RESUMO
Objective. CIGB-228 is a novel therapeutic vaccine consisting of HLA-restricted HPV16 E7 epitope adjuvated with VSSP. This trial was designed to evaluate the toxicity, safety, immunogenicity, HPV clearance, and lesion regression. Methods. Seven women were entered. All were HLA-A2 positive, had biopsy-proven high-grade CIN, histologically positive for HPV16, and beared persistent postbiopsy lesions visible by digital colposcopy. HLA-A2 women with biopsy-proven high-grade CIN, HPV16-positive, and beared persistent postbiopsy lesions visible by digital colposcopy were vaccinated. One weekly injections of CIGB-228 vaccine was given for four weeks. Then, loop electrosurgical excision procedure (LEEP) of the transformation zone was performed. Study subjects were followed for 1 year after LEEP. Results. No toxicity beyond grade 1 was observed during and after the four vaccinations. Five of seven women had complete and partial regression. Cellular immune response was seen in all patients. HPV was cleared in three of the patients with complete response. Conclusion. CIGB-228 vaccination was well tolerated and capable to induce IFNγ-associated T-cell response in women with high-grade CIN. In several patients, lesion regression and HPV clearance were observed.
RESUMO
BACKGROUND: Cervical cancer is now considered the second leading cause of death among women worldwide, and its incidence has reached alarming levels, especially in developing countries. Similarly, high grade squamous intraepithelial lesion (HSIL), the precursor stage for cervical cancer, represents a growing health problem among younger women as the HSIL management regimes that have been developed are not fully effective. From the etiological point of view, the presence of Human Papillomavirus (HPV) has been demonstrated to play a crucial role for developing cervical malignancies, and viral DNA has been detected in 99.7% of cervical tumors at the later stages. CIGB-300 is a novel cyclic synthetic peptide that induces apoptosis in malignant cells and elicits antitumor activity in cancer animal models. CIGB-300 impairs the Casein Kinase (CK2) phosphorylation, by targeting the substrate's phosphoaceptor domain. Based on the perspectives of CIGB-300 to treat cancer, this "first-in-human" study investigated its safety and tolerability in patients with cervical malignancies. METHODS: Thirty-one women with colposcopically and histologically diagnosed microinvasive or pre-invasive cervical cancer were enrolled in a dose escalating study. CIGB-300 was administered sequentially at 14, 70, 245 and 490 mg by intralesional injections during 5 consecutive days to groups of 7 - 10 patients. Toxicity was monitored daily until fifteen days after the end of treatment, when patients underwent conization. Digital colposcopy, histology, and HPV status were also evaluated. RESULTS: No maximum-tolerated dose or dose-limiting toxicity was achieved. The most frequent local events were pain, bleeding, hematoma and erythema at the injection site. The systemic adverse events were rash, facial edema, itching, hot flashes, and localized cramps. 75% of the patients experienced a significant lesion reduction at colposcopy and 19% exhibited full histological regression. HPV DNA was negative in 48% of the previously positive patients. Long term follow-up did not reveal recurrences or adverse events. CONCLUSION: CIGB 300 was safe and well tolerated. This is the first clinical trial where a drug has been used to target the CK2 phosphoaceptor domain providing an early proof-of-principle of a possible clinical benefit.