A new preclinical data from University of California (UC), San Diego School of Medicine offers proof-of-principle for a combination immunotherapy that suppresses tumor growth in the liver.

The Senior Author of the study, Gen-Sheng Feng, PhD, Professor of pathology and molecular biology at UC San Diego said “liver cancer is much more complicated than we thought.”

Published in Sciencedaily.com, Feng stated that “we and other researchers found recently that deleting classic oncogenes ironically aggravates liver cancer. The liver has a unique immune-tolerant microenvironment.

“That’s why we haven’t been able to develop an effective treatment for liver cancer by blocking oncogenic signaling. Immunotherapy with checkpoint inhibitors, while in many clinical trials worldwide, may have uncertain outcomes due to low or poor response.”

In a study published in 2017, Feng’s team discovered unexpectedly that polyinosinicpolycytidylic acid (polyIC) strongly boosts a variety of anti-tumor innate immune functions in the liver and that it has a positive effect in preventing primary liver cancer in mouse models, if administered in the pre-cancer stage.

However, they cautioned that polyIC alone has no therapeutic effect if injected after tumors are already formed. In fact, researchers showed polyIC injection can exacerbate liver cancer progression in some mouse models.

In the present study, researchers confirmed the previous experimental data in different animal models for liver cancer.

They also showed that the initiation of liver tumors was suppressed by reprogramming macrophages and activation of natural killer cells, resulting in the elimination of tumor-initiating cells.

Together, these data led them to believe that developing a liver cancer prevention strategy is possible by boosting innate immunity.

Which can benefit a large population of chronic liver diseases in patients who are at high risk for liver cancer development.

When polyIC was combined with a PD-L1 antibody, the number of activated CD8 T cells — a type of white blood cell called lymphocytes that attacks and kills cancer cells — increased dramatically in the liver, resulting in tumor suppression.

This study focuses on primary liver cancer, but researchers are already reviewing what effect this combination immunotherapy might have on metastatic liver cancer and the malignant disease at advanced or terminal stages, said Feng.

The team is also looking at optimal dosages and is considering other reagent combinations that might be more effective.

Feng added that “The most encouraging and important message from this study is that we have found a strategy or rationale to make liver cancer highly responsive to immunotherapy.

“Based on our preclinical data in animal models, a clinical trial could be designed and implemented quickly because both reagents are already being used separately to treat patients so there is no question about safety.

“We need to find effective new therapies for this disease. The best drugs in the world only extend a patient’s life by an average of three months.

“Many immunotherapeutic reagents or protocols are in clinic trials, but very few were based on or justified by solid preclinical data.

This study may shift the paradigm in liver cancer treatment, by carefully designing a combination therapy that activates multiple innate and adaptive immune functions within the liver”, said Feng.