Immunological effects of low-dose cyclophosphamide in cancer patients treated with oncolytic adenovirus

Abstract

Patients with advanced solid tumors refractory to and progressing after conventional therapies were treated with three different regimens of low-dose cyclophosphamide (CP) in combination with oncolytic adenovirus. CP was given with oral metronomic dosing (50mg/day, N = 21), intravenously (single 1,000mg dose, N = 7) or both (N = 7). Virus was injected intratumorally. Controls (N = 8) received virus without CP. Treatments were well tolerated and safe regardless of schedule. Antibody formation and virus replication were not affected by CP. Metronomic CP (oral and oral intravenous schedules) decreased regulatory T cells (T regs) without compromising induction of antitumor or antiviral T-cell responses. Oncolytic adenovirus given together with metronomic CP increased cytotoxic T cells and induced Th1 type immunity on a systemic level in most patients. All CP regimens resulted in higher rates of disease control than virus only (all P 0.0001) and the best progression-free (PFS) and overall survival (OS) was seen in the oral intravenous group. One year PFS and OS were 53 and 42% (P = 0.0016 and P 0.02 versus virus only), respectively, both which are unusually high for chemotherapy refractory patients. We conclude that low-dose CP results in immunological effects appealing for oncolytic virotherapy. While these first-in-human data suggest good safety, intriguing efficacy and extended survival, the results should be confirmed in a randomized trial. © 2011 The American Society of Gene & Cell Therapy.