HPV DNA Vaccine for HPV-Related Cervical Disease

Recruiting at 1 trial location

Overseen By Warner K Huh, MD

Age: 18+

Sex: Female

Trial Phase: Phase 1

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Must be taking: Antiretroviral therapy

Must not be taking: Immunosuppressants, Immune-modifying drugs

Disqualifiers: HPV16 negative, Hepatitis B/C, Autoimmune, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 3

Duration: 3 weeks

48 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new HPV DNA vaccine (pNGVL4aCRTE6E7L2) to determine its safety and tolerability. It focuses on women with high-grade cervical cell changes caused by HPV 16, a virus linked to cervical diseases. The trial includes three groups, each receiving different vaccine doses to identify the safest amount. Women diagnosed with these cell changes, whether HIV positive or negative, may be suitable for the trial. As a Phase 1 trial, participants will be among the first to receive this new treatment, aiding researchers in understanding its effects in people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on chronic immunosuppressants or immune-modifying drugs, you may not be eligible to participate.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that the pNGVL4aCRTE6E7L2 DNA vaccine is generally well-tolerated. Studies with similar HPV DNA vaccines have not reported severe side effects, suggesting the treatment is safe. Researchers are testing the vaccine at three different dose levels to confirm this. The primary focus has been on monitoring for any serious side effects that might limit the dose, and these have not been common. Overall, the vaccine appears safe for those considering joining a trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about the HPV DNA vaccine, pNGVL4aCRTE6E7L2, because it represents a novel approach to treating HPV-related cervical diseases. Unlike current treatments, which primarily focus on removing or destroying affected tissue, this vaccine aims to stimulate the body's immune system to target and eliminate HPV-infected cells. The vaccine is designed with components like E6, E7, and L2 proteins from the HPV virus, which help train the immune system to recognize and attack the virus more effectively. This immunotherapeutic approach could not only treat existing infections but also potentially prevent future HPV-related diseases, offering a dual benefit over traditional methods.

What evidence suggests that this vaccine might be an effective treatment for HPV-related cervical disease?

Research has shown that DNA vaccines like pNGVL4aCRTE6E7L2, administered at different dose levels in this trial, are generally safe for people. This vaccine specifically targets HPV16, a common virus linked to cervical conditions such as CIN II and III. It helps the immune system recognize and fight cells infected with HPV. Early results from other studies indicate that similar vaccines can help reduce HPV-related lesions. Although more research is needed to confirm its full effectiveness, its mechanism suggests promise for treating HPV-related cervical disease. ^{2 5 6 7 8}

Who Is on the Research Team?

Kimberly Levinson, MD

Principal Investigator

Johns Hopkins University

Are You a Good Fit for This Trial?

This trial is for adult women (19+ years) with high-grade cervical lesions (CIN2/3) that are HPV16 positive. It includes both HIV-negative and HIV-positive participants who have controlled their condition, with specific blood count levels and normal organ function. Pregnant or breastfeeding women, those allergic to similar vaccines, or with certain health conditions are excluded.

Inclusion Criteria

Participant is able to adhere to the study visit schedule and other protocol requirements.

Life expectancy of greater than 4 months.

I am a woman capable of becoming pregnant.

Exclusion Criteria

Individuals in which a skin-fold measurement of the cutaneous and subcutaneous tissue for all eligible injection sites (deltoid muscles with intact lymph drainage) exceeds 40 mm.

I do not have any ongoing or chronic neurological conditions, except for a one-time fever-related seizure in childhood.

My cervical condition is severe but not caused by HPV16.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive the pNGVL4aCRTE6E7L2 DNA vaccine via intramuscular injection with TriGrid™ electroporation. The treatment involves dose escalation to evaluate safety across three dosing levels: 0.3 mg, 1.0 mg, and 3.0 mg.

3 weeks

3 visits (in-person, one per dosing level)

Follow-up

Participants are monitored for safety and effectiveness after treatment, focusing on dose limiting toxicities.

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• pNGVL4aCRTE6E7L2

Trial Overview The study tests the safety and tolerability of a new HPV DNA vaccine called pNGVL4aCRTE6E7L2 delivered by injection with electroporation in women diagnosed with CIN II or III caused by HPV16. The trial will include both HIV-negative and HIV-positive subjects.

How Is the Trial Designed?

Group I: Vaccination Arm Level 3 Experimental Treatment 1 Intervention

The dose escalation of pNGVL4aCRTE6E7L2 will be conducted to evaluate the safety of three escalating doses; level 3 dose of 3.0 mg

Group II: Vaccination Arm Level 2 Experimental Treatment 1 Intervention

The dose escalation of pNGVL4aCRTE6E7L2 will be conducted to evaluate the safety of three escalating doses; level 2 at dose 1.0 mg

Group III: Vaccination Arm Level 1 Experimental Treatment 1 Intervention

The dose escalation of pNGVL4aCRTE6E7L2 will be conducted to evaluate the safety of three escalating doses; Level 1 dose of 0.3 mg

Who Is Running the Clinical Trial?

