Funded immunotherapy-related research

The following are active and completed projects funded by FCF centered on characterizing the immune environment and investigating new immunotherapy approaches for FLC.

Project summaries: Immunotherapy-related efforts

Defining the potential of DNAJB1-PRKACA fusion-specific T cells across human populationsSt. Jude Children’s Research HospitalActive

Timeframe: 2022 - 2024

Goal: Defining the most promising immunological targets that can be translated into effective cell-based immunotherapies

Principal Investigators: Paul G. Thomas, PhD

Study overview: New immunotherapeutic approaches have produced spectacular outcomes for a small subset of tumors, including certain melanomas, lung cancers, and leukemias, but these dramatic cures have not been broadly observed across all tumor types, including for fibrolamellar carcinoma (FLC). The goal of this proposal is to advance immunotherapy for FLC, by defining the most promising immunological targets that can be translated into effective cell-based immunotherapies. In addition, these results will provide sensitive diagnostic tools for determining which patients are most likely to benefit from diverse immunotherapeutic approaches, including those currently in use or in trials. Immunotherapies work by activating T cells, which can recognize tumor cells by identifying fragments of proteins not present in healthy cells. In principle, FLC is an outstanding candidate for immunotherapy because virtually all tumors across all patients contain the same tumor-specific fusion protein, DNAJB1-PRKACA. A difficulty with T cellbased therapies, however, is that the targets T cells recognize vary widely from person to person, even if derived from exactly the same protein, as in the case of FLC. Also, multiple types of T cells can attack the exact same target, and this diversity has limited the ability to identify effective T cells within and between patients.

This effort addresses both sides of this complex diversity—the diversity in tumor targets within the FLC fusion and the many different T cells that attack them. Using multiple innovative computational and technological approaches for T cell and antigen characterization, the study team will:

  1. Identify the most useful FLC fusion targets across the vast majority of the human population
  2. Isolate corresponding T cells (and the critical T cell receptor) that can attack these tumor antigens, and
  3. Determine which T cell-antigen combinations have the highest efficiency for tumor killing.

Collectively, the successful completion of this proposal will identify potential T cell-based therapies for clinical translation and an immediately applicable set of diagnostic tools for assessing a patient’s response to fusion-targeted immunotherapies.

Multicenter consortium to define the single-cell activity landscape of fibrolamellar carcinoma.Cornell, Johns Hopkins and St. JudeActive

Timeframe: 2022 - 2024

Goals: Advance immunotherapy for FLC by defining promising immunological targets that can be translated into effective cell-based immunotherapies

Principal Investigators: Praveen Sethupathy, PhD (Cornell University); Mark Yarchoan, MD (Johns Hopkins University); Paul G. Thomas, PhD (St. Jude Children’s Research Hospital)

Study overview: Like tumors of other cancer types, the microenvironment of FLC tumors is highly complex, comprising many different cell types. It is now well-established from investigation of other cancer types (such as lung, breast, and pancreatic cancer) that cross-talk among these different cell types can promote tumor development, growth, and spread. A recent study in the Sethupathy lab identified critical regions of the genome that are uniquely activated in FLC. These regions offer clues about the genes that might be most critical for the development of FLC. However, an important limitation of this work is that it was performed on bulk FLC tissue, which does not resolve different cell types, and instead treats tumor tissue as one whole unit. This means that the specific cell types in which these FLC genes are active is not yet known. This represents a major knowledge gap. Identification of the specific cell types in which FLC genes are active would then allow more precide study of the functions of these genes in FLC, and facilitate the development of more effective targeted therapeutics.

To help bridge this knowledge gap, the Sethupathy (Cornell), Yarchoan (Johns Hopkins), and Thomas (St. Jude Children’s) labs will participate in a collaborative research consortium to develop an FLC tumor “atlas”. They will leverage state-of-the-art genome-scale technologies to provide unprecedented resolution of the cellular and molecular landscape of FLC. This consortium brings together three groups with longstanding interests and experience in FLC research, as well as specific expertise in genomics and gene regulation (Sethupathy), clinical oncology (Yarchoan), and immunology (Thomas and Yarchoan).

