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Research Article

Nontoxic radioactive Listeriaat is a highly effective therapy against metastatic pancreatic cancer

Wilber Quispe-Tintaya, Dinesh Chandra, Arthee Jahangir, Matthew Harris, Arturo Casadevall, Ekaterina Dadachova, and Claudia Gravekamp
  1. aDepartment of Microbiology and Immunology and
  2. bDepartment of Radiology, Albert Einstein College of Medicine, Bronx, NY 10461

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PNAS first published April 22, 2013; https://doi.org/10.1073/pnas.1211287110
Wilber Quispe-Tintaya
aDepartment of Microbiology and Immunology and
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Dinesh Chandra
aDepartment of Microbiology and Immunology and
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Arthee Jahangir
aDepartment of Microbiology and Immunology and
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Matthew Harris
bDepartment of Radiology, Albert Einstein College of Medicine, Bronx, NY 10461
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Arturo Casadevall
aDepartment of Microbiology and Immunology and
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Ekaterina Dadachova
bDepartment of Radiology, Albert Einstein College of Medicine, Bronx, NY 10461
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  • For correspondence: claudia.gravekamp@einstein.yu.edu ekaterina.dadachova@einstein.yu.edu
Claudia Gravekamp
aDepartment of Microbiology and Immunology and
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  • For correspondence: claudia.gravekamp@einstein.yu.edu ekaterina.dadachova@einstein.yu.edu
  1. Edited by E. Peter Greenberg, University of Washington, Seattle, WA, and approved March 15, 2013 (received for review July 3, 2012)

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Abstract

No significant improvement in therapy of pancreatic cancer has been reported over the last 25 y, underscoring the urgent need for new alternative therapies. Here, we coupled a radioisotope, 188Rhenium, to an attenuated (at) live Listeria monocytogenes (Listeriaat) using Listeria-binding antibodies, thus creating a unique radioactive Listeriaat (RL). We then demonstrated in a highly metastatic pancreatic mouse tumor model (Panc-02) that RL delivered radioactivity to the metastases and less abundantly to primary tumors in vivo, without harming normal cells. This result was possible because Listeriaat was efficiently cleared by the immune system in normal tissues but not in the heavily immune-suppressed microenvironment of metastases and primary tumor. Multiple treatments with low doses of the RL resulted in a dramatic decrease in the number of metastases (∼90%) compared with control groups in the Panc-02 model. This is the first report of using live attenuated bacteria delivering a highly radioactive payload to the metastases, resulting in killing tumor cells in vivo without harming normal cells. The nontoxic RL treatment is attractive for clinical development as a therapy to prevent pancreatic cancer recurrence and metastases.

Footnotes

  • ↵1W.Q.-T. and D.C. contributed equally to this work.

  • ↵2To whom correspondence may be addressed. E-mail: claudia.gravekamp{at}einstein.yu.edu or ekaterina.dadachova{at}einstein.yu.edu.
  • Author contributions: W.Q.-T., D.C., E.D., and C.G. designed research; W.Q.-T., D.C., A.J., M.H., E.D., and C.G. performed research; A.C., E.D., and C.G. contributed new reagents/analytic tools; W.Q.-T., D.C., E.D., and C.G. analyzed data; and W.Q.-T., D.C., E.D., and C.G. wrote the paper.

  • Conflict of interest statement: A.C., E.D., and C.G. have jointly filed a patent application related to the work of this manuscript.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1211287110/-/DCSupplemental.

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Radioactive Listeria against pancreatic cancer
Wilber Quispe-Tintaya, Dinesh Chandra, Arthee Jahangir, Matthew Harris, Arturo Casadevall, Ekaterina Dadachova, Claudia Gravekamp
Proceedings of the National Academy of Sciences Apr 2013, 201211287; DOI: 10.1073/pnas.1211287110

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Radioactive Listeria against pancreatic cancer
Wilber Quispe-Tintaya, Dinesh Chandra, Arthee Jahangir, Matthew Harris, Arturo Casadevall, Ekaterina Dadachova, Claudia Gravekamp
Proceedings of the National Academy of Sciences Apr 2013, 201211287; DOI: 10.1073/pnas.1211287110
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