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lead Sponsor

Trials

578

Recruited

33,600+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

The novel DNA vaccine encoding the HPV-16 consensus E6/E7 fusion gene (pConE6E7) was found to be up to five times more effective than an earlier HPV-16 E7 vaccine in generating specific immune responses against the virus.

Prophylactic use of this vaccine provided complete protection against tumors expressing HPV E6 and E7, and it also showed promise in delaying tumor growth in therapeutic settings, suggesting its potential for enhancing antitumor immunity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Induction of antitumor immunity in vivo following delivery of a novel HPV-16 DNA vaccine encoding an E6/E7 fusion antigen. Yan, J., Reichenbach, DK., Corbitt, N., et al.[2022]

A new therapeutic HPV DNA vaccination strategy using the HPV-16 E7 antigen has been shown to enhance immune responses, specifically targeting CD8+ and CD4+ T cells, which are crucial for fighting tumors.

This approach demonstrated a strong anti-tumor effect against HPV-expressing tumors, suggesting that further research into HPV therapeutic vaccines could lead to effective treatments for cervical cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic human papillomavirus DNA vaccination strategies to control cervical cancer. Wu, TC.[2007]

The HPV16-DNA-E6E7 vaccine candidate effectively induced a specific immune response against HPV16 and provided significant protection against tumors in C57BL/6 mice, with a survival rate of 90% after 45 days post-tumor challenge.

The vaccine showed no harmful transforming activity, indicating its safety, and higher doses (200 microg) resulted in prolonged survival, suggesting its potential as a viable option for HPV16-related cancer prevention and treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A DNA vaccine constructed with human papillomavirus type 16 (HPV16) E7 and E6 genes induced specific immune responses. Yan, Q., Cheung, YK., Cheng, SC., et al.[2019]

The updated review of HPV vaccines, including the nonavalent (9vHPV) vaccine, analyzed data from 109 studies involving over 2.5 million vaccinated individuals and confirmed that all HPV vaccines have an acceptable safety profile.

There was no consistent evidence linking the 9vHPV vaccine to increased risks of adverse events of special interest, such as neurological conditions, reinforcing the favorable risk-benefit profile for HPV vaccination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of Human Papillomavirus Vaccines: An Updated Review. Phillips, A., Patel, C., Pillsbury, A., et al.[2018]

The study developed a therapeutic DNA vaccine (pCTLA4-E7E6) that combines CTLA-4 with HPV16 E7 and E6, showing significantly improved immune responses and anti-tumor effects in mice with TC-1 tumors compared to a non-fusion vaccine (pE7E6).

This research highlights the potential of using CTLA-4 fusion in therapeutic HPV vaccines, although it also notes that fusing the two HPV proteins (E7 and E6) can impair their individual functions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fusion of CTLA-4 with HPV16 E7 and E6 enhanced the potency of therapeutic HPV DNA vaccine. Gan, L., Jia, R., Zhou, L., et al.[2021]

There are three licensed HPV vaccines: bivalent, quadrivalent, and nonavalent, with the nonavalent vaccine introduced in 2014, yet vaccination coverage remains low in many developed countries due to safety concerns.

This review aims to clarify the safety profiles of all three HPV vaccines by summarizing data from both pre- and post-licensure studies, particularly focusing on the newer nonavalent vaccine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of HPV vaccines in the age of nonavalent vaccination. Quattrone, F., Canale, A., Filippetti, E., et al.[2018]

A codon-optimized HPV-16 E6 DNA vaccine (pNGVL4a-E6/opt) was developed, showing highly efficient translation and significantly enhancing E6-specific CD8+ T cell immune responses in vaccinated mice.

Vaccination with this optimized E6 DNA vaccine resulted in strong protective and therapeutic anti-tumor effects against HPV-associated tumors, suggesting it could improve the effectiveness of HPV vaccines in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A DNA vaccine encoding a codon-optimized human papillomavirus type 16 E6 gene enhances CTL response and anti-tumor activity. Lin, CT., Tsai, YC., He, L., et al.[2006]

DNA therapeutic vaccines targeting HPV E6 and E7 oncoproteins have shown promising results in phase I and II trials, demonstrating safety and clinical efficacy in treating cervical cancer.

These vaccines not only induce a strong T-cell mediated immune response leading to cervical lesion regression and viral clearance, but they also offer advantages such as cost-effectiveness and ease of production, making them a viable option for long-term treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Efficacy of Therapeutic DNA Vaccines Expressing the Human Papillomavirus E6 and E7 Oncoproteins for Treatment of Cervical Cancer: Systematic Review. Akhatova, A., Chan, CK., Azizan, A., et al.[2022]

The newly developed pBI-11 DNA vaccine, which targets HPV16 and HPV18 E6 and E7 proteins, showed improved immune responses in mice compared to previous vaccine versions, indicating its potential efficacy in treating cervical cancer.