Cancer Research Institute (CRI) fellowship partnershipCancer Research InstituteActive

Timeframe: 2016 - 2023

Goal: Develop and fund a series of three-year FLC research fellowships

Overview: 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 several years, FCF has worked with CRI to develop, staff and fund prestigious three-year research fellowships. The young researchers awarded these fellowships have been making great strides forward in investigating the applicability of immunotherapy to FLC treatment.

Therapeutic modulation of tumor-infiltrating T cell function in fibrolamellar carcinomaUniversity of WashingtonActive

Timeframe: 2023 - 2025

Goals: Identifying factors in the tumor environment that impair immune responses to FLC and defining potentially effective immunotherapy strategies

Principal Investigators: Venu Pillarisetty, MD (University of Washington); and Kevin Barry, PhD (Fred Hutchinson Cancer Center)

Study overview: Immunotherapy – harnessing patients’ immune systems to attack tumor cells – has become established as an exceptionally promising approach in cancer treatment. However, the few published studies of FLC to date have showed limited success of currently approved immunotherapies, such as immune checkpoint inhibitors. More promising results in FLC have been seen in (as of yet) unpublished laboratory tests and a clinical trial of a peptide vaccine targeting the cancer’s unique molecular driver. However, among patients who developed a strong immune response against the FLC driver, only a subset showed marked clinical benefit.

Prior work from Dr. Pillarisetty revealed characteristics of immune cells in the tumor environment indicating that their ability to find and kill cancer cells is suppressed in FLC. The main goal of the proposed research is to better understand factors responsible for this suppression, and to find ways to overcome the barriers and thereby fully unleash the therapeutic potential of immune cells against FLC. Certain classes of T lymphocytes, including some capable of directly killing cancer cells, are found within human FLC tumors. However, these immune cells are sequestered away from cancer cells. Second, receptors on T cells do not multiply as much as in other tumor types suggesting the immune system is not responding normally to immune triggers called antigens. Third, cytotoxic T cells—immune cells that can kill cancer cells—are dysfunctional. However, blocking key elements in immune pathways increases immune cell access to cancer cells, reinvigorates T cell antitumor activity, and enhances immune-mediated killing of cancer cells.

This project aim is to investigate how immunotherapy alters these attributes and thus may be employed to reverse the immunosuppression in FLC. The team will characterize the distribution of immune cells in relation to cancer cells and evaluate the proliferation of specific T cells after immunotherapy. They will use slices of FLC tumors from patients to test how combinations of immunotherapy influence the cancer-killing function of T cells. This work will focus on the roles of members of two broad classes of signaling molecules in the tumor microenvironment, known as cytokines and chemokines. These are secreted proteins that regulate inflammatory responses (cytokines) and control cell migration (chemokines). Finally, as an important resource for the field, they will develop a novel mouse model of FLC with an intact immune system to make studying the disease easier.

The ultimate goal is to discover immune system-based treatments that can prolong survival in—or even cure—FLC.

Developing the foundation for an immunotherapy program to treat fibrolamellar hepatocellular carcinomaUniversity of WashingtonCompleted

Timeframe: 2020 - 2021

Goal: Understand the characteristics of the immune cells within FLC, and use this knowledge to optimize immunotherapy for this disease

Principal Investigator
: Venu Pillarisetty, MD

Study overview: Despite the application of many advanced treatments, such as surgery and chemotherapy, most patients with FL-HCC die of the disease. The immune system serves to protect the body from not only from infections but also from cancer; therefore, it has long been a goal of scientists to understand how to create therapies for cancer that enhance this natural defense system. Immunotherapy has recently become a reality for many types of cancer including liver cancer, and it is hoped to extend this work to FL-HCC. The goals of this project were:

  • To learn more about the types of immune cells that exist in FL-HCC, as some of these cells called tumor infiltrating lymphocytes (TIL) play a critical role in how patients respond to immunotherapy
  • To attempt to grow these cells from fresh tumors,using a technique to grow slices of tumor in culture, which most closely mimics the real tumor in patients.
  • To apply time lapse microscopy in live tumor samples to be able to watch the interaction of the immune system with tumor cells.

This project aimed to expand the understanding of the characteristics of the immune cells within FL-HCC, while simultaneously using this knowledge to optimize immunotherapy for this disease.

