1009. A Phase I Study of the Clinical and Local Biological Effects of Intratumoral Injection of mda-7 (INGN 241) in Patients with Advanced Carcinoma

The melanoma differentiation-associated gene-7 (mda-7) is a tumor suppressor gene whose expression causes apoptotic cell death in cells from a wide variety of solid tumor types, but has little effect in non-malignant cell cultures. To begin to characterize the safety and biologic activity of mda-7 gene transfer in a clinical setting, we conducted a phase I trial using intratumoral injections of an adenovirus containing the mda-7 construct (Ad-mda7; INGN 241) in patients with resectable solid tumor lesions. Sequential cohorts of patients received escalating doses of INGN 241 from 2 × 1010 to 2 × 1012 viral particles (vp) injected into the center of the accessible target tumor lesion. In the first 5 cohorts, the injected lesions were resected at 24 to 96 hours post injection, serially sectioned, then analyzed to determine the distribution and concentration of the viral agent, mRNA and protein expression, and assess the resultant biologic effects on the tumor cells. The last two cohorts had incisional biopsies performed pre-treatment and 30 days post treatment with the final cohort receiving 2 × 1012 vp injected twice weekly for 3 weeks of a 28 day cycle. All injected lesions demonstrated INGN 241 vector DNA and mRNA copies with the highest level near the injection site, then decreasing inversely with distance. Protein expression of MDA-7 determined by immunostaining paralleled the geographic and temporal pattern of expression of DNA and mRNA. Apoptosis staining by TUNEL reactivity also closely correlated with the expression pattern of the MDA-7 protein. Toxicity attributable to the injections consisted of transient low grade fever and mild injection site pain and erythema. Evidence of activity in two patients was seen with the repeat injections. One was a patient with metastatic melanoma who achieved a complete response in two separately injected lesions. In summary, INGN 241 delivered through intratumoral injection is well tolerated, induces apoptosis in a large percentage of tumor cells where protein expression is seen, and, with repeat injections, demonstrates evidence of clinically significant activity.