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Interleukin-2 in cancer therapy
1Department of Clinical Immunology and Biological Therapy, University of Texas, M.D. Anderson Cancer Center, Houston 77030.
Interleukin-2 (IL-2) is a true biological response modifier. Unlike alpha-interferon, which acts directly, IL-2 mediates its antitumor effects through complex indirect effects on the immune system. IL-2 used alone shows documented antitumor activity, which is both dose and schedule related. Antitumor activity may be increased by the use of either IL-2 in combination with other cytokines or monoclonal antibodies or both types of agents in combination with activated effector cytotoxic lymphocytes. In humans, data suggest that IL-2s rapid initial clearance is due to movement into an extravascular compartment from which IL-2 returns more slowly to the plasma. Toxicity appears to be due entirely to IL-2, rather than to transfused lymphocytes. IL-2 administered by continuous infusion is superior to bolus administration. However, at total daily-dose equivalence continuous infusion of IL-2 is both more toxic and more biologically active than bolus administration, with respect to the height of post-IL-2 rebound lymphocytosis, the generation of activated circulating lymphocytes, and lymphokine-activated killer-cell precursors. The question remains unresolved as to whether the toxicity of IL-2 therapy is necessary for the attainment of optimal clinical results. From currently available data, it appears that a minority of patients treated with IL-2 show clinically significant responses, and only 5% to 10% achieve durable complete responses. Nevertheless, these reproducible responses have occurred in tumors refractory to more conventional treatment. The reasons for non-response are unclear, but many avenues of investigation suggest that IL-2 therapy may be made both more active and more tolerable through the use of alternative doses and schedules and the use of IL-2 in combination with defined antitumor effector lymphocytes, with concomitant or sequential administration of other cytokines, or together with monoclonal antibodies.
Interleukin-2 (IL-2) is a true biological response modifier. Unlike alpha-interferon, which acts directly, IL-2 mediates its antitumor effects through complex indirect effects on the immune system. IL-2 used alone shows documented antitumor activity, which is both dose and schedule related. Antitumor activity may be increased by the use of either IL-2 in combination with other cytokines or monoclonal antibodies or both types of agents in combination with activated effector cytotoxic lymphocytes. In humans, data suggest that IL-2s rapid initial clearance is due to movement into an extravascular compartment from which IL-2 returns more slowly to the plasma. Toxicity appears to be due entirely to IL-2, rather than to transfused lymphocytes. IL-2 administered by continuous infusion is superior to bolus administration. However, at total daily-dose equivalence continuous infusion of IL-2 is both more toxic and more biologically active than bolus administration, with respect to the height of post-IL-2 rebound lymphocytosis, the generation of activated circulating lymphocytes, and lymphokine-activated killer-cell precursors. The question remains unresolved as to whether the toxicity of IL-2 therapy is necessary for the attainment of optimal clinical results. From currently available data, it appears that a minority of patients treated with IL-2 show clinically significant responses, and only 5% to 10% achieve durable complete responses. Nevertheless, these reproducible responses have occurred in tumors refractory to more conventional treatment. The reasons for non-response are unclear, but many avenues of investigation suggest that IL-2 therapy may be made both more active and more tolerable through the use of alternative doses and schedules and the use of IL-2 in combination with defined antitumor effector lymphocytes, with concomitant or sequential administration of other cytokines, or together with monoclonal antibodies.