Gene Therapy and the Radiation Response

Monday, October 17, 2005 10:15 AM-12:00 PM Room No. 603
Chair(s): Scott, Simon

(SY022) Clinical trials combining oncolytic viral therapy and suicide gene therapy with radiotherapy.

Freytag, Svend*,1, Kim, Jae Ho1, Brown, Steve, Stricker, Hans2, Pegg, Jan1, Lu, Mei3, 1 Department of Radiation Oncology, Detroit, MI, USA2 Vattakuti Urology Institute, Detroit, MI, USA3 Department of Biostatistics, Detroit, MI, USA

ABSTRACT- Adenovirus-mediated suicide gene therapy may hold much promise in the treatment of human cancer. Although originally conceived as a monotherapy, we have pioneered the concept of using suicide gene therapy as an adjuvant to radiation therapy. We have developed a novel, trimodal approach that utilizes an oncolytic, replication-competent adenovirus to selectively and efficiently deliver a therapeutic CD/HSV-1 TK fusion gene to tumors. The efficacy of oncolytic viral 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 importantly, sensitizes them to radiation. Our preclinical work has provided the scientific basis for five prostate cancer clinical trials, two of which were recently completed with excellent results. The safety and efficacy of our oncolytic adenoviral/double suicide gene therapy approach was evaluated in combination with conventional dose 3D-CRT in patients with newly diagnosed, intermediate- to high-risk prostate cancer. Fifteen patients received a single intraprostatic injection of the replication-competent Ad5-CD/TKrep adenovirus on Day 1. Two days later, patients were administered 5-FC and vGCV prodrug therapy along with 70 - 74 Gy 3D-CRT. There were no dose-limiting toxicities and no significant treatment-related adverse events. With a median follow-up of 31 months, 15 of 15 (100%) patients have achieved a serum PSA ⩽1 ng/ml, and 9 of 10 (90%) patients not treated with hormone therapy have achieved a serum PSA ⩽0.5 ng/ml. Ten of 15 (67%) patients were negative for adenocarcinoma at one year, which is better than expected (45%) for this group of patients treated with conventional dose 3D-CRT alone. Based on these very encouraging results, a randomized, prospective, two-arm Phase II trial will be initiated that will compare the efficacy of replication-competent adenovirus-mediated double suicide gene therapy in combination with 78 Gy IMRT vs. 78 Gy IMRT alone using a second-generation adenovirus (Ad5-yCD/mutTKSR39rep-ADP) that is much more efficacious than the parental Ad5-CD/TKrep virus. We believe that novel biological therapies, such as gene therapy, have much potential to improve the efficacy of conventional cancer therapies such as radiation therapy.

Key words: radiation, gene, adenovirus, replication

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2005 RRS