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Vaccination With Irradiated, Autologous Melanoma Cells Engineered to Secrete Granulocyte-Macrophage Colony-Stimulating Factor by Adenoviral-Mediated Gene Transfer Augments Antitumor Immunity in Patients With Metastatic Melanoma

Robert Soiffer, F. Stephen Hodi, Frank Haluska, Ken Jung, Silke Gillessen, Samuel Singer, Kenneth Tanabe, Rosemary Duda, Steven Mentzer, Michael Jaklitsch, Raphael Bueno, Shirley Clift, Steve Hardy, Donna Neuberg, Richard Mulligan, Iain Webb, Martin Mihm, Glenn Dranoff

From the Departments of Medical Oncology, Surgery, and Biostatistics, Dana-Farber Cancer Institute; Departments of Medicine and Surgery, Brigham and Women’s Hospital; Departments of Medicine, Surgery, Biostatistics, Genetics, and Pathology, Harvard Medical School; Department of Medicine, Division of Hematology-Oncology, and Departments of Surgery and Pathology, Massachusetts General Hospital; Department of Surgery, Beth Israel Deaconess Medical Center; and Children’s 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; e-mail: glenn_dranoff{at}dfci.harvard.edu.

Purpose: Vaccination with irradiated, autologous melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) by retroviral-mediated gene transfer generates potent antitumor immunity in patients with metastatic melanoma. Further clinical development of this immunization scheme requires simplification of vaccine manufacture. We conducted a phase I clinical trial testing the biologic activity of vaccination with irradiated, autologous melanoma cells engineered to secrete GM-CSF by adenoviral-mediated gene transfer.

Patients and Methods: Excised metastases were processed to single cells, transduced with a replication-defective adenoviral vector encoding GM-CSF, irradiated, and cryopreserved. Individual vaccines were composed of 1 x 10⁶, 4 x 10⁶, or 1 x 10⁷ tumor cells, depending on overall yield, and were injected 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 745 ng/10⁶ cells/24 hours. Toxicities were restricted to grade 1 to 2 local skin reactions. Eight patients were withdrawn early because of rapid disease progression. Vaccination elicited dense dendritic cell, macrophage, granulocyte, and lymphocyte infiltrates at injection sites in 19 of 26 assessable patients. Immunization stimulated the development of delayed-type hypersensitivity reactions to irradiated, dissociated, autologous, nontransduced tumor cells in 17 of 25 patients. Metastatic lesions that were resected after vaccination showed brisk or focal T-lymphocyte and plasma cell infiltrates with tumor necrosis in 10 of 16 patients. One complete, one partial, and one mixed response were noted. Ten patients (29%) are alive, with a minimum follow-up of 36 months; four of these patients have no evidence of disease.

Conclusion: Vaccination with irradiated, autologous melanoma cells engineered to secrete GM-CSF by adenoviral-mediated gene transfer augments antitumor immunity in patients with metastatic melanoma.

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

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