Opening of FLC Peptide Vaccine Clinical Trial 2020
A new clinical trial of an immune therapy for fibrolamellar carcinoma (FLC) is now recruiting subjects at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, MD. The study asks if individuals can mount an effective immune response against FLC by specifically targeting the unique chimeric protein (resulting from a DNAJB1-PRKACA gene fusion) believed to drive the growth of almost all such tumors. Trial subjects will be given an experimental vaccine containing a peptide (small segment of a protein) that corresponds to the junction region linking the two parts of the chimeric protein. They will simultaneously receive two FDA-approved drugs, Opdivo (nivolumab) and Yervoy (ipilimumab), that may enhance the immune response against FLC by overcoming “checkpoint” systems that can limit the immune system’s ability to fight a cancer. The study’s principal investigator is Dr. Mark Yarchoan. Details and contact information can be found at: https://www.clinicaltrials.gov/ct2/show/NCT-04248569
A Pilot Study of a DNAJB1-PRKACA Fusion Kinase Vaccine Combined with Nivolumab and Ipilimumab for Patients with Fibrolamellar Carcinoma (FLC) 2019-2021
Principal Investigator: Mark Yarchoan, MD, Assistant Professor, Oncology/Division of GI Malignancies, Sidney Kimmel Comprehensive Cancer Center
FLC is a rare and often lethal form of liver cancer for which there is no standard treatment option beyond surgery. Immune checkpoint inhibitors are a revolutionary new form of cancer therapy. These drugs “take the brakes off” the immune system, enhancing its ability to fight cancer. Examples of these new medicines include the PD1 inhibitor nivolumab (Opdivo), and the CTLA-4 inhibitor ipilimumab (Yervoy). Many patients with FLC currently receive an immune checkpoint inhibitor off-label. However, our clinical experience suggests that they generally do not achieve strong anti-tumor responses from single checkpoint inhibitors. We seek to develop immunotherapy approaches to FLC that offer greater clinical benefit.
This project entails the first test in patients of a combination of two checkpoint inhibitors (nivolumab and ipilimumab) plus a new vaccine designed to direct the immune response against FLC by targeting the DNAJ-PKAc fusion protein found in almost every case of this cancer. The fusion protein serves as a neoantigen – an abnormal protein found in the cancer but absent from normal cells. The selective component of the vaccine is a peptide (short segment of a protein) overlapping the junction between the DNAJ and PKAc segments of the fusion protein, which is precise and consistent among FLC tumors. Thus, potentially the vaccine could be harnessed by the immune system to recognize and eliminate cancer cells in any FLC patient with the characteristic gene fusion, in contrast to cancers for which a neoantigen vaccine must be personalized for each individual patient.
The primary goal of the study is to begin assessment of the safety and clinical activity of the FLC-vaccine in combination with nivolumab and ipilimumab in patients for whom complete surgical resection of the cancer is not possible. We also seek to determine if the combination of peptide vaccine and checkpoint inhibitors will promote induction and/or expansion of T cells that specifically recognize the DNAJ-PKAc fusion protein.
Blood markers for fibrolamellar 2010
While at Johns Hopkins (he is now at Mayo Clinic in Rochester, MN), Dr. Michael Torbenson wrote the first paper on blood markers for fibrolamellar which was published in the journal, Modern Pathology, in late 2010. The article recognized FCF for their financial support. Dr. Torbenson was studying the microRNA of fibrolamellar cells and his laboratory was working on a genetic sequencing study of fibrolamellar to determine if there are genetic mutations unique to fibrolamellar cells.