Yale researchers launched an international trial of ancient Chinese medicine for liver cancer


More than 20 years ago, Yale pharmacology professor Yung-Chi Cheng, a leader in drug development for hepatitis B, cancer, and HIV, had a radical idea: What if he could unlock the therapeutic potential of ancient Chinese medicines for treating cancer? What if he could design botanical drugs that would make traditional cancer treatments work better?


No one had done it before. The Food and Drug Administration didn’t even have a process in place for approving multi-ingredient botanical drugs, and wouldn’t until 2004, when the agency released botanical drug-specific guidelines.


Fellow researchers and drug development experts advised him to change course. Developing botanical drugs was too complicated, they said, too risky.

But the idea had taken hold, and Cheng, the Henry Bronson Professor of Pharmacology at Yale School of Medicine, was not going to let it go.


“Chinese medicine works by taking advantage of multiple chemicals, but also the capability of different organs in metabolizing these chemicals,” he said, surrounded by careening stacks of paper in his office at Yale’s Sterling Hall of Medicine. “It’s a totally new paradigm. I’ve been met with a lot of suspicion, but I think the results will speak for themselves.”


Now, in a landmark moment in cancer research, Cheng and research partners are launching the first international clinical trial for a botanical drug, YIV-906. The trial, involving patients with liver cancer and hepatitis B, will take place at 20 institutions across the United States, China, Taiwan, and Hong Kong. Lead sites include Memorial Sloan Kettering and Northwell Health Cancer Institute in New York, Taipei Medical University, the National Cancer Center of China, and Queen Mary Hospital in Hong Kong.


“He is a pioneer,” said Jon Soderstrom, managing director of Yale’s Office of Cooperative Research, who began advising Cheng in 1996. “He is Lewis and Clark going into the Pacific Northwest without a map. By the sheer force of his personality and his empirical results, he made people pay attention to this space.”


Major drug companies are watching Cheng’s progress from the sidelines for now, said Shwu-Huey Liu, who began working in Cheng’s Yale lab as a postdoctoral researcher in 1993, when his focus was on antivirals and traditional anticancer drugs. “They monitor us and come to meetings,” she said, “but until we get approved, big pharma is not going to jump in.”


Today Liu is cofounder and chief scientific officer of Yiviva, Cheng’s biotech company, which is developing YIV-906. Combining Chinese and Spanish words, Yiviva translates as “long live medicine.” It’s a fitting slogan for a company that has resurrected an 1,800-year-old formula for stomach ailments to help fight cancer.


Liu discovered with about 20 formulations of Chinese medicine. One of them, an 1,800-year-old treatment for stomach ailments, was called Huang Qin Tang. It combined licorice, dates, peonies, and skullcap, and was traditionally prepared as a tea. After lab testing, the Cheng team found that Huang Qin Tang had a high inhibitory property against the debilitating side effects of a chemotherapy drug called CPT-11 (later approved as irinotecan), including diarrhea, nausea, and vomiting. Cheng and team developed a drug based on the formula and tested it on one thousand mice.


Not only did their drug, YIV-906, reduce the toxic GI side effects of the chemo drug, but it also enhanced irinotecan’s anti-tumor activity — a major discovery that revealed YIV-906’s powerful therapeutic potential.


“It was a surprise to us to see not only a reduction in the GI side effects of chemo but also an increase in the chemo action against tumors,” Cheng said.


What followed were years of additional testing of the drug’s effectiveness for a range of cancers — including liver, pancreatic, and colorectal — in multiple human studies involving over 200 patients. The positive effects were replicated again and again. YIV-906 not only diminished the side effects of chemo drugs and radiation therapy, but also led to a stabilization of cancer, faster recovery, and longer survival rates.


In 2019, Cheng and his research partners ran a study with Yale immunobiology professor Lieping Chen to test YIV-906’s effectiveness with Chen’s immunotherapy drug anti-PD1, and found that YIV-906 enhanced the immunotherapy drug’s anti-tumor property. The combination of the drugs not only eradicated all tumors in mice, but when new tumors were implanted, the tumors did not grow. This suggested that YIV-906 with anti-PD1 “created a tumor-specific vaccine-like effect,” they wrote in their study.


Before this trial was launched, in 2011, Dr. Cheng received the first PO1 grant awarded by the NCI to explore Chinese medicine for the treatment of cancer.


The focus of this study is to explore PHY906, a 4-herb Chinese medicine based on a 1,800 year old traditional Chinese formula, also known as Huang Qin Tang, in a clinical phase II setting as adjuvant therapy for Irinotecan based chemotherapy in advanced colon carcinoma. Dr. Cheng will be working in collaboration with Dr. Edward Chu at the University of Pittsburgh and Dr. Hongyu Zhao at the Yale School of Public Health. Clinical studies is being conducted at the University of Pittsburgh with Dr. Chu, at Yale with Dr. Howard Hochster, and at City of Hope with Dr. Yun Yen.


References:

1. Ancient Chinese Medicine Unlocks New Possibilities for Cancer Treatment. https://medicine.yale.edu/news-article/ancient-chinese-medicine-unlocks-new-possibilities-for-cancer-treatment/

2. Yale Researcher Receives NCI Award to Study Chinese Herbal Medicine for the Treatment of Cancer. https://medicine.yale.edu/news-article/yale-researcher-receives-nci-award-to-study-chinese-herbal-medicine-for-the-treatment-of-cancer/

3. YIV-906 (Formerly PHY906/KD018) With Sorafenib in HBV(+) Hepatocellular Carcinoma (HCC). https://clinicaltrials.gov/ct2/show/NCT04000737

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