Combination immunotherapy may stop liver cancer growth, study finds
A combination immunotherapy treatment of two reagents, a synthetic double-stranded RNA (dsRNA) polyinosinicpolycytidylic acid (polyIC) with a programmed death-ligand 1 (PD-L1) antibody, was effective at stopping the progression of hepatocellular carcinoma (HCC), with complete tumor remission and tumor-free survival observed in some mouse models, according to new research from the University of California San Diego School of Medicine, which was recently published in the journal Hepatology.
The number of people diagnosed with liver cancer is on the rise, with an estimated 42,220 people diagnosed each year, according to the American Cancer Society. Current therapies for liver cancer are largely ineffective, resulting in poor outcomes, but the new preclinical data from offers proof-of-principle for a combination immunotherapy that suppresses tumor growth in the liver., researchers say.
"Liver cancer is much more complicated than we thought," said Gen-Sheng Feng, PhD, professor of pathology and molecular biology at the university and senior author on the paper, in a statement released yesterday. "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."
Researchers confirmed 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 the research team 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.
In analyzing why polyIC has no therapeutic effect on liver cancer, Feng and colleagues noticed that polyIC administration potently induced PD-L1 expression in the liver. 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 say they are already reviewing what effect this combination immunotherapy might have on metastatic liver cancer and the malignant disease at advanced or terminal stages. The team is also looking at optimal dosages and is considering other reagent combinations that might be more effective, Feng said.
"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," said Feng.
Based on the 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, according to Feng.
"We need to find effective new therapies for this disease,” said Feng. 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."