A number of potential advantages, development of promising new agents, and the discovery of synergy with cytokines or cell products continue to spur research into the application of chemical immunomodulators for the treatment of cancer and AIDS. In preclinical in vitro and in vivo systems, chemical immunomodulators definitely modulate the immune system and have therapeutic efficacy. Although clinical trials have shown the ability of these agents to modulate the human immune system, thus far chemical immunomodulators have generally not fulfilled the therapeutic promise generated in animal models for the treatment of human diseases. While the discrepancy in results between animal models and human trials is obvious, the basis is not apparent. Species differences in elimination kinetics, presentation of active drug at the site of action, and the development of tachyphylaxis have been postulated as reasons for the minimal activity of these agents in humans. In addition, the use of investigational techniques established for cytotoxic agents may not be appropriate for immunomodulators. As with any immunomodulator, determining an optimal immunostimulatory dose and schedule and applying the therapy to patients with minimal tumor burden would perhaps be more appropriate than use of a maximally tolerated dose in patients with advanced disease. A dose-immunological effect relationship has recently been demonstrated for levamisole at doses higher than those used for many years in levamisole trials (99). While research and clinical investigation have identified several potentially useful chemical immunomodulators, the elementary understanding of the biochemical mechanisms involved in immunoregulation remains basic. Future research must elucidate these mechanisms, particularly in humans, to maximize the benefits of chemical immunomodulators as single agents or combined with cytotoxic chemotherapeutic agents, surgery, radiation therapy, other immunomodulators, and antiviral agents.
