YIV-906 potentiated anti-PD1 action against hepatocellular carcinoma by enhancing adaptive and innate immunity in the tumor microenvironment

Lieping Chen,Yung-Chi Cheng,Nicholas J W Rattray,Xue Han,Wei Cai,Zaoli Jiang,Shwu-Huey Liu,Peikwen Cheng,Fulan Guan,Xiaochen Yang,Wing Lam,William Cheng,Caroline H Johnson,Yuping Cai,Rong Hu

doi:10.1038/s41598-021-91623-3

Abstract

YIV-906 (PHY906) is a standardized botanical cancer drug candidate developed with a systems biology approach—inspired by a traditional Chinese herbal formulation, historically used to treat gastrointestinal symptoms including diarrhea, nausea and vomiting. In combination with chemotherapy and/or radiation therapy, preclinical and clinical results suggest that YIV-906 has the potential to prolong survival and improve quality of life for cancer patients. Here, we demonstrated that YIV-906 plus anti-PD1 could eradicate all Hepa 1–6 tumors in all tumor bearing mice. YIV-906 was found to have multiple mechanisms of action to enhance adaptive and innate immunity. In combination, YIV-906 reduced PD1 or counteracted PD-L1 induction caused by anti-PD1 which led to higher T-cell activation gene expression of the tumor. In addition, YIV-906 could reduce immune tolerance by modulating IDO activity and reducing monocytic MDSC of the tumor. The combination of anti-PD1 and YIV-906 generated acute inflammation in the tumor microenvironment with more M1-like macrophages. YIV-906 could potentiate the action of interferon gamma (IFNg) to increase M1-like macrophage polarization while inhibiting IL4 action to decrease M2 macrophage polarization. Flavonoids from YIV-906 were responsible for modulating IDO activity and potentiating IFNg action in M1-like macrophage polarization. In conclusion, YIV-906 could act as an immunomodulator and enhance the innate and adaptive immune response and potentiate anti-tumor activity for immunotherapies to treat cancer.

Highlights

YIV-906 (PHY906) is a standardized botanical cancer drug candidate developed with a systems biology approach—inspired by a traditional Chinese herbal formulation, historically used to treat gastrointestinal symptoms including diarrhea, nausea and vomiting
As YIV-906 could promote more M1-like macrophage polarization, we investigated if YIV-906 had direct impact on polarizing bone marrow derived macrophages (BMDM) into either M1-like or M2-like phenotype in culture
The results indicated that YIV-906GU had a stronger induction effect on interferon gamma (IFNg), IL1a, TNFa mRNA expression of BMDM than YIV-906 alone (Fig. 5A)

Summary

Introduction

YIV-906 (PHY906) is a standardized botanical cancer drug candidate developed with a systems biology approach—inspired by a traditional Chinese herbal formulation, historically used to treat gastrointestinal symptoms including diarrhea, nausea and vomiting. YIV-906 could act as an immunomodulator and enhance the innate and adaptive immune response and potentiate anti-tumor activity for immunotherapies to treat cancer. In 2017, the FDA granted Nivolumab (anti-PD1) accelerated approval to treat hepatocellular carcinoma (HCC) patients who do not respond to sorafenib. In seven Phase I/II to II clinical studies in liver, pancreatic and colorectal cancer at research institutions, including Yale University, Stanford University, UPMC Hillman Cancer Center and City of Hope Comprehensive Cancer Center, results from over 170 patients receiving irinotecan, capecitabine or chemo-radiation[8,9,10,11] in combination with YIV-906, reported no YIV-906-related toxicity at the dosage used along with zero-to-minimal Grade 3/4 non-hematological toxicities, including diarrhea, nausea, vomiting, fatigue—demonstrating improved quality of life as well as survival for patients

Methods

Results

Conclusion