Using an attenuated (double-deleted) Listeria m. strain carrying intact OVA as a vaccine, Hochnadel and Hoecnicke et al. demonstrated immune activity, tumor control, and survival benefit in autochthonous multifocal models of two types of primary liver cancer, and immune activity in a chemical model of pre-malignant fibrosis. The vaccine was safe and induced a strong Th1-skewed response (CD4+ and strong CD8+ T cells; no IL-4 induction; reduction in B cells and antigen-specific IgG) and epitope spreading. Tumor control and immune response were dose- and boost-dependent, and synergized with ICB while controlling inflammation.
Contributed by Ed Fritsch
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 ÆactA/ÆinlB 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 ÆactA/ÆinlB 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.
Author Info: (1) Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany. (2) Department of Gastroenterology, Hepatology and Endocrinology
Author Info: (1) Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany. (2) Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany. (3) Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany. (4) Institute of Pathology, MHH, Hannover, Germany. (5) Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany. (6) Immune Regulation Group, HZI, Braunschweig, Germany and Infection Immunology Group, Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg, Magdeburg, Germany. (7) Department of Systems Immunology, Technical University Braunschweig and HZI, Braunschweig, Germany. (8) Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany. (9) Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany. (10) Genome Analytics, HZI, Braunschweig, Germany. (11) Department of Clinical Chemistry, MHH, Hannover, Germany. (12) Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany. (13) Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany. (14) Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany. (15) Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany. (16) Immune Regulation Group, HZI, Braunschweig, Germany and Infection Immunology Group, Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg, Magdeburg, Germany. (17) Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany. Yevsa.Tetyana@mh-hannover.de.
