B7-H3 CAR T Cell-Based Immunotherapy to Eradicate Micrometastatic Disease and Prevent Recurrence Following Removal of the Primary Tumor in Intrahepatic Cholangiocarcinoma
Abstract
The fiscal year 2022 Rare Cancers Research Program - Concept Award Focus Area that will be addressed in this application is Therapy The biliary tree is a morpho-functional part of the liver constituted by cells called cholangiocytes that can give rise to a type of cancer called cholangiocarcinoma. While cholangiocarcinoma is relatively rare, it is the second most common primary hepatic cancer. Surgery provides the best possibility for potentially curative treatment, but only a minority of patients present with early-stage disease that is amenable to surgical resection with curative intent. More than 50% of patients are unresectable at presentation due to multifocal, locally advanced, or metastatic disease. Even for patients who can receive curative surgical resection, the long-term prognosis remains dismal, with a 5-year survival rate of 20%-35%. The primary reason for the unfavorable long-term outcome even after the surgical resection of ICC is the high incidence of tumor recurrence, which occurs in 50% to 70% of patients. Tumor recurrence occurs intra-hepatically (either at the surgical margin or at a different site within the liver) and/or extra-hepatically (typically lungs, lymph nodes, peritoneum, and bones). Alternative therapies include chemotherapy, radiotherapy, and more recently, checkpoint inhibitor-based immunotherapy; however, their efficacy remains limited, and virtually all patients with ICC will ultimately succumb to their disease. Disease recurrence is assumed to be caused by residual very small tumors called micrometastases, which are not eliminated by chemo- and/or radiotherapy and reside in the patient. The chemo- and radiotherapy resistance of micrometastases supports the cancer stem cell theory, which postulates that cancer-initiating cells (CICs) play a major role in disease recurrence and metastatic spread, the two major causes of patients morbidity and mortality. The lack of efficacy of conventional therapies to eradicate ICC emphasizes the urgent need to design radically novel treatment strategies for patients with ICC that can specifically target and eradicate CICs. To address this unmet medical need, we aim to develop a cancer immunotherapy in which immune cells, called T cells, are genetically engineered to target only the tumor cells. These immune cells are called CAR T cells (Chimeric Antigen Receptor T cells). Our preliminary in vitro experiments indicate that they can eradicate not only differentiated ICC cells but also ICC CICs, the cells likely responsible for tumor relapse. In this study, we aim to utilize CAR T cells as a therapeutic strategy to eliminate residual cancer cells which persist after the surgical removal of the primary tumor and are responsible for disease relapse, which ultimately leads to death. Oncologists call this type of treatment an adjuvant therapy to target minimal residual disease. The innovative high-risk/high-gain strategy we have designed for the treatment of intrahepatic cholangiocarcinoma micrometastases represents a paradigm shift in the application of CAR T cell therapy for solid tumors since it will be utilized in an adjuvant setting in hosts harboring minimal residual disease. If the results generated from this proposal are positive, the clinical application of this strategy has the potential to provide a potentially curative therapeutic option to the subset of intrahepatic cholangiocarcinoma patients at high risk for disease relapse following curative surgical resection. Completing preclinical studies like the one outlined in this application will take 1-2 years and, if it advances to clinical settings, will require an additional 4-5 years before patients can directly avail and benefit from it. In the short term, we expect that the results of this proposed study will help us better explain the process of cancer spread in ICC and further enlighten us on the relationship between tumor burden and the effectiveness of C
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310886
Entities
People
- Cristina Ferrone
Organizations
- Cedars-Sinai Medical Center
- United States Army