FCF has partnered with the prestigious Cancer Research Institute (“CRI”) to specifically focus on the role immunotherapy may have in creating curative therapies for fibrolamellar. CRI has been promoting immunotherapy research for 65 years, long before the establishment cancer treatment and research community recognized immunotherapy as a legitimate prospect for cancer patients.
For the past 5 years, FCF has worked with CRI to develop and fund prestigious three-year fibrolamellar (FLC) research fellowships. These young researchers are making great strides forward. FCF/CRI fellowships that FCF has funded include:
- Role of the innate immune system in Fibrolamellar Hepatocellular Carcinoma (FL-HCC) using zebrafish as a model system
2016 – 2019
Principal Investigator: Sofia de Oliveira, Ph.D., EMBO Postdoctoral Fellow, Huttenlocher Immunology Lab
About 80% of FHC cases are characterized by the presence of an activated form of a protein called Protein Kinase A (PKA). The mechanism of how active PKA leads to disease remains unclear. Normal PKA is involved in complex signaling pathways that among other processes control innate immune response. A better understanding of the mechanisms triggered by this active PKA and how it modulates innate immune response is crucial to develop more efficient drug therapies and increase the survival rate of fibrolamellar patients. Up to now, there are limited animal models to study FHC, which hampers our knowledge about the disease. This research proposes to take advantage of the outstanding characteristics of zebrafish and develop a FHC model. Zebrafish has proven to be an extremely useful tool to study innate immunity and cancer biology. Additionally, it has been used to study liver development, conventional hepatocellular carcinoma and several other liver disorders, displaying remarkable similarities and sharing genetic signatures with human diseases. More over zebrafish is the only vertebrate model with high homology with humans that allows visualization of cellular and molecular interactions in a whole organism context without the need to use invasive imaging methods since the larvae are transparent.
Innate immune cells, such as neutrophils and macrophages are important players in cancer development. Their presence in the tumor microenvironment might be beneficial or detrimental to cancer progression, depending on the type of cancer. This study will leverage the zebrafish models to study the role of different innate immune cells in FHC, and assess the potential role of neutrophils and macrophages as therapeutic targets for FHC.
- T cell immunotherapy in fibrolamellar cancer
2016 – 2019
Principal Investigator: Kevin M. Sullivan, M.D., General Surgery
Immunotherapy is a form of cancer treatment that harnesses the patient’s own immune system to fight the disease. The immune system can precisely target cancer cells, while also minimizing damage to the remainder of the body’s normal cells. In this project, we will investigate a well-established method of using the immune system, successful in treating other cancers such as melanoma, as a treatment for fibrolamellar. We will start by using a variety of techniques to look at which types of immune cells reside within the fibrolamellar tumors. One type of immune cell, called the T cell, is of particular interest because it can specifically recognize and destroy cancer cells. In preliminary work, our group has confirmed that T cells are found within a fibrolamellar tumor. In this project, we will gain a detailed understanding of the characteristics of the T cells that are active within fibrolamellar tumors. We then plan to grow and activate these T cells and test their ability to fight cancer cells in cell cultures and slices of fibrolamellar tumor grown in the laboratory. Ultimately, our project will provide the basis for making this type of T cell as a treatment against fibrolamellar a reality.
- Investigating immune checkpoint biomarkers in tissue and peripheral blood of patients with fibrolamellar hepatocellular carcinoma
2016 – 2019
Principal investigator: Amy K. Kim, M.D., Assistant Professor
The understanding of immune checkpoint molecules that suppress host immune response against tumor cells and the discovery of drugs that block these immune checkpoints have revolutionized current cancer treatment. Anti-PD1 (programmed cell death protein 1) immunotherapy has shown benefit in many cancer types, but certain cancers have also shown strong resistance to this immunotherapy. It is unclear how fibrolamellar cancer would respond to different immune checkpoint blockade, including anti-PD1 therapy. In addition, there is a need to investigate how circulating tumor cells (CTCs) in the blood that have disseminated from the primary tumor site induce anti-tumor immune response outside the tumor environment. This project will address these issues by pursuing the following specific aims: 1) to define the dominant immune checkpoint pathway in fibrolamellar cancer and its interaction with the patient’s immune response in the tumor, and; 2) to determine how immune checkpoint markers are associated with circulating tumor cells in the peripheral blood, in comparison to the primary tumor site. Understanding the immune checkpoint expressions in fibrolamellar cancers will guide in the future selection of immunotherapy and studying the role of circulating tumor cells and tumor-associated immune cells can reveal a novel way to predict cancer treatment response that does not require an invasive procedure for tumor tissue from the patients.
- Pre-clinical studies of the interactions of the immune system with FL-HCC
2016 – 2019
Principal Investigator: Kevin Barry, Ph.D., Postdoctoral Scholar
All sequenced human fibrolamellar hepatocellular carcinoma (FL-HCC) samples contain a mutation that leads to a fusion of the proteins DNAJB1 and PRKACA. The mutant DNAJB1-PRKACA protein is thought to drive the development of FL-HCC. There is a clear need to further understand the mechanism of FL-HCC tumorigenesis and to develop novel treatments.
Cancer immunotherapies harness the power of the immune system to kill tumors. Checkpoint blockade immunotherapies are an exciting class of cancer immunotherapies that remove the brakes from the immune system by targeting molecules that inhibit tumor-directed responses by immune cells called T cells. T cells are important for protecting patients from tumors as these cells directly kill tumor cells and modulate the global immune response towards tumors. Immunotherapies targeting T cells have been remarkably effective in treating cohorts of non FL-HCC cancer patients, leading to tumor regression and immune memory which offers long-term protection; effectively providing a cure to cancer in some patients. However, very little is known about how the immune system interacts with FL-HCC or if immunotherapy would be an effective treatment for FL-HCC. The study of the efficacy of immunotherapy in the treatment of FL-HCC is hampered by the fact that the current pre-clinical animal model of FL-HCC utilizes the transplantation of human tumor into immune compromised animals, making it impossible to study the interactions between the immune system and FL-HCC in a tractable system.
This research, in collaboration with Dr. Julien Sage’s group and Stanford University, will generate a pre-clinical animal model of FL-HCC in mice with fully functional immune systems and will undertake the initial studies of how the immune system interacts with FL-HCC. These studies represent the first step in moving towards treating FL-HCC patients with immunotherapy in the clinic.