Mechanisms Mediating the Immune Response After Proton Versus Photon Radiotherapy in IDH-Mutant Liver Cancer
Abstract
This proposal broadly addresses several 2020 Peer Reviewed Cancer Research Program Topic Areas: “liver cancer,” “metastatic cancer,” and “immunotherapy.” We will study the safe implementation of a new and potentially much more efficacious modality of radiation treatment called proton beam radiotherapy for a deadly and highly metastatic liver cancer type – cholangiocarcinoma. Proton beam radiotherapy employs precise irradiation of the tumor while sparing surrounding liver tissue. We have previously shown that this modality has the potential for controlling local liver cancer growth in the vast majority of the patients with cholangiocarcinomas that cannot be surgically removed. Another potential benefit for this strategy is that it could be particularly efficacious against cancers with a specific mutation profile, readily identifiable using widely available diagnostic tests, and in combination with emerging immunotherapies. Specifically, proton beam radiotherapy could be combined with therapies targeting the immune system (called immune checkpoint blockers, which can reactivate the immune system and are already approved for some liver cancers) and produce profound responses to treatment of the primary and metastatic lesions outside of the irradiated area. In this manner, proton beam radiotherapy could decrease the suffering from liver cancer and increase survival for this disease, which is currently one of the cancers with a dismal prognosis (i.e., less than 10% of patients survive at least 5 years after being diagnosed with cholangiocarcinoma). These objectives will be achieved within the 3 years of funding through this grant. Finding a setting where proton beam radiotherapy is highly efficacious for liver cancer treatment in mice in this time interval could immediately lead to its application in several Cancer Centers in the country (including through the U.S. Department of Veteran’s Affairs), given the previous experience with this treatment modality in unselected patients. The proposed research will also reveal within 3 years the impact of combination/schedules of proton beam radiotherapy with immune checkpoint blockade strategies to help achieve durable responses in models using immunotherapy-resistant tumors. In the longer term (3-4 years), this could lead to clinical testing of this new approach to prevent the spread of cholangiocarcinoma to distant organs in patients by leveraging novel immunotherapy. Any of these developments would be a major advance for safely implementing radiotherapy and immunotherapy in patients with unresectable, deadly liver cancers. These goals will be reached by combining the diverse and complementary expertise of the basic scientist, Principal Investigator Dr. Duda (immunotherapy, liver cancer microenvironment, animal models of advanced liver cancers) and physician-scientist, Co-Investigator Dr. Willers (proton beam radiotherapy research, clinical translation, DNA repair). This collaborative effort will also provide a highly fertile ground for rapid progress of this study and clinical translation of the results, which could be transformative for the treatment of this dismal cancer. Our proposal addresses the Military Relevance Focus Area “gaps in cancer prevention, early detection/diagnosis, prognosis, treatment, and/or survivorship that may affect the general population but have a particularly profound impact on the health and well-being of military Service Members, Veterans, and their beneficiaries.” The incidence of primary liver cancer has been steadily increasing in the U.S. and is strongly linked with risk factors present in the Veteran population such as male gender, poor nutrition, repeated exposure to toxins (including chemicals, alcohol, nicotine), and viral hepatitis. A study in a large group of U.S. Veterans found that the risk for cholangiocarcinoma is increased more than two-fold in subjects with viral infection. Moreover, in contrast to the stable and declining incide
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110738
Entities
People
- Dan G Duda
Organizations
- Massachusetts General Hospital
- United States Army