癌治療とＤＤＳ 癌免疫療法へのＤＤＳ応用 薬剤学の立場から

Abstract

Since the 1970's, a wide variety of cancer immunotherapies have been attempted, but to date none have been established as a general cancer therapy. We present here in data clearly indicating that Drug Delivery System (DDS) plays an important role in the establishment of cancer immunotherapy. Tumor necrosis factor-α (TNF-α)has been shown to exhibit striking cytotoxicity against various tumor cells in vitro, and has attracted attention as a potential anti-cancer drug. However, TNF-α is rapidly eliminated from blood circulation, and thus a very high dose is required to obtain a significant clinical anti-tumor effect. Systemic administration of TNF-α frequently induces toxic side-effects. Thus, cancer immunotherapy involving the use of TNF-α has been limited to local intra-tumoral administration. We previously reported that chemical modification of TNF-α with polyethylene glycol (PEG) prolonged its plasma half-life, and increased its and-tumor activity in the Meth-A marine model, Furthermore, we also synthesized TNF-α conjugated with divinely ether and maleic anhydride (DIVEMA), which is a biological response modifier that shows anti-tumor activity against various tumors. DIVEMA-TNF-α demonstrated a dramatic anti-tumor effect that was approximately 100 times greater than native TNF-α and was capable of inducing complete regression in all five mice bearing Meth-A solid tumors without causing any apparent side effects. In recent years, cancer vaccines have received a great deal of attention among various cancer immunotherapies. The major focus in cancer vaccine development has been on the generation of antigen specific cytotoxic T lymphocyte (CTL) responses. CTL recognizes antigens derived from endogenously expressed proteins present on the cell surface in the form of major histocompatibility complex(MHC)class I molecules. Moreover, the delivery of antigens to the class I pathway has been a matter of great importance to the development of cancer vaccines. Generation of CTL via immunization with exogenous proteins is often ineffective due to the fact that these Antigens typically enter the MHC class II pathway. We previously reported that fusogenic liposomes(FLs), prepared by simple fusion of liposomes with Sendai virus particle, fused with cell membranes and delivered their contents directly and efficiently into the cytoplasm both in vivo and in vitro. We show here that FLs as antigen carriers directly deliver into the class I pathway and effectively induce tumor-antigen specific CTL and anti-tumor effects.