inform what we put into the carrier virus the next time around.

PAGE BREAK

Q: How soon before we see this in practice?

A: We are not yet at a phase 3 trial, so we still have to figure out whether or not we will take this vaccine forward. Regardless, I think that these results are incredibly encouraging. – by Jennifer Southall

Reference:

Harper DM, et al. Gynecol Oncol. 2019;doi:10.1016/j.ygyno.2019.03.250.

For more information:

Diane M. Harper, MD, MPH, MS, can be reached at University of Michigan, 1018 Fuller St., Ann Arbor, MI 48102; email: harperdi@med.umich.edu.

Disclosure: Harper reports no relevant financial disclosures.

    See more from Immuno-Oncology Resource Center