Safety and efficacy of prophylactic and therapeutic vaccine based on live-attenuated Listeria monocytogenes in hepatobiliary cancers

Inga Hochnadel,Lisa Hoenicke,Robert Geffers,Lavinia Neubert,Tetyana Yevsa,Henrike Lenzen,Thomas Longerich,Carlos Alberto Guzmán,Ralf Lichtinghagen,Nataliia Petriv,Heiner Wedemeyer,Elena Reinhard,Juan Carlos Lopez Alfonso,Michael Peter Manns,Tatjana Hirsch,Dunja Bruder,Huizhen Suo

doi:10.1038/s41388-022-02222-z

Abstract

Primary liver cancer (PLC) comprising hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) represents the third deadliest cancer worldwide with still insufficient treatment options. We have previously found that CD4 T helper 1 (Th1) response is indispensable for the protection against PLC. In the present research, we aimed to test the potent inducers of Th1 responses, live-attenuated Listeria monocytogenes ∆actA/∆inlB strain as preventive/therapeutic vaccine candidate in liver fibrosis, HCC, and CCA. Studies were performed using autochthonous models of HCC and CCA, highly reflecting human disease. L. monocytogenes ∆actA/∆inlB demonstrated strong safety/efficacy in premalignant and malignant liver diseases. The protective mechanism relied on the induction of strong tumor-specific immune responses that keep the development of hepatobiliary cancers under control. Combination therapy, comprising Listeria vaccination and a checkpoint inhibitor blockade significantly extended the survival of HCC-bearing mice even at the advanced stages of the disease. This is the first report on the safety and efficacy of Listeria-based vaccine in liver fibrosis, as well as the first proof of principle study on Listeria-based vaccines in CCA. Our study paves the way for the use of live-attenuated Listeria as safe and efficient vaccine and a potent inducer of protective immune responses in liver fibrosis and hepatobiliary malignancies.

Highlights

Primary liver cancer (PLC) is the third deadliest cancer worldwide encountering 830,000 deaths per year [1, 2]
Mice injected with NRASG12V-Ova developed Hepatocellular carcinoma (HCC) and occasionally combined HCC-CCA as demonstrated by cytokeratin 7 (CK7)-positive ductal areas (Fig. 1C, D), whereas intrahepatic delivery of KRASG12V-Ova resulted in the formation of predominantly CK7+ CCA (Fig. 1E, F)
Early therapeutic vaccination with Listeria was more efficacious than standard therapy sorafenib: LmAIO-vaccinated mice demonstrated a prolongation of survival by 48 days, whereas only 8 days survival benefit was induced by sorafenib in NRASG12V-driven HCCs [26]

Summary

Introduction

Primary liver cancer (PLC) is the third deadliest cancer worldwide encountering 830,000 deaths per year [1, 2]. Treatment options for HCC and CCA include curative resection, liver transplantation for HCC, locoregional and systemic therapies [4, 5]. Most cases present with advanced unresectable disease and systemic therapies are still associated with a poor outcome in both PLC subtypes. The immunotherapy combination of atezolizumab (inhibitor of programmed death-ligand 1 (PD-L1)) and bevacizumab (inhibitor of vascular endothelial growth factor) demonstrated an extended median progression-free and overall survival compared to sorafenib and has been approved by the Food and Drug Administration (FDA) [7]. Trials with immune checkpoint inhibitors (ICIs) revealed very promising data, currently pembrolizumab and nivolumab (inhibitors of PD-1) are approved by the FDA as a second-line treatment in advanced HCC [8]. Several phase II and III trials are investigating different combination therapies with various ICIs and tyrosine kinase inhibitors in advanced HCC [9, 10]

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