In Vivo Mechanistic Characterization of the Angiogenic Immune Checkpoint in Liver Cancer
Abstract
The FY22 PRCRP Topic Area addressed by this proposal is liver cancer. Liver cancers are a major cause of death worldwide and occur commonly in Veterans. Hepatocellular carcinoma is the most common kind of liver cancer. While we now have two very good medical treatment options for patients with hepatocellular carcinoma that cannot be controlled by surgery, we do not know which option is best for which patient. We are addressing the PRCRP Military Health Focus Area of gaps in cancer research that may affect mission readiness by identifying patients most likely to benefit from one of the two current options, the combination of an inhibitor of blood vessel formation (an angiogenesis inhibitor) with a medicine that makes it easier for the immune system to find and attack tumors (an immune checkpoint inhibitor). Our objective is to understand how angiogenesis inhibitors increase the impact of immune checkpoint inhibitors in liver cancer. The rationale of our proposal is based on our own work and many other studies showing that some of the mechanisms that drive blood vessel formation also specifically block the antitumor immune response. We hypothesize that some patients will have tumors that drive blood vessel formation with those immune suppressive mechanisms. By understanding the exact mechanistic changes that angiogenesis inhibitors cause in liver cancer, we can identify those patients where an angiogenesis inhibitor/immune checkpoint inhibitor combination is most likely to cause the tumor to regress, extending that patient s life. Relevance to Intent: Our project builds on results from a clinical trial run by a member of the project team. In that study, liver cancer patients who had large tumors were treated with an angiogenesis inhibitor and an immune checkpoint inhibitor. Most of them had their tumors shrink and were able to undergo surgery. Many samples were collected in this study and have already been studied in detail for how the immune system changed during treatment. We will now study them for how the factors that influence blood vessel formation changed, connecting those findings to the immune analysis we have already done. These studies will be extended with experiments in cell lines and patient tumors grown in mice with humanized immune systems to allow us to confirm the findings from the patient samples from our trial. While liver cancer treatment will continue to advance, it is very likely that the treatments we are studying will continue to be the cornerstone of treatment for many patients. With two possible options, making the right choice at the start of treatment is essential, particularly as many liver cancer patients are only ever able to get one treatment. Our project is designed to uncover predictors of benefit from the combination of an angiogenesis inhibitor and an immune checkpoint inhibitor. Once those predictors are found, they will need to be directly tested in patients receiving these treatments to confirm that they are widely applicable, a process that could likely be completed within 5 years from the completion of our work and may be started while we are underway. Our analysis investigates the mechanisms by which how angiogenesis inhibitors enhance immune therapy. Thus, we are addressing the FY22 PRCRP Overarching Challenges of Therapeutics: Advance immunotherapy and Therapeutics: Elucidate mechanisms to improve treatment. Because HCC is such a dire diagnosis, making the right treatment choice for patients can allow them to feel better and live longer, improving the situations of active-duty Service Members, Veterans, and their Families afflicted by this grim diagnosis.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310762
Entities
People
- Terence Gade
Organizations
- United States Army
- University of Pennsylvania