Attenuated Listeria monocytogenes as a promising vaccine candidate in the settings of hepatobiliary cancer
L. Hoenicke1*, I. Hochnadel1*, T. Hirsch3, E. Reinhard2, C. A. Guzmán2, M. P. Manns1, D. Bruder3, T. Yevsa1 1Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany; 2Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research (HZI), Brunswick, Germany; 3Immune Regulation, HZI, Brunswick, Germany
Primary liver cancer, comprising hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), is the second leading cause of cancer-related deaths with a constantly growing incidence. Current treatment approaches are insufficient and the disease prognosis is dismal. Therefore, new therapies are urgently needed. Since CCA and HCC are highly immunogenic, immunotherapy represents a promising alternative strategy. Therefore in our present study we concentrated on attenuated Listeria monocytogenes (Lm) strains that have been recently successfully tested in the treatment of various solid tumors and that are potent inducers of anti-tumor immune responses.
We took advantage of recently established transposon-based autochthonous mouse models of HCC and CCA, both expressing a model antigen Ovalbumin (OVA). In these tumor models we tested the prophylactic- as well as therapeutic vaccination potential of the attenuated strain Lm ΔactA/ΔinlB (LmAI) expressing the tumor model antigen OVA (designated LmAIO) (both strains kindly provided by D. Portnoy).
Prophylactic approach using two vaccination doses of LmAIO strain resulted in a full protection against both, HCC and CCA. One prophylactic vaccination with LmAIO strain was sufficient to decrease the tumor burden and prolong the survival of 60% of mice in which highly aggressive HCCs have been induced 14 days post vaccination. In a therapeutic approach one treatment vaccination dose with LmAIO strain was efficient in decreasing tumor burden and led to an increase of overall survival comprising 16- and 7 weeks, respectively, in early- and advanced HCCs. In both prophylactic- and therapeutic approaches vaccination with LmAIO delivering tumor antigen OVA showed an induction of tumor antigen (OVA)-specific CD4+/CD8+ T cells which correlated with the observed protection against HCC development.
In conclusion, the attenuated strain LmAI delivering tumor antigens represents a promising vaccine candidate for prophylactic and treatment of hepatobiliary malignancies.