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St. Jude Children’s Research Hospital

2022

Defining the potential of DNAJB1-PRKACA fusion-specific T cells across human populations

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

Principal Investigators: Paul G. Thomas, PhD

Grant length: Two years

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.

2022

Multicenter consortium to define the single-cell activity landscape of fibrolamellar carcinoma

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)

Grant length: Two years

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 precise 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).