FusionVAC22_01: a phase I clinical trial evaluating a DNAJB1-PRKACA fusion transcript-based peptide vaccine combined with immune checkpoint inhibition for fibrolamellar hepatocellular carcinoma and other tumor entities carrying the oncogenic driver fusion

Abstract

The DNAJB1-PRKACA fusion transcript was identified as the oncogenic driver of tumor pathogenesis in fibrolamellar hepatocellular carcinoma (FL-HCC), also known as fibrolamellar carcinoma (FLC), as well as in other tumor entities, thus representing a broad target for novel treatment in multiple cancer entities. FL-HCC is a rare primary liver tumor with a 5-year survival rate of only 45%, which typically affects young patients with no underlying primary liver disease. Surgical resection is the only curative treatment option if no metastases are present at diagnosis. There is no standard of care for systemic therapy. Peptide-based vaccines represent a low side-effect approach relying on specific immune recognition of tumor-associated human leucocyte antigen (HLA) presented peptides. The induction (priming) of tumor-specific T-cell responses against neoepitopes derived from gene fusion transcripts by peptide-vaccination combined with expansion of the immune response and optimization of immune function within the tumor microenvironment achieved by immune-checkpoint-inhibition (ICI) has the potential to improve response rates and durability of responses in malignant diseases. The phase I clinical trial FusionVAC22_01 will enroll patients with FL-HCC or other cancer entities carrying the DNAJB1-PRKACA fusion transcript that are locally advanced or metastatic. Two doses of the DNAJB1-PRKACA fusion-based neoepitope vaccine Fusion-VAC-XS15 will be applied subcutaneously (s.c.) with a 4-week interval in combination with the anti-programmed cell death-ligand 1 (PD-L1) antibody atezolizumab starting at day 15 after the first vaccination. Anti-PD-L1 will be applied every 4 weeks until end of the 54-week treatment phase or until disease progression or other reason for study termination. Thereafter, patients will enter a 6 months follow-up period. The clinical trial reported here was approved by the Ethics Committee II of the University of Heidelberg (Medical faculty of Mannheim) and the Paul-Ehrlich-Institute (P-00540). Clinical trial results will be published in peer-reviewed journals.

Trial registration numbers: EU CT Number: 2022-502869-17-01 and ClinicalTrials.gov Registry (NCT05937295).

Keywords: DNAJB1-PRKACA fusion transcript; FL-HCC; FLC; immune checkpoint inhibition; neoepitope; peptide vaccination.

Figure 1

Treatment schedule of the FusionVAC22_01 clinical trial. Trial duration for each patient is approximately 1.5 years including 54 weeks of treatment and 6 months follow-up time. The vaccine Fusion-VAC-XS15 (500µl) will be administered subcutaneously (s.c.). Two vaccinations will take place with a 4-week interval at the beginning of the treatment phase. After 11 months a booster vaccination can be applied depending on T-cell responses. 1680mg atezolizumab will be applied every 4 weeks starting at day 15 after the first vaccination. Anti-PD-L1 treatment will be continued after end of vaccination phase until end of treatment phase or until disease progression or occurrence of a ≥ grade 3 adverse event that requires permanent discontinuation of Fusion-VAC-XS15 or atezolizumab or other reason for study termination. In case of temporary therapy interruptions, the planned therapy time may be extended to apply the planned maximum number of 13 atezolizumab doses. End of treatment (EOT) visit will be conducted 4 weeks after the 13^th and last atezolizumab application or in case of preliminary termination of the treatment 4 weeks after last administration of an investigational medicinal product (IMP). After end of treatment phase, patients will enter a 6-month follow-up period, including 2 follow-up visits taking place 2 and 4 months after last administration of an IMP. The final end of study visit (EOS) will be performed 6 months after last administration of an IMP. pVac, peptide vaccination with Fusion-VAC-XS15; IM, Immune monitoring; m, month. This figure was created with BioRender.com.

Figure 2

Vaccine composition. The DNAJB1-PRKACA fusion transcript-based peptide vaccine (Fusion-VAC-XS15) consists of 300µg of a 22mer neoepitope spanning the fusion region (FusionVAC-22) adjuvanted with the TLR 1/2 ligand XS15 (50µg) emulsified in Montanide ISA 51 VG (1:1).