Immunotherapy Combo Halts Tumor Growth in Patients With Liver Cancer

Gen-Sheng Feng, PhD, Professor of Pathology and Biology, UC San Diego, spoke with Oncology Learning Network about the clinical significance of his team’s recent study, which demonstrated the potential efficacy of a combination immunotherapy that suppresses liver tumor growth (Hepatology. 2019 Jan 28. Epub ahead of print).

What existing data led you to evaluate the use of a synthetic double-stranded RNA polyIC and a PD-L1 antibody in animal models of liver cancer tumors?

In recent studies of liver cancer, our lab and a few others have found that removing tumorigenic molecules in the liver ironically aggravated liver cancer development. These unanticipated results might explain why drugs designed to block tumorigenic pathways have not worked well in treating liver cancer patients. Indeed, there is no efficacious drug for liver cancer patients in the world so far. These data also argue that the mechanisms and pathogenesis of liver cancer are much more complicated than we thought previously. Therefore, the focus of my lab research is currently on elucidating the previously unappreciated complexity in liver tumorigenesis, in order to design effective mechanism-based therapy for the malignant disease.

In experiments aimed at deciphering cell-cell communications in hepato-carcinogenesis using cell type-specific gene deletion approach, we unexpectedly identified a liver tumor-preventing effect of a synthetic double-stranded RNA polyIC. However, polyIC alone did not have therapeutic effect if given after tumor initiation. In dissecting the underlying mechanism, we observed that polyIC treatment induced expression of PD-L1, among many other proteins, in the liver. It was this data that prompted us to try the combination of polyIC plus anti-PD-L1 antibody in treating liver cancer in animal models. Importantly, we have found a robust inhibitory effect on liver tumor progression in mice given this combined treatment, although neither of the two reagents alone had any significant effect.

Therefore, we used the strategy of PD-L1/PD-1 blockade, not because it’s currently very hot in immunotherapy. Design of the experiments was driven by our own experimental data.

Please briefly describe your study and its findings. Were any of the outcomes particularly surprising?

In this study, we established mouse models for hepatocellular carcinoma (HCC) driven by transfection of oncogenes that are frequently detected in human HCC patients. Consistent with previous results, we found that injection of the synthetic dsRNA molecule polyIC effectively prevented liver tumor initiation if given at pre-cancer stage, by activating innate immunity, such as macrophages and NK cells.

More importantly, we demonstrated that combined treatment of polyIC and PD-L1 antibody dramatically suppressed HCC progression and significantly extended survival time of the tumor-bearing mice. Given a potent induction of PD-L1 expression by polyIC in the liver, we expected to see this outcome of the combination. However, the therapeutic effect was even better than we anticipated, as this study did not test different dosages and time points yet, to obtain the optimal recipe. We believe optimization of the protocol may achieve even better results and lead to development of an efficacious combination immunotherapy for HCC.

It's a bit surprising that we observed remarkably elevated expression of PD-L1 in liver sinusoid endothelial cells (LSECs) in the liver following polyIC injection, but not in tumor cells, which stimulated infiltration of CD8 T cells into the liver. Elucidating mechanisms of these immunosuppressive pathways in the liver will be instrumental for design of new therapy.

How can these findings potentially affect the treatment landscape for patients with HCC?

Immunotherapy by blocking inhibitory pathways in T-lymphocytes, such as the PD-L1/PD-1 axis, is being widely tested in various solid tumors. This emerging therapeutic approach is already in clinical trials for advanced HCC in multi-centers around the globe. Two latest reports on open-label, nonrandomized, phase 1/2 trials with pembrolizumab or nivolumab indicated manageable safety in advanced HCC patients with or without prior sorafenib treatment, albeit with very limited therapeutic benefit observed so far.

The outcome of immunotherapy for liver cancer is obviously compounded by the unique immunotolerant microenvironment in the liver. A variety of clinical trials are ongoing to evaluate various combinations of immune checkpoint inhibitors or with other drugs, without clear justification or support by preclinical data in animal models.

This study suggests that although HCC is a type of “cold” tumor, with low or poor response to immunotherapy in most cases, it is feasible to turn it to be a “hot” tumor and become responsive to immunotherapy with checkpoint inhibitors. The key point is to boost innate and adaptive immunity simultaneously. We expect that this combo immunotherapy strategy will soon be widely tested in the clinic. It may become a most efficacious therapeutic means for HCC patients.

Do you and your co-investigators intend to expand upon this research? If so, will you be incorporating any new end points or tumor types?

Absolutely, we are already in the process of examining the therapeutic effect of the combination of polyIC and anti-PD-L1 antibody in metastatic liver tumors. We shall explore the optimal dosages and time points to inject the two reagents. More importantly, based on the principle of simultaneously boosting innate and adaptive immune functions, we will explore other reagents, which might be even better than the combination of polyIC and PD-L1 antibody.

We have started to explore opportunities to launch multi-center clinical trials for HCC patients, based on the preclinical data in animal models. However, our research is mainly focused on liver cancer. In addition to the widely known immune checkpoints, we are searching for new molecules that suppress anti-tumor immunity in the liver, to further improve the efficacy of immunotherapy for liver cancer.