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Delayed Disease Progression after Allogeneic Cell Vaccination in Hormone-Resistant Prostate Cancer and Correlation with Immunologic Variables

Authors' Affiliations: ¹ Department of Oncology and ² Onyvax Ltd., St. George's Hospital Medical School, London, ³ School of Biomedical and Natural Sciences, Nottingham Trent University, Nottingham, and ⁴ Department of Clinical Oncology, Derbyshire Royal Infirmary, Derby, United Kingdom

Requests for reprints: Hardev Pandha, Department of Oncology, St. George's Hospital Medical School, Cranmer Terrace, London, SW17 0RE, United Kingdom; E-mail: hpandha{at}sghms.ac.uk.

Purpose: There are a significant number of patients with asymptomatic hormone-resistant prostate cancer who have increasing prostate-specific antigen (PSA) levels but little or no evaluable disease. The immunogenicity and minimal toxicity associated with cell-based vaccine therapy makes this approach attractive for these patients.

Experimental Design: We have evaluated a vaccine comprising monthly intradermal injection of three irradiated allogeneic prostate cell lines (8 x 10⁶ cells each) over 1 year. The first two doses were supplemented with bacille Calmette-Guérin as vaccine adjuvant. Twenty-eight hormone-resistant prostate cancer patients were enrolled. Patients were assessed clinically and PSA levels were measured monthly. Radiologic scans (X-ray, computed tomography, and bone scan) were taken at baseline and at intervals throughout the treatment period. Comprehensive monthly immunologic monitoring was undertaken including proliferation studies, activation markers, cytokine protein expression, and gene copy number. This longitudinal data was analyzed through predictive modeling using artificial neural network feed-forward/back-propagation algorithms with multilayer perceptron architecture.

Results: Eleven of the 26 patients showed statistically significant, prolonged decreases in their PSA velocity (PSAV). None experienced any significant toxicity. Median time to disease progression was 58 weeks, compared with recent studies of other agents and historical control values of around 28 weeks. PSAV-responding patients showed a titratable T_H1 cytokine release profile in response to restimulation with a vaccine lysate, while nonresponders showed a mixed T_H1 and T_H2 response. Furthermore, immunologic profile correlated with PSAV response by artificial neural network analysis. We found predictive power not only in expression of cytokines after maximal stimulation with phorbol 12-myristate 13-acetate, but also the method of analysis (qPCR measurement of IFN- > qPCR measurement tumor necrosis factor- > protein expression of IFN- > protein expression of interleukin 2).

Conclusions: Whole cell allogeneic vaccination in hormone-resistant prostate cancer is nontoxic and improves the natural history of the disease. Longitudinal changes in immunologic function in vaccinated patients may be better interpreted through predictive modeling using tools such as the artificial neural network rather than periodic "snapshot" readouts.

Key Words: antigen • vaccination • therapy

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