724. Phase I Study of Replication-Competent Adenovirus-Mediated Suicide Gene Therapy in Combination with Conformal Radiotherapy for the Treatment of Intermediate- to High-Risk Prostate Cancer: Two Year Efficacy Results

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Adenovirus-mediated suicide gene therapy may hold much promise in the treatment of human cancer. We have developed a novel approach that utilizes an oncolytic, replication-competent adenovirus to deliver a therapeutic CD/HSV-1 TK fusion gene to tumors. The efficacy of oncolytic adenoviral therapy can be enhanced significantly by invoking two suicide gene systems (CD/5-FC and HSV-1 TK/GCV), which render malignant cells sensitive to specific pharmacological agents, and sensitizes them to radiation. Our preclinical work has provided the scientific basis for three Phase I prostate cancer clinical trials that were recently completed with excellent results. In our second trial, we evaluated the safety and efficacy of our oncolytic adenoviral/suicide gene therapy approach in combination with conformal radiotherapy in patients with newly diagnosed, intermediate- to high-risk prostate cancer. Fifteen patients in five cohorts received a single intraprostatic injection (1012 vp) of a first-generation, replication-competent adenovirus (Ad5-CD/ TKrep) on Day 1. Two days later, subjects were administered 5-FC and vGCV prodrug therapy along with 70 Gy conformal radiotherapy. The median follow-up is 40 months and all subjects have passed the two-year primary efficacy endpoint. Fifteen of 15 (100%) subjects have achieved a serum PSA |[le]| 1 ng/mL and 8 of 10 (80%) subjects not treated with hormone therapy have achieved a serum PSA |[le]| 0.5 ng/mL. Only one subject (high-risk) has failed biochemically. One- and two-year prostate biopsies have generated provocative results. Whereas 30% of intermediate-risk patients treated with 70 Gy radiotherapy alone are expected to be positive for adenocarcinoma at two years, 0 of 5 (0%) subjects treated with the gene therapy and radiotherapy combination had cancer at the two-year time point. None of these subjects received hormone therapy. Two (of 7) intermediate-risk subjects were not biopsied at two years because of concomitant medical issues. Both subjects were negative for adenocarcinoma at one-year. Thus, 7 of 7 (100%) of intermediate-risk subjects were negative for cancer at their last biopsy and none have any evidence of disease. By contrast, 4 of 8 (50%) high-risk subjects were negative for cancer at their last biopsy, which is comparable to that expected (44%) for 70 Gy radiotherapy alone. It has been demonstrated previously that CAR is down- regulated in high-grade prostate cancer, which may explain why this adenovirus-based approach failed to show a benefit in the high-risk patient group. The results indicate that oncolytic adenoviral and suicide gene therapies may improve the effectiveness of conformal radiotherapy in intermediate-risk prostate cancer. Based on these encouraging results, a randomized, prospective, two-arm Phase II trial will soon be initiated that will compare the efficacy of replication- competent adenovirus-mediated suicide gene therapy in combination with 76 Gy IMRT vs. 76 Gy IMRT alone using an improved, second-generation adenovirus (Ad5-yCD/mutTKSR39rep-ADP) that has already demonstrated to be safe in a Phase I trial.