A phase I/II study of adenovirus-mediated interleukin-12 gene therapy for hormone refractory prostate cancer: An interim report.

Abstract

148 Background: A phase I/II study of adenovirus-mediated interleukin-12 (IL–12) gene therapy for castration resistant prostate cancer has been initiated from May 2008 in Okayama University Hospital. Interim results of 10 cases including a positive clinical response are reported. Methods: Major inclusion criteria was a recurrence of prostate cancer following hormonal therapy with/without metastasis. Replication–defective adenovirus vector expressing IL–12 (Adv.IL–12) was injected directly into the prostate (or metastatic lesion in patients who received prostatectomy) in escalating doses from 1.0×1010 to 5.0×1012 viral particle (vp). GMP grade vector was produced at Center for Cell and Gene Therapy, Baylor College of Medicine (Director: Malcolm K. Brenner). Each patient received total of 3 times viral injections every 4 weeks. In addition to the safety profile, cancer control efficacy and immunological changes after viral injections were evaluated. Results: Ten patients received the gene therapy in doses of 1.0×1010 to 5.0×1011 vp from May 2008 to October 2010. 9 cases completed, and 1 patient dropped out the study because of rapid cancer progression. Major adverse effects are following: urinary retention (G1), trasaminase elevation (G3), fever up (G3). These adverse effects were rapidly disappeared after proper treatments. One patient with highest dose (5.0×1011 vp) showed some clinical positive responses (PSA decrease, shrinkage of lymphnode metastasis), therefore received an additional viral injection. Temporal decreases just after each vector injections and gradual increases at the peak of 7-14 days after each vector injections in some immunocompetent cells (CD3+CD19–, CD3–CD19– CD16+CD56+, CD3+CD4–CD8–) were seen in relatively high dose group. Elevations of serum cytokines were observed in parallel with vector dose escalation. Conclusions: This interim report suggests the favorable safety profile and positive clinical responses in a clinical trial of Adv.IL–12 gene therapy for hormone refractory prostate cancer in higher doses of viral vectors. Further evaluations in the next higher vector doses are needed and in progress. No significant financial relationships to disclose.