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Vaccination of Metastatic Melanoma Patients With Autologous Tumor-Derived Heat Shock Protein gp96-Peptide Complexes: Clinical and Immunologic Findings

From the Units of General Surgery 2, Immunotherapy of Human Tumors, Immunohematology and Blood Bank, Pathology, Diagnostic Radiology, and Pharmacy, Istituto Nazionale Tumori; Divisions of Surgery and Pathology, Istituto Europeo di Oncologia, Milan; Units of Cancer Biotherapy, Anesthesiology, and Surgery, Centro di Riferimento Oncologico, Aviano; Divisions of Medical Oncology and Surgery, Istituto Scientifico Tumori, Genoa; and Sigma Tau, i.f.r. S.p.A., Rome, Italy; Antigenics, Inc, Woburn, MA; and Center for Immunotherapy of Cancer and Infectious Diseases, University of Connecticut School of Medicine, Farmington, CT.

Address reprint requests to Giorgio Parmiani, MD, Unit of Immunotherapy of Human Tumors, Istituto Nazionale Tumori, Via Venezian, 1-20133 Milan, Italy; email: parmiani{at}istitutotumori.mi.it

PURPOSE: To determine the immunogenicity and antitumor activity of a vaccine consisting of autologous, tumor-derived heat shock protein gp96-peptide complexes (HSPPC-96, Oncophage; Antigenics, Inc, Woburn, MA) in metastatic (American Joint Committee on Cancer stage IV) melanoma patients.

PATIENTS AND METHODS: Sixty-four patients had surgical resection of metastatic tissue required for vaccine production, 42 patients were able to receive the vaccine, and 39 were assessable after one cycle of vaccination (four weekly injections). In 21 patients, a second cycle (four biweekly injections) was given because no progression occurred. Antigen-specific antimelanoma T-cell response was assessed by enzyme-linked immunospot (ELISPOT) assay on peripheral blood mononuclear cells (PBMCs) obtained before and after vaccination. Immunohistochemical analyses of tumor tissues were also performed.

RESULTS: No treatment-related toxicity was observed. Of 28 patients with measurable disease, two had a complete response (CR) and three had stable disease (SD) at the end of follow-up. Duration of CR was 559+ and 703+ days, whereas SD lasted for 153, 191, and 272 days, respectively. ELISPOT assay with PBMCs of 23 subjects showed a significantly increased number of postvaccination melanoma-specific T-cell spots in 11 patients, with clinical responders displaying a high frequency of increased T-cell activity. Immunohistochemical staining of melanoma tissues from which vaccine was produced revealed high expression of both HLA class I and melanoma antigens in seven of eight clinical responders (two with CR, three with SD, and the three with long-term disease-free survival) and in four of 12 nonresponders.

CONCLUSION: Vaccination of metastatic melanoma patients with autologous HSPPC-96 is feasible and devoid of significant toxicity. This vaccine induced clinical and tumor-specific T-cell responses in a significant minority of patients.

Supported by a grant from Sigma Tau i.f.r. S.p.A. (Rome). P.S. is supported by National Institutes of Health grant no. 84479 and a sponsored research agreement with Antigenics, Inc., in which he has a significant financial interest. R.C. and M.C. are employees of the Sigma Tau i.f.r. S.p.A., and J.J.L. is an employee of Antigenics, Inc.

Presented in part at the Thirty-Seventh Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12-15, 2001.

© 2002 by American Society of Clinical Oncology.

0732-183X/02/2020-4169/$20.00

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