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J Thorac Cardiovasc Surg 2002;124:123-129
© 2002 The American Association for Thoracic Surgery

General Thoracic Surgery (GTS)

Replication-competent herpes virus NV1020 as direct treatment of pleural cancer in a rat model

Michael I. Ebright, MD, Jonathan S. Zager, MD, Sandeep Malhotra, MD, Keith A. Delman, MD, Tracey L. Weigel, MD, Valerie W. Rusch, MD, Yuman Fong, MD

From the Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY.

Supported in part by training grant T32 CA 09501 (M.I.E.) and US Public Health Service grants RO1CA75416, RO1CA72632, and RO1CA61524 from the National Institutes of Health and MBC-99366 (Y.F.) from the American Cancer Society.

Read at the Eighty-first Annual Meeting of The American Association for Thoracic Surgery, San Diego, Calif, May 6-9, 2001.

Received for publication May 14, 2001. Revisions requested Aug 21, 2001; revisions received Nov 27, 2001. Accepted for publication Dec 12, 2001. Address for reprints: Yuman Fong, MD, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021 (E-mail: fongy{at}mskcc.org).

Objective: Innovative treatments are needed for metastatic disease involving the pleura. NV1020 is a novel, multimutated, replication-restricted herpes simplex virus under investigation for its ability to selectively kill tumors by means of direct cell lysis. This study examines NV1020 in a rat model of pleura-based lung cancer.
Methods: Cytotoxicity and viral proliferation were evaluated in vitro by exposure of the human non-small cell lung cancer cell line A549 to virus. NV1020 was also tested in an in vivo pleura-based cancer model established by injecting 1 x 107 A549 cells into the thoracic cavity of nude rats. Intrapleural treatments (1 x 107 viral particles) were given 3 hours or 3 days after tumor injection to model treatment of microscopic or macroscopic disease (n = 8-9/group). Tumor burden was assessed at 5 weeks. NV1020 infection and dissemination within the thoracic cavity was determined by means of immunohistochemistry.
Results: In vitro, at multiplicities of infection (viral particles per tumor cell) of 0.01, 0.1, and 1.0, cell killing of A549 by NV1020 was 66%, 90%, and 97%, respectively, at 7 days after infection. Viral burst occurred by day 2. Intrapleural treatment was effective for both the microscopic (P < .001) and macroscopic (P < .05) in vivo tumor models. Virus was detectable by means of immunohistochemistry in tumors but not in adjacent normal intrathoracic tissues.
Conclusions: NV1020 is not only highly cytotoxic to the human lung cancer line A549 in vitro but can be delivered in a clinically relevant fashion to safely and effectively treat pleura-based tumor in vivo in a rat model.




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