FCF Funded Projects

A Pilot Study of a DNAJB1-PRKACA fusion kinase vaccine combined with nivolumab and ipilimumab for patients with fibrolamellar carcinoma (FLC)

Status: Active

Timeframe: 2019-2022

Goal: Assess potential to induce immune response with a FLC therapeutic vaccine

Principal Investigator: Mark Yarchoan, MD, Associate 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,clinical experience suggests that they generally do not achieve strong anti-tumor responses from single checkpoint inhibitors. This study seeks 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, 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.