A Novel Immuno-Oncology Pipeline for FGFR2 Fusion-Positive Cholangiocarcinoma
Abstract
The overall scientific objective of this project is to identify and validate more effective immunotherapeutic strategies able to improve the outcome of patients with intrahepatic cholangiocarcinoma (iCCA). With an incidence of 1-2 cases per 100,000 people and steadily increasing mortality rates, iCCA is a rare but devastating type of liver cancer. Currently, the only potential cure for iCCA is to diagnose the cancer at an early stage when it can be removed surgically. Unfortunately, early diagnosis is extremely difficult since iCCA generally presents with mild and unspecific symptoms. Therefore, the majority of patients are diagnosed at advanced stages when the only option is a combination of chemotherapy plus immunotherapy, with 95% of patients dying within 5 years, highlighting the urgent need to improve the therapeutic arsenal for this disease. Oncogenic fusions involving the FGFR2 gene occur in up to 20% of all iCCA patients and positive results from pivotal phase 2 clinical studies have confirmed that they are promising therapeutic targets for FGFR2-positive iCCA patients. Despite this success, initial clinical responses are modest and short-lived due to complex mechanisms of resistance. Therefore, the design of combination strategies able to enhance the extent of initial responses in FGFR fusion-driven iCCA patients remains of the utmost importance. Checkpoint inhibitors (ICIs) are immunotherapeutic drugs that boost the patient’s own immune response by blocking key checkpoint proteins that prevent immune cells to kill the tumor. While blockade of the checkpoint protein PD1 or its ligand PD-L1 has shown promise in many solid cancers, including iCCA, only a small fraction of patients respond. Emerging evidence suggest that specific oncogenic pathways, including FGFR signaling, can promote immunosuppression and thereby, compromise antitumor immune responses and sensitivity to ICIs. If inhibition of oncogenic FGFR fusion signaling could reduce the immunosuppression and evasion mechanisms, combining FGFR inhibitors with ICIs could overcome the limitations of each strategy alone. The rationale of this study is that by understanding how FGFR2 fusions impact immune cell composition and functions, we will be able to design novel immunotherapy-based combination regimens that enhance initial clinical responses in FGFR2 fusion-driven iCCA. In pursuing this project, we seek to establish and characterize a novel series of immunocompetent iCCA murine models driven by FGFR2 fusions (Research Method Focus) and use them to thoroughly investigate the immunoregulatory role of FGFR gene fusions (Biology Focus) as well as identify promising immunotherapeutic combinations (Therapy Focus). We expect that the discoveries made through this project will impact the design of forthcoming clinical trials in FGFR2 fusion-driven iCCA patients. Overall, the results of our efforts will provide the benefit of improving the outcome of a large fraction of patients with this cancer and bringing new drugs to these patients faster than ever as we estimate that the timeframe for translating results obtained in this project into clinical results can be of around 3 years. There are no risks to patients that are directly attributable to the studies proposed in this application. Should new drugs be tested, however (which is beyond the scope of this application), these agents could lead to unwanted toxicities or side effects. As noted, however, such clinical studies are not a direct component of this application. The ultimate applicability of this research will be widespread, and could improve the outcome for patients with iCCA, including Veterans and the U.S. population suffering from this disease. Indeed, despite being a rare cancer, iCCA disproportionately impact U.S. Veterans, their families, and other military beneficiaries. This is in part due to the fact that the prevalence of risk factors associated with iCCA (i.e., viral hepa
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310641
Entities
People
- Daniela Sia
Organizations
- Icahn School of Medicine at Mount Sinai
- United States Army