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

Nontoxic radioactive Listeria^at is a highly effective therapy against metastatic pancreatic cancer

1. Wilber Quispe-Tintaya^a,¹,
2. Dinesh Chandra^a,¹,
3. Arthee Jahangir^a,
4. Matthew Harris^b,
5. Arturo Casadevall^a,
6. Ekaterina Dadachova^b,², and
7. Claudia Gravekamp^a,²

Author Affiliations

1. Edited by E. Peter Greenberg, University of Washington, Seattle, WA, and approved March 15, 2013 (received for review July 3, 2012)

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 (Listeria^at) using Listeria-binding antibodies, thus creating a unique radioactive Listeria^at (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 Listeria^at 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@einstein.yu.edu or ekaterina.dadachova@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.