SUPPRESSION OF THE IMMUNE-RESPONSE TO AN ADENOVIRUS VECTOR AND ENHANCEMENT OF INTRATUMORAL TRANSGENE EXPRESSION BY LOW-DOSE ETOPOSIDE

Adenoviral vectors are commonly used in gene therapy trials because of their efficiency in gene transfer. However, their use is limited by c ellular and humoral immune responses that result in temporary transgen e expression and reduced efficacy of repeated vector administration. W e hypothesized that certain oncolytic agents commonly used to treat ca ncer patients could suppress the immune response to adenoviral vectors , and enable repeated adenovirus-mediated cancer gene therapy. Etoposi de and cyclophosphamide were tested for their ability to suppress the humoral and cellular immune responses to an adenoviral vector in immun ocompetetn C3H mice. Intratumoral transgene expression was monitored i n adenovirus-immunized animals treated with etoposide or cyclophospham ide. Neutralizing antibodies to adenovirus and cytotoxic T lymphocyte (CTL) lysis of virally transduced cells were significantly suppressed in mice treated with etoposide at 2 or 10 mg/kg/day or cyclophosphamid e at 10 mg/kg/day compared with untreated mice (P < 0.05). Significant ly larger areas of gene transduction were observed in treated animals compared with untreated mice or the mice treated with cyclophosphamide at 2 mg/kg/day (P < 0.05). Our results suggest that repeated adenovir ally mediated gene therapy is achievable in cancer patients who are co ncurrently undergoing treatment with chemotherapy.