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Lipid A mutant Salmonella with suppressed virulence and TNFα induction retain tumor-targeting in vivo

Nature Biotechnology volume 17, pages 37–41 (1999)Cite this article

Abstract

Systemically administered tumor-targeted Salmonella has been developed as an anticancer agent, although its use could be limited by the potential induction of tumor necrosis factor α (TNFα)-mediated septic shock stimulated by lipid A. Genetic modifications of tumor-targeting Salmonella that alter lipid A and increase safety must, however, retain the useful properties of this bacteria. We report here that disruption of the Salmonella msbB gene reduces TNFα induction and increases the LD 50 of this pathogenic bacteria by 10,000-fold. Notwithstanding this enormous difference, Salmonella retains its tumor-targeting properties, exhibiting tumor accumulation ratios in excess of 1000:1 compared with normal tissues. Administration of this bacteria to mice bearing melanoma results in tumors that are less than 6% the size of tumors in untreated controls at day 18. Thus, the antitumor activity previously demonstrated using tumor-targeting Salmonella with normal lipid A is retained. Lipid modification of tumor-specific bacterial vectors provides a means for reducing septic shock and further suggests that the antitumor activity of these bacteria may be independent of TNFα.

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Figure 1: Southern blot analysis following transfection of the linearized knockout construct.
Figure 2: TNFα production by human monocytes.
Figure 3: Effect of msbB– disruption on survival in murine macrophage cell line J774.
Figure 4: Survival of mice and Sinclair swine.
Figure 5: Tumor retardation by msbB– Salmonella.

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Acknowledgements

We thank Jean Bolognia, Keith Joiner, and Terry Doyle for helpful discussions. This work was supported by Vion Pharmaceuticals, Inc.

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Authors and Affiliations

  1. Department of Therapeutic Radiology, New Haven, 05620, CT

    K. Brooks Low

  2. Department of Dermatology, Yale University, School of Medicine, New Haven, 05620, CT

    James Platt, Stefano Sodi, Ashok Chakraborty & John M. Pawelek

  3. Vion Pharmaceuticals, Inc., New Haven, 06511, CT

    Martina Ittensohn, Trung Le, Ellen Carmichael, Jessica Fischer, Stanley L. Lin, Xiang Luo, Li-mou Zheng, Ivan King & David Bermudes*

  4. Texas A&M University, College of Veterinary Medicine, College Station, 77843-2147, TX

    Max Amoss & Olivia Ash

  5. University of Washington, Health Sciences Center, Seattle, 98195, WA

    Samuel I. Miller

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Low, K., Ittensohn, M., Le, T. et al. Lipid A mutant Salmonella with suppressed virulence and TNFα induction retain tumor-targeting in vivo. Nat Biotechnol 17, 37–41 (1999). https://doi.org/10.1038/5205

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