Safety, efficacy, and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a randomised, double-blind, placebo-controlled phase 2b trial

Abstract

Summary Background Despite preventive vaccines for oncogenic human papillomaviruses (HPVs), cervical intraepithelial neoplasia (CIN) is common, and current treatments are ablative and can lead to long-term reproductive morbidity. We assessed whether VGX-3100, synthetic plasmids targeting HPV-16 and HPV-18 E6 and E7 proteins, delivered by electroporation, would cause histopathological regression in women with CIN2/3. Methods Efficacy, safety, and immunogenicity of VGX-3100 were assessed in CIN2/3 associated with HPV-16 and HPV-18, in a randomised, double-blind, placebo-controlled phase 2b study. Patients from 36 academic and private gynaecology practices in seven countries were randomised (3:1) to receive 6 mg VGX-3100 or placebo (1 mL), given intramuscularly at 0, 4, and 12 weeks. Randomisation was stratified by age (<25 vs ≥25 years) and CIN2 versus CIN3 by computer-generated allocation sequence (block size 4). Funder and site personnel, participants, and pathologists were masked to treatment. The primary efficacy endpoint was regression to CIN1 or normal pathology 36 weeks after the first dose. Per-protocol and modified intention-to-treat analyses were based on patients receiving three doses without protocol violations, and on patients receiving at least one dose, respectively. The safety population included all patients who received at least one dose. The trial is registered at ClinicalTrials.gov (number NCT01304524) and EudraCT (number 2012-001334-33). Findings Between Oct 19, 2011, and July 30, 2013, 167 patients received either VGX-3100 (n=125) or placebo (n=42). In the per-protocol analysis 53 (49.5%) of 107 VGX-3100 recipients and 11 (30.6%) of 36 placebo recipients had histopathological regression (percentage point difference 19.0 [95% CI 1.4–36.6]; p=0.034). In the modified intention-to-treat analysis 55 (48.2%) of 114 VGX-3100 recipients and 12 (30.0%) of 40 placebo recipients had histopathological regression (percentage point difference 18.2 [95% CI 1.3–34.4]; p=0.034). Injection-site reactions occurred in most patients, but only erythema was significantly more common in the VGX-3100 group (98/125, 78.4%) than in the placebo group (24/42, 57.1%; percentage point difference 21.3 [95% CI 5.3–37.8]; p=0.007). Interpretation VGX-3100 is the first therapeutic vaccine to show efficacy against CIN2/3 associated with HPV-16 and HPV-18. VGX-3100 could present a non-surgical therapeutic option for CIN2/3, changing the treatment outlook for this common disease. Funding Inovio Pharmaceuticals.

The importance of correctly timing cancer immunotherapy

“…Vaccination with a HPV16 E6-E7-L2 fusion protein vaccine in combination with Aldara treatment also achieved clinical success in patients with this disease [34]. Moreover, treatment of high-grade premalignant lesions of the cervix was efficacious when the patients received a DNA vaccine targeting the HPV16 oncoproteins [35]. Moreover, vaccination of patients with HER + breast ductal carcinoma in situ resulted in measurable decreases of residual ductal carcinoma [36].…”

Potent therapeutic efficacy of an alphavirus replicon DNA vaccine expressing human papilloma virus E6 and E7 antigens

“…29,30 The potent anti-tumor effect of DREP is likely also attributable to enhanced in vivo delivery using EP previously shown to be superior above others in the case of HPV vaccination. 31,32 Intradermal administration of DREP-E6,7 with in vivo EP significantly increased E7-specific T cell frequencies above that of pVAX. The immunogenicity of the two DNA vectors was compared with equivalent molar doses administered.…”

GTL001, A Therapeutic Vaccine for Women Infected with Human Papillomavirus 16 or 18 and Normal Cervical Cytology: Results of a Phase I Clinical Trial

“…In addition, GTL001 appeared to induce an imiquimod-enhanced E7-specific T-cell response. Although effector T-cell responses in the blood are weak, require ex vivo sensitization to be detected and have been considered to not reflect the T-cell response at the site of infection in the cervix or reliably identify persons whose lesions will regress (9), a recent study showed that peripheral ELISpot responses generated by a therapeutic synthetic DNA vaccine statistically correlated with high-grade lesion regression (13). Whether this is the case with GTL001 will be investigated in future clinical trials.…”

“…Clearance rates in other clinical trials have ranged from 23% to 37% for the active treatment versus 0% to 14% for placebo (34)(35)(36). A more recent randomized trial showed higher rates of clearance (approximately 80%) with both the DNA vaccine VGX-3100 and the placebo (approximately 50%), although this may have been due to the calculations being limited to patients with histopathologic regression (13). It is important to note, however, that clearance at a single time point is not the same as sustained clearance and, furthermore, that assays, experimental conditions, and thresholds differ, so that the sustained clearance rates determined in this study cannot be compared directly with the clearance rates reported elsewhere.…”

“…Several have shown promise in treating vulvar and high-grade CIN, and some induce cellular immunity against HPV, but these vaccines have only been tested in women who already have high-grade lesions. For example, recent studies showed that two therapeutic DNA vaccines, one targeting HPV16 and HPV18 E6 and E7 (13) and the other targeting HPV16 E7 (14), can induce regression of CIN2/3. GTL001 is a candidate therapeutic vaccine that targets HPV16 and HPV18, which are associated with the highest risk of developing CIN3 and cervical cancer (15).…”