Cancer Therapy: Clinical Phase I Clinical Trial of an Adenovirus/Prostate-Specific Antigen Vaccine for Prostate Cancer: Safety and Immunologic Results

Purpose: We performed a phase I clinical trial of adenovirus/prostate-specific antigen (PSA) vaccine in men with measurable metastatic hormone-refractory disease. Experimental Design: Men with measurable metastatic disease received one vaccine injection. Toxicity, immune responses, changes in PSA doubling times, and patient survival were assessed. Thirty-two patients with hormone-refractory metastatic prostate cancer were treated with a single s.c. vaccine injection at one of three dose levels, either as an aqueous solution or suspended in a Gelfoam matrix. All patients returned for physical and clinical chemistry examinations at regular intervals up to 12 months after injections. Results: The vaccine was deemed safe at all doses in both administration forms. There were no serious vaccine-related adverse events; the most prevalent were localized erythema/ecchymoses and cold/flu-like symptoms. Anti-PSA antibodies were produced by 34% of patients and anti-PSA T-cell responses were produced by 68%. PSA doubling time was increased in 48%, whereas 55% survived longer than predicted by the Halabi nomogram. Conclusions: The adenovirus/PSA vaccine was proven safe with no serious vaccinerelated adverse events. The majority of vaccinated patients produced anti-PSA T-cell responses and over half survived longer than predicted by nomogram. Although the latter data are only derived from a small number of patients in this phase I trial, they are encouraging enough to pursue further studies. (Clin Cancer Res 2009;15(23):7375–80) We have previously shown that immunizations with adenovirus (Ad) carrying the human prostate-specific antigen (PSA) gene can induce vigorous anti-PSA T-cell responses and cause the destruction of PSA-secreting tumors in a preclinical mouse model of prostate cancer (1, 2). Such active immunization against prostate cancer–associated antigens might be more effective than active nonspecific or adoptive/passive immunotherapy. Therefore, we have pursued a vaccination strategy based on an Ad that carries the gene for PSA. In preclinical studies, our group has shown that the Ad/PSA vaccine was able to induce stronger anti-PSA immune responses than other viral PSA vaccines. These include vaccinia viruses, both replication competent and deficient, and canarypox. The frequency of PSAspecific CD8+ T cells generated by the Ad/PSA vaccine was greater than were generated by any other vaccines tested. In addition to the superior immunizing property of the Ad/PSA, the incorporation of Gelfoam (Pharmacia and Upjohn), a collagen matrix, has been shown in preclinical studies to enhance the ability of the vaccine to induce strong anti-PSA immune responses (1). Lastly, immunization of mice with Ad/PSA inmatrix can induce anti-PSA responses even in the presence of high-titer anti-Ad antibodies (1). This latter finding is important in light of the fact that most humans have pre-existing levels of anti-Ad antibodies as a result of prior natural exposure to the virus. We initiated a phase I clinical trial of the Ad/PSA vaccine in men with measurable hormone-refractory prostate cancer (3). This was a dose escalation trial, with the vaccine injected s.c. in either an aqueous suspension or collagenmatrix. Our primary 6 D.M. Lubaroff, unpublished observations. Authors' Affiliations: Departments of Urology, Microbiology, and Internal Medicine, Prostate Cancer Research Group, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa Received 7/27/09; revised 8/24/09; accepted 9/1/09; published OnlineFirst 11/17/09. Grant support: Supported in part by grants from the Carver College of Medicine and Holden Comprehensive Cancer Center, University of Iowa, General Clinical Research Center NCRR #M01 RR00059, and NCI #CA096691. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: Current address for B.R. Konety: Department of Urologic Surgery, University of Minnesota Medical School, 420 Delaware Street Southeast, Minneapolis, MN 55455. Current address for T.L. Ratliff: Purdue Cancer Center, Hansen Life Sciences Research Building, 201 University Street, West Lafayette, IN 47907-2064. Requests for reprints: David M. Lubaroff, Department of Urology, University of Iowa, 375 Newton Road, 3210 MERF, Iowa City, IA 52242. Phone: 319335-8423; Fax: 319-353-4556; E-mail: [email protected]. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-09-1910 7375 Clin Cancer Res 2009;15(23) December 1, 2009 www.aacrjournals.org Research. on April 10, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst November 17, 2009; DOI: 10.1158/1078-0432.CCR-09-1910