Modulating stromal-immune cell interactions to activate anti-tumor immunity to fibrolamellar carcinomaUniversity of WashingtonCompleted

Timeframe: 2019 - 2020

Goal: Assess whether supressing checkpoints or signaling by a specific chemokine (CXCL12) can enhance immune response

Principal Investigator: Venu Pillarisetty, MD

Study overview: Immunotherapy, harnessing the patient’s immune system to precisely target cancer cells, has emerged as a promising approach to treat many cancers. It has been discovered that fibrolamellar carcinoma (FLC) tumors contain a class of immune cells called T cells that potentially could recognize and destroy the cancer cells. However, the therapeutic ability of T cells can be limited by suppressive factors made by both cancer cells and other cells in the tumor such as the abundant fibroblastic stromal cells that give FLC its name. Suppressive molecules in the tumor microenvironment that may limit anti-cancer immune responses include “immune checkpoints” and signaling molecules known as cytokines. The latter include chemokines, small protein chemical messengers that influence cell migration.

This study aimed to determine whether blockade of checkpoints and/or signaling by a specific chemokine (CXCL12) can enhance T cell mediated immunity against fibrolamellar cancer cells, using slice cultures of human FLC tumors.

T cell immunotherapy in fibrolamellar cancerUniversity of WashingtonCompleted

Timeframe: 2016 - 2019

Goal: Characterize T-cells in the FLC tumor microenvironment

Principal Investigator: Kevin M. Sullivan, MD

Study Overview: 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, the team investigated a well-established method of using the immune system, successful in treating other cancers such as melanoma, as a treatment for fibrolamellar. They used a variety of techniques to look at which types of immune cells reside within fibrolamellar tumors. One type of immune cell, called the T cell, is of particular interest because it can specifically recognize and destroy cancer cells. The study group has previously confirmed that T cells are found within fibrolamellar tumors. Specific goals included:

  • Gaining a detailed understanding of the characteristics of the T cells that are active within fibrolamellar tumors.
  • Growing and activating these T cells and testing their ability to fight cancer cells in cell cultures and slices of fibrolamellar tumor grown in the laboratory.

The goal of his project was to build knowledge of the immune microenvironment that will help make T cell immunotherapy against fibrolamellar a reality.

Investigating immune checkpoint biomarkers in tissue and peripheral blood of patients with fibrolamellar hepatocellular carcinomaJohns Hopkins UniversityCompleted

Timeframe: 2016 - 2019

Goal: Define the dominant immune checkpoint pathway in FLC

Principal investigator: Amy K. Kim, MD

Study overview: Tumor cells produce immune checkpoint molecules that suppress host immune response and allow evasion from immune responses. 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. At the time of this study, it was unclear how fibrolamellar carcinoma would respond to different immune checkpoint blockades, including anti-PD1 therapy. In addition, it was unclear how circulating tumor cells (CTCs) in the blood that have disseminated from the primary tumor induce anti-tumor immune response outside the tumor environment.

This study aimed to addressed these issues and create a deeper understanding the immune checkpoint landscape in fibrolamellar carcinoma to help guide the development of future immunotherapies. Specifically, this study sought to:

  • define the dominant immune checkpoint pathway in fibrolamellar cancer and its interaction with the patient’s immune response in the tumor, and
  • determine how immune checkpoint markers are associated with circulating tumor cells in the peripheral blood, in comparison to the primary tumor.
Pre-clinical studies of the interactions of the immune system with FL-HCCUniversity of California at San FranciscoCompleted

Timeframe: 2016 - 2019

Goal: Study the interactions between the immune system and FLC in a mouse model

Principal Investigator: Kevin Barry, PhD

Study overview: 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 and allow effective killing of tumor cells. These therapies function 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 non-FLC cancer patients, leading to tumor regression and offering long-term protection, effectively providing a cure to cancer in some patients. However, at the time of this study,very little was known about how the immune system interacts with FLC or if immunotherapy would be an effective treatment for FLC.

The study of the efficacy of immunotherapy in the treatment of FLC is hampered by the fact that the current patient-derived xenograft animal models of FLC utilize the transplantation of human tumor into immune compromised animals. The lack of an effective immune system allows the host mice to grow tumors, but also makes it impossible to study the interactions between the immune system and FLC in this model system. This study harnessed a preclinical mouse model of FLC developed by Dr. Julien Sage and Stanford University with a fully functional immune system to understand how the immune system interacts with FLC. These studies represented the first steps towards treating FLC patients with immunotherapy in the clinic.