Local application of bacteria improves safety of Salmonella -mediated tumor therapy and retains advantages of systemic infection
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Dino Kocijancic1,*, Sebastian Felgner1,2,*, Tim Schauer1, Michael Frahm1, Ulrike Heise3, Kurt Zimmermann4, Marc Erhardt2 and Siegfried Weiss1,5
1Molecular Immunology, Helmholtz Center for Infection Research, Braunschweig, Germany
2Infection Biology of Salmonella, Helmholtz Center for Infection Research, Braunschweig, Germany
3Mouse-Pathology Service Unit, Helmholtz Center for Infection Research, Braunschweig, Germany
4Symbio Gruppe GmbH & Co KG, Herborn, Germany
5Institute of Immunology, Medical School Hannover, Hannover, Germany
*These authors have contributed equally to this work
Dino Kocijancic, email: email@example.com
Keywords: Intra-tumoral injection, Salmonella, E. coli, bacteria mediated tumor therapy, murine tumor model
Received: October 29, 2016 Accepted: May 05, 2017 Published: June 07, 2017
Cancer is a devastating disease and a large socio-economic burden. Novel therapeutic solutions are on the rise, although a cure remains elusive. Application of microorganisms represents an ancient therapeutic strategy, lately revoked and refined via simultaneous attenuation and amelioration of pathogenic properties. Salmonella Typhimurium has prevailed in preclinical development. Yet, using virulent strains for systemic treatment might cause severe side effects. In the present study, we highlight a modified strain based on Salmonella Typhimurium UK-1 expressing hexa-acylated Lipid A. We corroborate improved anti-tumor properties of this strain and investigate to which extent an intra-tumoral (i.t.) route of infection could help improve safety and retain advantages of systemic intravenous (i.v.) application. Our results show that i.t. infection exhibits therapeutic efficacy against CT26 and F1.A11 tumors similar to a systemic route of inoculation. Moreover, i.t. application allows extensive dose titration without compromising tumor colonization. Adverse colonization of healthy organs was generally reduced via i.t. infection and accompanied by less body weight loss of the murine host. Despite local application, adjuvanticity remained, and a CT26-specific CD8+ T cell response was effectively stimulated. Most interestingly, also secondary tumors could be targeted with this strategy, thereby extending the unique tumor targeting ability of Salmonella. The i.t. route of inoculation may reap the benefits of systemic infection and aid in safety assurance while directing potency of an oncolytic vector to where it is most needed, namely the primary tumor.
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