Gene Therapy of Melanoma Using Inactivated Sendai Virus Envelope Vector (HVJ-E) with Intrinsic Anti-Tumor Activities

Abstract

Despite the development of various cancer treatments, including surgical treatment, radiation, and anti-cancer reagents, cancer cells are not completely eliminated from the body in many cases, which allows the tumors to recur. Disease recurrence is the most difficult problem in cancer treatment. Much attention has been paid to cancer immunotherapy as a strategy to eliminate cancer cells from patients (1). However, numerous failures of cancer immunotherapy have indicated the difficulty of achieving anti-cancer immunity (1, 2). Cancer tissues produce factors that attenuate anti-tumor immunity and eventually induce immunotolerance against cancers in tumor-bearing individuals (3, 4). Therefore, to successfully eradicate cancer, first the tumor mass must be reduced as much as possible through surgery, radiation and chemotherapy; then, immunotherapy should be provided to increase the immune-activation signals and decrease the immune-suppression signals (5-7). Thus, multi-lateral strategies are needed in cancer treatment. Gene therapy has been anticipated to be a new tool for cancer treatment (8). Much attention has been also paid to immuno-gene therapy (9). However, it is still very difficult to achieve long-term remissions in cancer patients (10). Based on the concept of multi-lateral strategies, the control of multiple pathways of cancer growth is also necessary in gene therapy. We have developed a hemagglutinating virus of Japan envelope (HVJ-E) vector by using inactivated Sendai virus as a pseudovirion for gene and drug delivery (11). This vector can deliver siRNA, DNA, proteins, and anti-cancer drugs to cells in vitro and in vivo (12). We previously reported that HVJ-E itself has a strong anti-tumor effect against mouse tumors, such as colon carcinoma and renal carcinoma, by the activation of cytotoxic T lymphocytes and natural killer cells and the suppression of regulatory T cells (13, 14). Recently, we also determined the direct tumor-killing activity of HVJ-E through the induction of type I interferon on hormone-resistant human prostate cancer cells and human glioblastoma cells (15, 16). Thus, HVJ-E is a versatile gene and drug delivery vector with