Goal: Identify and validate a portfolio of DNAJB1-PRKACA-specific T cell receptors
Principal Investigator: Paul Thomas, PhD
Grant length: Two years
Study overview: The DNAJB1-PRKACA fusion protein is the defining genetic driver of fibrolamellar carcinoma (FLC) and represents one of the most attractive targets for precision immunotherapy. Because this abnormal protein is present in cancer cells but absent from healthy tissues, fragments of the fusion protein can be recognized by the immune system as tumor-specific neoantigens. Researchers have shown that some FLC patients naturally develop T cells capable of recognizing these neoantigens, and recent clinical studies demonstrated that vaccination against the fusion protein can further enhance these anti-tumor immune responses.
Despite this promise, many patients either fail to generate sufficiently strong immune responses or are unable to maintain them over time. One strategy to overcome this challenge is T cell receptor-engineered T cell (TCR-T) therapy. In TCR-T therapy, a patient’s T cells are genetically modified to express receptors that recognize specific cancer targets, then expanded and returned to the patient to attack tumor cells. Several TCRs capable of recognizing DNAJB1-PRKACA fusion-derived peptides have already been identified, providing proof that this approach could be feasible in FLC.
A major obstacle, however, is the diversity of human leukocyte antigen (HLA) molecules. T cell receptors recognize cancer targets only when they are presented by a specific HLA molecule on the surface of a cell. Because HLA types vary substantially across the human population, a TCR developed for one HLA subtype may only benefit a limited subset of FLC patients. To date, the known DNAJB1-PRKACA-specific TCRs are restricted to relatively few HLA types, limiting their potential clinical applicability.
Dr. Thomas and his team aim to address this challenge by creating a much broader catalog of DNAJB1-PRKACA-specific T cell receptors that collectively recognize the fusion protein across many different HLA backgrounds. The project will leverage blood samples collected from patients who participated in DNAJB1-PRKACA peptide vaccine studies. Because these patients have already mounted immune responses against the fusion protein, their T cells represent a rich source of potentially therapeutic receptors.
The ultimate deliverable of the project will be a library of validated DNAJB1-PRKACA-specific T cell receptors with broad HLA coverage. Such a resource could serve as the foundation for future TCR-T cell therapies that are accessible to the vast majority of FLC patients rather than only a small subset defined by a particular HLA type. Beyond enabling future cellular therapies, these data will provide important insights into how the immune system recognizes the defining oncogenic driver of FLC and may help guide the next generation of fusion-targeted immunotherapies.
If successful, this work will help move the field from demonstrating that fusion-specific immune responses are possible in FLC to establishing a practical framework for developing broadly applicable T cell therapies directed against the cancer’s molecular driver.