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Translation of the radio- and chemo-inducible TNFerade vector to the treatment of human cancers

Cancer Gene Therapy volume 16, pages 609–619 (2009)Cite this article

Abstract

Radiotherapy is a widely used treatment for localized malignancies that is often delivered in combination with cytotoxic chemotherapeutic agents. The concept that treatment of localized tumors can be improved with a radio- and chemo-inducible gene therapy strategy has been investigated in the laboratory and now translated to the clinic. The TNFerade (Ad.Egr-TNF11D) adenoviral vector was engineered by inserting radio- and chemo-inducible elements from the Egr-1 promoter upstream to a cDNA encoding tumor necrosis factor-α (TNF-α). Transduction of tumor cells with TNFerade and then treatment with radiation or chemotherapy is associated with spatial and temporal control of TNF-α secretion and enhanced antitumor activity. TNFerade has been evaluated in trials for patients with sarcomas, melanomas and cancers of the pancreas, esophagus, rectum and head and neck. If the ongoing phase III trial for pancreatic cancer is successful, TNFerade will likely become the first gene therapy approved for cancer in the United States.

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Abbreviations

Ad:

adenoviral vector

CArG element:

CC(A+T rich)GG

Egr-1:

early growth response gene 1

FLIP:

FLICE-like inhibitory protein

5FU:

5-fluorouracil

IR:

ionizing radiation

RIP1:

receptor-interacting protein

ROS:

reactive oxygen species

SOC:

standard of care;

TACE:

TNF-α converting enzyme

TNF-α:

tumor necrosis factor α

TNFerade:

Ad.Egr-TNF11D

TNF-R:

TNF receptor

TRADD:

TNF receptor-associated death domain

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Acknowledgements

We thank Mark Thornton, M.D., Ph.D., C. Richter King, Ph.D., and Lisa Wei, Ph.D., of GenVec, Inc., for their helpful discussions.

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  1. Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, USA

    R R Weichselbaum

  2. Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    D Kufe

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Weichselbaum, R., Kufe, D. Translation of the radio- and chemo-inducible TNFerade vector to the treatment of human cancers. Cancer Gene Ther 16, 609–619 (2009). https://doi.org/10.1038/cgt.2009.37

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