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Vaccination With Irradiated Autologous Tumor Cells Engineered to Secrete Granulocyte-Macrophage Colony-Stimulating Factor Augments Antitumor Immunity in Some Patients With Metastatic Non–Small-Cell Lung Carcinoma

Ravi Salgia, Thomas Lynch, Arthur Skarin, Joan Lucca, Cathleen Lynch, Ken Jung, F. Stephen Hodi, Michael Jaklitsch, Steve Mentzer, Scott Swanson, Jean Lukanich, Raphael Bueno, John Wain, Douglas Mathisen, Cameron Wright, Panos Fidias, Dean Donahue, Shirley Clift, Steve Hardy, Donna Neuberg, Richard Mulligan, Iain Webb, David Sugarbaker, Martin Mihm, Glenn Dranoff

From the Departments of Adult Oncology, Surgery, and Biostatistics, Dana-Farber Cancer Institute; Departments of Adult Oncology and Surgery, Brigham and Women’s Hospital; Departments of Adult Oncology, Surgery, Biostatistics, Genetics, Pathology, and Medicine, Division of Hematology-Oncology, and Children’s Hospital, Harvard Medical School; Departments of Surgery, Medicine, and Pathology, Division of Hematology-Oncology, Massachusetts General Hospital, Boston, MA; and Cell Genesys, Foster City, CA.

Address reprint requests to Glenn Dranoff, MD, Dana-Farber Cancer Institute, Dana 510E, 44 Binney St, Boston, MA 02115; email: glenn_dranoff{at}dfci.harvard.edu.

Purpose: We demonstrated that vaccination with irradiated tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates potent, specific, and long-lasting antitumor immunity in multiple murine models and patients with metastatic melanoma. To test whether this vaccination strategy enhances antitumor immunity in patients with metastatic non–small-cell lung cancer (NSCLC), we conducted a phase I clinical trial.

Patients and Methods: Resected metastases were processed to single-cell suspension, infected with a replication-defective adenoviral vector encoding GM-CSF, irradiated, and cryopreserved. Individual vaccines consisted of 1 x 10⁶, 4 x 10⁶, or 1 x 10⁷ cells, depending on overall yield, and were administered intradermally and subcutaneously at weekly and biweekly intervals.

Results: Vaccines were successfully manufactured for 34 (97%) of 35 patients. The average GM-CSF secretion was 513 ng/10⁶ cells/24 h. Toxicities were restricted to grade 1 to 2 local skin reactions. Nine patients were withdrawn early because of rapid disease progression. Vaccination elicited dendritic cell, macrophage, granulocyte, and lymphocyte infiltrates in 18 of 25 assessable patients. Immunization stimulated the development of delayed-type hypersensitivity reactions to irradiated, dissociated, autologous, nontransfected tumor cells in 18 of 22 patients. Metastatic lesions resected after vaccination showed T lymphocyte and plasma cell infiltrates with tumor necrosis in three of six patients. Two patients surgically rendered as having no evidence of disease at enrollment remain free of disease at 43 and 42 months. Five patients showed stable disease durations of 33, 19, 12, 10, and 3 months. One mixed response was observed.

Conclusion: Vaccination with irradiated autologous NSCLC cells engineered to secrete GM-CSF enhances antitumor immunity in some patients with metastatic NSCLC.

Supported by grant no. CA74886 from the National Institutes of Health, Bethesda, MD, the Cancer Research Institute, New York; the Leukemia and Lymphoma Society, White Plains, NY; and Cell Genesys, Foster City, CA.

R.S. and T.L. contributed equally to this article.

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