514. Clinical Trials of Oncolytic Adenovirus-Mediated Gene Therapy

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For the past 20 years we have been developing a multi-modal, gene therapy-based approach for the treatment of cancer. Our therapeutic platform utilizes an oncolytic adenovirus to deliver a pair of cytotoxic “suicide” genes to the tumor. The oncolytic adenovirus generates an anti-tumor effect by replicating in, and destroying, cancer cells (oncolytic viral therapy). The therapeutic effect of the oncolytic adenovirus is enhanced by invoking two cytotoxic gene systems, which render malignant cells sensitive to specific pharmacological agents (cytotoxic gene therapy) and sensitize them to ionizing radiation (radiosensitization). The combined effects of these three modalities result in significant tumor cell destruction and release of tumor antigens, which, when coupled with the robust immune response elicited by the oncolytic adenovirus, generate an environment suitable for tumor antigen processing and cross-presentation that may culminate in the development of anti-tumor immunity. Under four Investigational New Drug (IND) applications, we have evaluated the toxicity and efficacy of our multi-modal approach in six phase 1/2 trials of prostate cancer using four different oncolytic adenoviruses (Figure 1Figure 1). These studies have demonstrated that our approach is safe and evidence of efficacy has been obtained. With respect to safety, there were no dose-limiting toxicities (DLTs) or treatment-related serious adverse events (SAEs) in over 100 patients treated to date. Only 6% of the adverse events were ≥ grade 3 with the vast majority being transient and asymptomatic. With respect to efficacy, in the locally recurrent setting following radiation failure, men who received the gene therapy exhibited a significant lengthening of PSA doubling time (PSADT), a surrogate endpoint that is highly prognostic for the development of distant metastases and prostate cancer-specific mortality. At 7 years, there was an improvement in disease-specific survival relative to well-matched historical controls. When combined with radiation therapy in the newly-diagnosed setting, the gene therapy reduced by 42% the percentage of men who had a positive prostate biopsy 2 years after treatment in a prospective, randomized, controlled phase 2 trial. An even greater treatment effect (i.e., 60% reduction) was observed in men with a low tumor burden at baseline. Together, the results demonstrate that oncolytic adenovirus-mediated gene therapy has the potential to improve tumor control in multiple settings of prostate cancer. To improve our approach further, we have generated a new oncolytic adenovirus expressing IL-12, which is now in the clinic. Updated results of our randomized controlled phase 2 trial (median follow-up 6 years) will be presented along with early results of our ongoing phase 1 trial with the oncolytic adenovirus expressing IL-12.View Large Image | Download PowerPoint Slide