Synergy in the toxicity of cytokines: preclinical studies

Synergistic therapeutic activity has been observed both preclinically and clinically with combinations of chemotherapeutic and immunotherapeutic agents as well as with several combinations of immunotherapeutic agents. Frequently the synergistic therapeutic activity has been accompanied by unexpected toxicities demonstrating the need for the development of systematic studies to determine the nature and origin of the toxicity observed when these potent immunoregulatory agents are combined. Several examples have been demonstrated including IFN-gamma and TNF and AZT and IFN-alpha. In this paper approaches to study the pathobiology of combination cytokine therapy and strategies to limit the toxicity, to understand its mechanism, and to retain the synergistic therapeutic activity are discussed.