A team of researchers composed of physicians and scientists from the University of Missouri School of Medicine has discovered an immunotherapy combination that could be effective in patients with liver cancer. The study focused on mice samples, and the findings suggest that this combination reduced tumor growth and extended the lifespan of the mice with liver cancer. This treatment could potentially save many lives, as liver cancer is the third-leading cause of cancer-related deaths in the United States.
Challenges in Liver Cancer Treatment
There are several different types of liver cancer, but hepatocellular carcinoma (HCC) is by far the most common. Cancer in the liver most commonly spreads from other parts of the body, although cancer can begin in the liver as well.
Patients with liver cancer have worse-than-average outcomes compared to patients with other types of cancers. The average five-year survival rate for patients diagnosed with localized liver cancer is just 20 percent, according to the American Cancer Society.
Liver cancer rarely shows symptoms in the early stages of the disease, which makes treatment a challenge. Earlier diagnoses are correlated with higher chances of survival in liver cancer and other cancers.
Late-stage liver cancer often causes severe damage to the liver before the cancer has been diagnosed, which can make patients ineligible for surgery. Patients who are unable to have surgery generally have a worse prognosis than patients who can.
LipC6 and Anti-CTLA-4 Combination Treatment
The treatment in the University of Missouri study was a combination of a tumor-suppressing lipid molecule called nanoliposome C6-ceramide (LipC6) and an antibody for cytotoxic T-lymphocyte antigen 4 (CTLA-4). Both of these treatments already have FDA approval for use in human patients.
Past research has indicated that LipC6 can be used to slow the growth of tumors in the liver. Additionally, this substance has been proven to fight suppression of the body’s anti-tumor immune response and can increase the anti-tumor defenses of CD8+ T-cells.
Anti-CTLA-4 antibodies have been proven to encourage long-lasting protection against melanoma. In 2011 the FDA approved the first anti-CTLA-4 antibody, Ipilimumab, for the treatment of melanoma.
Methodology
To test this combination treatment, researchers generated orthotopic mice with hepatocellular liver cancer and treated them with both LipC6 and CTLA-4 antibodies. The team then monitored tumor growth using magnetic resonance imaging and checked the intrahepatic immune profiles using flow cytometry in response to the treatment. Additionally, the researchers used real-time polymerase chain reaction to detect the expression of target genes.
Results of the Combo Immunotherapy Study
The combination of these two treatments looks to be promising, according to the results of the study. Researchers found that LipC6 treatment drastically improved the ability of the anti-CTLA-4 antibodies to fight against liver cancer. When used together, the treatment slowed tumor growth and increased the strength of tumor-fighting T-cells in the mice with liver cancer.
The researchers also tested another commonly used immunotherapy called anti-PD-1 in combination with LipC6. Anti-PD-1 has historically been ineffective with liver cancer patients, delivering a response rate of only 14 percent. When combined with LipC6, however, there was no benefit compared to the strong response observed with the combination of LipC6 and anti-CTLA-4 antibodies.
Other Potential Combination Therapeutic Strategies
The University of Missouri researchers also believe that they have produced data that supports the use of other combination therapeutic strategies for the treatment of HCC, such as:
- LipC6 plus TSA CD8+ T-cells
- Sunitinib plus anti-PD1
- Sunitinib plus radiofrequency ablation
- Laser ablation plus immune-activator N-dihydro-galacto-chitosan
Where to Go from Here
While the results of this immunotherapy combination in mice samples are promising, the next step will be transitioning the research to clinical application. The study’s authors believe this should be relatively easy because both treatments are already FDA-approved. If similar results are found in human trials, this combination treatment could be used to treat patients with liver cancer relatively quickly compared to other treatments not yet approved by the FDA.
Additional research is necessary to better understand why this combination of treatments was so successful in the mice samples. A deeper understanding of these underlying mechanisms could potentially be applied to develop similar treatments for other types of cancer.
The university researchers have already begun taking their next steps. This study analyzed mice with relatively small tumors, suggesting that the tested cancers were early stage. The study’s authors believe this may explain why LipC6 was not effective on its own but only in combination with the anti-CTLA-4 antibodies. The researchers are currently developing a mouse model with liver fibrosis and will treat these tumor-bearing mice once their tumors have grown beyond 150 mm. These results will be reported shortly following the conclusion of the study.