Combining the pBI-11 vaccine with a tissue-antigen HPV vaccine (TA-HPV) and PD-1 antibody blockade significantly enhanced tumor control and survival in mice, suggesting a promising strategy for future clinical applications in HPV-associated cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of DNA Vaccine Targeting E6 and E7 Proteins of Human Papillomavirus 16 (HPV16) and HPV18 for Immunotherapy in Combination with Recombinant Vaccinia Boost and PD-1 Antibody. Peng, S., Ferrall, L., Gaillard, S., et al.[2023]

The HPV16 DNA vaccine was found to be safe and well tolerated among 15 women with HPV16+ cervical intraepithelial neoplasia (CIN)2/3, with most side effects being mild and temporary, such as injection-site discomfort.

In the highest-dose group, 33% of participants experienced complete histologic regression of their lesions, which is slightly higher than the expected 25% regression rate in unvaccinated individuals, suggesting potential efficacy in promoting lesion regression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I trial of a human papillomavirus DNA vaccine for HPV16+ cervical intraepithelial neoplasia 2/3. Trimble, CL., Peng, S., Kos, F., et al.[2022]

The hCRTE6E7L2 DNA vaccine effectively induced a strong immune response in mice, specifically generating CD8+ T cells that target HPV16 E6 and E7 proteins, which are crucial for combating HPV-related tumors.

This vaccine also produced significant neutralizing antibodies against the HPV L2 protein, suggesting it could prevent new infections while also treating existing HPV-related diseases, highlighting its potential as both a preventive and therapeutic option for cervical cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Generation and characterization of a preventive and therapeutic HPV DNA vaccine. Kim, D., Gambhira, R., Karanam, B., et al.[2021]

The DNA vaccine encoding E7/HSP70 significantly increased E7-specific CD8+ T cell precursors and showed strong antitumor effects against HPV-16 expressing tumors in mice, indicating its potential for cancer immunotherapy.

Administering the DNA vaccine via a gene gun was found to be the most effective method, generating the highest number of E7-specific T cells and requiring a lower dose for similar or better antitumor effects compared to other administration methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the CD8+ T cell responses and antitumor effects generated by DNA vaccine administered through gene gun, biojector, and syringe. Trimble, C., Lin, CT., Hung, CF., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04131413

Study Details | NCT04131413 | HPV DNA Vaccine Via ... The primary goal of this phase I open label study is to determine the safety and tolerability of pNGVL4aCRTE6E7L2 DNA vaccine, as administered by intramuscular ...

2. reporter.nih.gov reporter.nih.gov/project-details/10490563

75N91019D00027-0-759102100001-1 A Phase I Open Label, Dose Escalation Clinical Trial Assessing the Safety, Tolerability, and Feasibility of pNGVL4aCRTE6E7L2 HPV DNA Vaccine Administration Via ...

3. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2024-00827

A Pair of Vaccinations (pNGVL4aCRTE6E7L2) and (TA ... Giving the pNGVL4aCRTE6E7L2 vaccine together with the TA-CIN vaccine may be safe, tolerable and/or effective in treating patients with HPV16 positive cervical ...

4. withpower.com withpower.com/trial/phase-1-carcinoma-in-situ-8-2020-1983a

HPV DNA Vaccine for HPV-Related Cervical Disease The HPV DNA vaccines, including those similar to pNGVL4aCRTE6E7L2, have been shown to be well-tolerated in clinical trials, meaning they are generally safe for ...

5. labs.pathology.jhu.edu labs.pathology.jhu.edu/ccspore/project-3/

Project 3 – SPORE in Cervical Cancer - Pathology Labs Our goalis to test the safety and toxicity of a therapeutic HPV vaccine, the CRTE6E7L2 DNA vaccine, delivered intramuscularly (IM) via the TriGrid ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04131413

Study Details | NCT04131413 | HPV DNA Vaccine Via ... The safety and tolerability of pNGVL4aCRTE6E7L2 DNA vaccine will be determined using the number of participants experiencing dose limiting toxicities at ...

7. gynecologiconcology-online.net gynecologiconcology-online.net/article/S0090-8258(24)00794-7/fulltext

Phase I clinical trial to assess the safety of ... Phase I clinical trial to assess the safety of pNGVL4aCRTE6E7L2 DNA and TA-CIN protein vaccinations and to seek the appropriate dose of the pNGVL4aCRTE6E7L2 DNA ...

8. reporter.nih.gov reporter.nih.gov/project-details/10535434

Mouse modeling of HPV infection - NIH RePORTER Many groups are bringing candidate therapeutic HPV vaccines to the clinic, including our pNGLV4aCRTE6E7L2 DNA, but to date there has been limited success in ...