A Placebo-Controlled, Double-Blind Randomized (Phase IIB) Trial of Oral Administration with HPV16 E7-Expressing Lactobacillus, GLBL101c, for the Treatment of Cervical Intraepithelial Neoplasia Grade 2 (CIN2).

Yuji Ikeda,Tomoyuki Fujii,Tetsushi Tsuruga,Yukari Uemura,Shizunobu Igimi,Satoko Eguchi-Kojima,Kensuke Tomio,Ai Kawana-Tachikawa,Katsutoshi Oda,Katsuyuki Adachi,Takeshi Nagamatsu,Kei Kawana,Ayumi Taguchi,Yutaka Osuga,Mayuyo Uchino-Mori,Atsushi Komatsu

doi:10.3390/vaccines9040329

Abstract

Cervical intraepithelial neoplasia (CIN), a precursor lesion to cervical cancer, is caused by high-risk human papillomavirus (HPV); high-grade CIN lesions (CIN2-3) are precancerous and require treatment. No globally approved therapy is available for CIN2-3 treatment. This study is a placebo-controlled randomized clinical trial of GLBL101c treatment for CIN2 in 40 patients with HPV16-positive CIN2 who were 1:1 randomized to receive GLBL101c (1 g/daily) or placebo for 5 days at 1, 2, 4, and 8 weeks. No differences were noted between the GLBL101c and placebo groups for patient background and adverse events. Moreover, no statistically significant difference was noted between the two groups at the primary endpoint, pathological regression after 16 weeks of the first oral dose; however, only in the GLBL101c group, two patients had complete regression (CR; regression to normal within 16 weeks). IFNγ production was significantly correlated with the number of spots identified by the interferon gamma enzyme-linked immunospot (IFNγ-ELISPOT) assay using cervical lymphocytes (CxLs) or peripheral blood mononuclear cells. In the two cases of CR, E7-specific Th1 immune responses were observed at week 16. Therefore, we concluded as a novel Lactobacillus-based vaccine with stronger immunogenicity than GLBL101c should be developed.

Highlights

Cervical cancer is the cause of more than 300,000 deaths worldwide each year [1]
It is expected that human papillomavirus (HPV) vaccines will be able to eradicate cervical cancer in the future, the HPV vaccination rate is currently limited in many countries and regions due to cost issues; it will take a long time to eliminate cervical cancer globally [4]
We previously demonstrated that approximately 20–40% of CD3+ T cells in the cervical epithelium of patients with Cervical intraepithelial neoplasia (CIN) were gut-derived T cells expressing integrin β7+; we found that CIN was more likely to regress when the number of T cells expressing integrin β7+ was high [12]

Summary

Introduction

Cervical cancer is the cause of more than 300,000 deaths worldwide each year [1]. Approximately 99% of cervical cancer cases are associated with genital infection with highrisk human papillomaviruses (HR-HPVs). The development of therapeutics to treat precursor lesions (such as cervical intraepithelial neoplasia (CIN)) is essential even though HPV vaccination programs have been implemented worldwide. Surgical resection is the only treatment for early cervical cancer and precancerous cervical lesions (CIN2-3), which peak in women in their 20s and 30s. Conization is considered as a standard surgical treatment of CIN2-3 especially for patients who is willing to preserve their fertility; the risk of preterm birth and the rate of cesarean delivery and low birth weight are approximately three times higher after conization [5,6,7]. Because the age at which CIN2-3 develops coincides with the age at which a woman becomes pregnant and gives birth, the worsening of obstetrical outcomes because of cervical incompetence after partial resection of the cervix is the major issue for reproductive health of young women. The development of a therapeutic agent for CIN as a non-surgical treatment for CIN2-3 is an unmet medical requirement

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