Objective
We sought to evaluate the safety and efficacy of TG4001 in patients with human papillomavirus (HPV) 16–related cervical intraepithelial neoplasia (CIN) 2/3 at 6 and 12 months.
Study Design
In all, 21 patients with HPV 16–related CIN 2/3 received 3 weekly subcutaneous injections of TG4001. Regression of the CIN 2/3 lesion and the clearance of HPV 16 infection were monitored by cytology, colposcopy, and HPV DNA/messenger RNA (mRNA) detection. A clinical response was defined by no CIN 2/3 found on conization, or no conization performed because not suspected at cytology or colposcopy.
Results
Ten patients (48%) were evaluated as clinical responders at month 6. Nine patients experienced an improvement of their HPV 16 infection, by mRNA ± DNA eradication. HPV 16 mRNA clearance was associated with CIN 2/3 cytologic and colposcopic regression in 7 of 10 patients. At month 12, 7 of 8 patients without conization reported neither suspicion of CIN 2/3 relapse nor HPV 16 infection. The remaining patient was lost to follow-up.
Conclusion
These promising data warrant further development of TG4001 in CIN 2/3 treatment.
Cervical cancer arises from moderate and severe cervical intraepithelial neoplasia (CIN) 2/3, which has been shown to be induced by persistent high-risk (HR) human papillomavirus (HPV) infection, particularly HPV 16. In France, HPV 16 was found to be responsible for 62% of CIN 2/3 and 73% of invasive cervical cancer. Eight times more CIN 2/3 is managed every year in French public and private hospitals than invasive cancers, accounting for a public health problem. Current treatment for CIN 2/3 is limited to excision procedures, which are associated with a short-term efficacy rate of about 90%. However, obstetrical complications and recurrence after excision may occur, with >30% of the patients being positive for HR-HPV types during the follow-up. It has been shown that the 2-year cumulative risk of posttreatment CIN 2/3 was 37% for HPV 16, 11% for other HR-HPV types, and only 1.5% for low-risk HPV types.
Because of the frequency and the severity of the lesions induced by this genotype, HPV 16 is the main target of prophylactic vaccination. Randomized clinical trials have shown that both bivalent (types 16 and 18) and quadrivalent (types 6, 11, 16, and 18) HPV L1 viruslike particle vaccines were safe and effective against HPV 16/18–related CIN 2/3 in HPV-naïve women. However, prophylactic vaccines are not effective in women already infected with HPV 16 or 18. Indeed, both vaccine efficacies fell to 30-52% in intention-to-treat populations comprising women with or without a prevalent infection. In addition, in women infected with HPV 16/18, the viral clearance was not significantly different at 6 months (35% vs 31%) and 12 months (53% vs 55%) after injection of bivalent vaccine or placebo, respectively.
Targeted immunotherapy was therefore developed as an alternative to cervical loop excision and cold-knife conization in patients diagnosed with a CIN 2/3 lesion. The American Association of Cancer Research Task Force on the Treatment and Prevention of Intraepithelial Neoplasia suggested that reaching a 50% regression rate would be clinically meaningful in the setting of high-grade cervical intraepithelial lesions. Moreover, even if the worldwide population was covered by prophylactic vaccination, it would take decades to decrease the incidence of CIN 2/3. By treating patients who are already infected with or without a lesion, therapeutic vaccines/targeted immunotherapeutics would be a means of bridging this gap.
This study aimed to evaluate the safety and 6-month efficacy of the TG4001 targeted immunotherapeutics in patients with HPV 16–related CIN 2/3, with a follow-up of responders up to 12 months after lesion diagnosis and TG4001 administration.
Materials and Methods
Study design and patient enrollment
In this single-arm, multicenter phase II trial, patients were recruited by the gynecological outpatient departments of 8 participating hospitals in France from 2004 through October 2005 for management of high-grade CIN. The study design was approved by the ethics committee of all participating centers. Written informed consent was obtained from each patient.
Patients were enrolled in the study if they met the following inclusion criteria: age ≥25 years, lesion entirely visualized by colposcopy, CIN 2/3 histologically confirmed by colposcopy-directed punch biopsy, and HPV 16 positivity detected by polymerase chain reaction on the baseline biopsy specimen.
Exclusion criteria were as follows: history of CIN 2/3 management; coinfection with HPV 18, HPV 31, or HPV 33; active systemic infectious disease (human immunodeficiency virus [HIV], Hepatitis B virus, Hepatitis C virus); steroid therapy or any other immunomodulating concomitant treatment; pregnancy or breast-feeding; and allergy to eggs due to chick embryo fibroblasts being used in TG4001 production. Patients were asked to avoid pregnancy until 3 months after the last TG4001 injection.
Targeted immunotherapeutic formulation and administration
TG4001 is a suspension of MVATG8042 vector particles consisting of an attenuated recombinant vaccinia virus, modified vaccinia virus of Ankara, containing the sequence coding for the modified E6 and E7 early genes of HPV 16 and human interleukin-2 gene, as shown in Figure 1 . E6 and E7 sequences were mutated to eliminate their oncogenic properties.
The final product, a suspension of MVATG8042 vector particles, is filled into glass ampoules stored at −70°C. The human dose is expressed in plaque-forming units (pfu).
Patients received 3 subcutaneous injections of TG4001 at the dose of 5 × 10 7 pfu. Each dose was administered on right and left thighs alternately on days 1, 8, and 15. Patients were monitored for 30 minutes after each injection before leaving hospital.
Patient follow-up between TG4001 administration and efficacy evaluation
After enrollment, at TG4001 administration (month 0) and at each follow-up period (months 2, 4, and 6), patients underwent a colposcopy and 2 liquid-based samples were taken with the ThinPrep collection device (Cytyc Corp, Boxborough, MA). One was taken from the transformation zone and the other from the posterior cul-de-sac to collect enough material to be able to perform cytology and to assess virologic parameters as described in Table 1 . All samples collected at each study site were submitted to the central laboratory (Laboratoire Pol Bouin, Reims, France) for processing of cytology and HPV testing. A cervical biopsy was taken in case of an unexpected change of the lesion at colposcopy, which could be evocative of a progression or if the colposcopic impression and the cytologic results were not congruent at any time point. Results were reported using CIN classification.
| Methods | Description | Results |
|---|---|---|
| Colposcopy |
|
|
| Cytology |
|
|
| High-risk HPV DNA detection |
|
Identification of at least 1 of 13 high-risk HPV types (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68) |
| Specific HPV DNA detection |
|
Identification of 15 high-risk types (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82), 3 probable high-risk types (HPV 26, 53, and 66), 10 low-risk types (HPV 6, 11, 40, 42, 54, 61, 70, 72, 81, and CP6108), and 9 types of unknown risk (HPV 55, 62, 64, 67, 69, 71, 83, 84, and IS39) |
| HPV E6/E7 mRNA detection |
|
Individual identification of E6/E7 mRNA full-length transcripts of HPV 16, 18, 31, 33, and 45 |
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