Adenovector-mediated gene delivery of interleukin-2 in metastatic breast cancer and melanoma: results of a phase 1 clinical trial

We conducted a phase 1 trial of direct injection of an E1,E3-deleted adenov irus encoding interleukin-2 (AdCAIL-2) into subcutaneous deposits of melano ma or breast cancer. Twenty-three patients were injected at seven dose leve ls (10(7)-10(10) p.f.u). Local inflammation was observed at the site of inj ection in 60% of patients but side-effects were otherwise minor. Incomplete local tumor regression occurred at the site of injection in 24% of patient s, but no conventional clinical responses were seen. Circulating CD4 and CD 8 counts fell significantly 24 h after injection. Post-injection biopsies d emonstrated tumor necrosis and lymphocytic infiltration with the predominan t fumor-infiltrating cells both CD3- and CD8-positive. Vector-derived seque nces were detected in 14 of 18 biopsies examined 7 days after injection and vector-derived hIL-2 mRNA was detected in 80% of 7-day biopsies processed after injection of 10(8) p.f.u. of AdCAIL-2 or higher. While IL-2 was detec table by ELISA in tumor biopsies at 48 h, no protein was detectable in inje cted tumors after 7 days and no circulating IL-2 was detectable at any time -point. No Ad5E1 sequences were detected either before or after injection i ndicating absence of replication-competent virus or endogenous E1-like sequ ence; furthermore, only rare vector shedding was detected Anti-adenovirus a nd neutralizing antibody titers were elevated 1 month after injection in al l patients. This trial therefore confirms the safety of use of adenoviral v ectors for gene delivery in humans and demonstrates successful transgene ex pression even in the face of pre-existing immunity to adenovirus.