National Translational Science Network of Precision-based Immunotherapy for Primary Liver Cancer

Background: Primary liver cancer (PLC) is the 2nd most common cause of cancer-related death worldwide and the one cancer with the fastest rising incidence and mortality in the U.S. PLC consists of two main histological subtypes, i.e., hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), in which diagnoses and treatment decisions are solely based on their baseline clinical features. However, whether these subtypes are truly distinct or share some fundamental features which can be pursued to improve clinical management is currently unclear. In addition, chronic liver diseases, due to complex etiologies such as viral hepatitis, alcohol consumption, chemicals, parasites or dietary factors, underlie and contribute to liver damage, increasing the risk of HCC and CCA development and progression. Consequently, PLC is clinically and biologically heterogeneous which has impeded biological assessment and clinical treatment. Despite considerable efforts towards improving diagnosis and development of new treatment modalities, the improvement of PLC patient survival is minimal. For certain patients at early or intermediate disease stages, resection and percutaneous local ablation or Transarterial chemoembolization are available. However, the majority of patients present at advanced stages of disease, where the current gold standard of treatment is sorafenib, providing only a minimal improvement in survival time. PLC therefore remains among the most difficult-to-treat malignancies, with a 5-year survival rate of less than 15% in the United States. Thus, it is imperative that new treatment modalities are developed to limit cancer development and treat advanced PLC. Immunotherapy (IO) is a promising new approach in PLC treatment. Alterations of the immune system, a component of the revised hallmarks of cancer, is recognized as a central player in carcinogenesis and cancer progression. Thus, strategies to inhibit or re-direct the immune response to the presence of tumors are currently being employed or developed. Immune-checkpoint inhibitors have shown promise in clinical trials of several solid tumors. Of particular note are monoclonal antibody-based therapy to block immune-inhibitory molecules, including programmed cell death protein-1 (PD-1), programmed cell death 1 ligand 1 (PDL-1) and cytotoxic T lymphocyte antigen 4 (CTLA4), which block anti-tumor T cell activity. However, the capacity of these therapies to reduce incidence and progression of PLC are still relatively unknown. Currently, several trials are underway to study the impact of immune checkpoint inhibitors as single agents or in combination with targeted therapy, on PLC development and outcome. Initial findings from Phase I/II clinical trials of PLC are promising but suggest that only certain patients respond to such treatment regimens while others do not or suffer from resistance/relapse. At the moment, it is difficult to determine which patient may benefit from immune therapy, due in large part to the lack of large comprehensive studies, biobank resources of specimens and biospecimen collection in clinical trial protocols, which deter our ability to understand and define critical genomic or genetic factors that contribute to patient response. Hence, we plan to collect PLC patient specimens and clinical data from those undergoing immunotherapies at NIH Clinical Center and a few extramural clinical sites to develop predictors for (a) response or resistance to immunotherapy and (b) acquired resistance to immunotherapy. Objective: To establish a biospecimen repository for genomic, genetic and epigenetic analysis to study the biology of PLC development and progression. Eligibility: Individuals with histologically/ultrasound/imaging confirmed or suspicious lesions of HCC or CCA. Individualss with planned or a history of at least 1 dose of immunotherapy for HCC or CCA. Age \>= 18 years old at date of study consent Design: This will be a long-term multi-center study to comprehensively study participants with primary liver cancer (PLC). Participants will provide clinical information (including medical history, clinical tests, imaging studies and reports, surgical pathology reports, genetic test results). Tissue samples, blood, urine and fecal samples will be obtained from participants during this study. Broad spectrum of scientific experiments, including genomics, metabolome, microbiome and immune monitoring will be performed. Local physicians will be provided with test results of genomics panel evaluation (TruSight Oncology 500 (TSO-500). Since long-term follow-up of individuals with PLC is a major feature of the study, local sites intend to maintain active contact with study participants for as long as possible. Participants will be followed throughout the course of their illnesses, with particular attention to patterns of disease recurrence and progression, response to therapies and duration of responses. National death index data can also be utilized to obtain patient outcome information.