Immunotherapy of cancer with a pressurized, surface reduced tumor-cell vaccine

Immunotherapy of cancer has proven to be of limited clinical value thus far, largely because of its failure to overcome the multiple escape strategies deployed by tumor cells. Renewed interest in cancer immunotherapy was stimulated in recent years by the identification of distinct tumor antigens, which are capable of eliciting specific antitumor immune responses. However, the availability of synthetic or purified tumor antigens may not in itself be sufficient to offer an improved therapeutic modality, because their immunogenic hierarchy is largely unknown, and because metastatic tumor cells mutate frequently, thereby altering their overall antigenic character. During the past decade, we have developed a novel method in which tumor cells are exposed to high hydrostatic pressure (P) in the presence of a biologically compatible crosslinker (CL), 2'-3'-adenosine dialdehyde. The newly acquired immunogenic topology of surface proteins created by application of pressure converted the modified cells into potent stimulators of an antitumor response. Recently, we suggested that subsequent reduction of surface protein disulfides with N-acetyl-L-cysteine (NAC) could augment the immunogenic potential of PCL-modified tumor cells. An immunotherapeutic regimen combining PCL + NAC modified carcinoma cells plus intravenous delivery of NAC provoked an effective antitumor response capable of eradicating the metastatic nodules. We propose that this novel two-prong strategy, based on local immunization with irradiated PCL + NAC modified tumor cells and systemic administration of NAC, could provide a practical, effective immunotherapeutic approach for the treatment of human cancer. Drug Dev. Res. 50:272-284, 2000. (C) 2000 Wiley-Liss, Inc.