AUTHOR=Smith Judith A. , Mathew Lata , Gaikwad Anjali , Rech Barbara , Burney Maryam N. , Faro Jonathan P. , Lucci Joseph A. , Bai Yu , Olsen Randall J. , Byrd Teresa T. 

TITLE=From Bench to Bedside: Evaluation of AHCC Supplementation to Modulate the Host Immunity to Clear High-Risk Human Papillomavirus Infections

JOURNAL=Frontiers in Oncology

VOLUME=9

YEAR=2019

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2019.00173

DOI=10.3389/fonc.2019.00173

ISSN=2234-943X

ABSTRACT=<p><bold>Objective:</bold> There is currently no effective medicine or supplement for clearance of high risk- human papillomavirus (HR-HPV) infections. We have taken a systematic approach evaluating the potential use of AHCC supplementation to support clearance of HR-HPV infections. The primary objective of this research was to evaluate AHCC supplementation to modulation of the host immune system to clear HR-HPV infections from bench to bedside.</p><p><bold>Methods:</bold> Cervical cancer cells, CaSki (HPV16<sup>+</sup>), HeLa(HPV18<sup>+</sup>), SiHa(HPV16/18<sup>+</sup>), and C-33A(HPV<sup>−</sup>), were treated <italic>in vitro</italic> with AHCC 0.42 mg/mL daily x7 days then observed x7 days with daily sample collection. A confirmatory study in cervical cancer mouse models, SiHa(HPV16/18<sup>+</sup>) and C-33A(HPV<sup>−</sup>), was conducted: mice were divided into three groups per cell line then dosed with AHCC 50 mg/kg/d (<italic>N</italic> = 10), or vehicle alone (<italic>N</italic> = 10), or no supplementation (<italic>N</italic> = 10) for a total of 90 days followed by 30 days of observation. Tumors were measured 3x/week and blood samples collected bi-weekly to evaluate interferon (IFN) alpha(α), beta(β), and gamma(γ) and immunoglobulin G(IgG) by immunoassays. Tumors were evaluated for HR-HPV expression by PCR. Two pilot studies of 10 patients each were conducted in women with confirmed persistent HR-HPV+ infections. The 1<sup>st</sup> study evaluated AHCC 3g from 5 weeks up to 6 months and 2nd study evaluated AHCC 1g &lt; 8 months. HR-HPV DNA status and the immune panel were monitored at each visit.</p><p><bold>Results:</bold> HR<bold>-</bold>HPV clearance was observed <italic>in vitro and</italic> confirmed in the animal studies as a durable response. Four of six (66.7%) patients had confirmed HR-HPV clearance after 3–6 months of AHCC 3g. Similarly, 4 of 9 (44%) patients had confirmed HR-HPV clearance after 7 months of AHCC 1g. Suppression of IFNβ &lt;25 pg/mL was observed in those clearing the HR-HPV infection.</p><p><bold>Conclusion:</bold> Pre-clinical <italic>in vitro</italic> and <italic>in vivo</italic> studies demonstrated durable clearance of HR-HPV infections. The preliminary data from the two pilot studies suggested that AHCC supplementation supports the host immune system for successful clearance of HR-HPV infections. A confirmatory phase II randomized, double-blinded, placebo-controlled study is ongoing.</p>