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Interleukin-2 (IL-2) induces cytolytic activity and proliferation of human blood lymphocytes. Yet, prior to activation, these cells do not express IL-2 receptors recognized by monoclonal antibodies to the Tac antigen. A novel glycoprotein (IL-2R beta), identified on several lymphocytoid cell lines, has the ability to bind IL-2 alone and to associate with Tac antigen (IL-2R alpha) to form high-affinity IL-2 receptors. It is now reported that IL-2R beta is expressed on both circulating T lymphocytes and large granular lymphocytes in quantities approximately proportional to their responsiveness to IL-2. Studies of the responses of these cells to IL-2 suggest that IL-2R beta mediates the initial phase of induction of lymphokine activated killer (LAK), natural killer (NK), and proliferative activities. Subsequently, IL-2R alpha is induced and functional high-affinity IL-2 receptors are expressed.

Because of the ability of interleukin-2 (IL-2) to support the proliferation and activation of numerous types of immunocompetent cells and to support the survival of adoptively transferred lymphocytes, there has been considerable interest in its use in the immunotherapy of malignancies. While studies to date have indicated that IL-2 has activity against some malignancies, considerable toxicity has also been observed. Careful prescreening and selection of patients and appropriate management of toxicity can minimize adverse outcomes. Studies of IL-2 effects have provided intriguing evidence of interactions of the immune/cytokine system with the neuroendocrine, cardiovascular, and other systems. Studies in animal models have demonstrated the central role of an intact immune system in mediating many toxicities of IL-2. Several adverse effects of IL-2 appear to be mediated by other cytokines whose production is induced by IL-2. Studies into the pathogenesis and manifestations of IL-2 toxicity have offered the hope of developing less toxic approaches to IL-2 therapy. Several lessons from the IL-2 experience are likely to be applicable in the clinical development of other cytokines.

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This article summarizes recommendations on the design and conduct of clinical trials of a National Research Council study on missing data in clinical trials. Key findings of the study are that (a) substantial missing data is a serious problem that undermines the scientific credibility of causal conclusions from clinical trials; (b) the assumption that analysis methods can compensate for substantial missing data is not justified; hence (c) clinical trial design, including the choice of key causal estimands, the target population, and the length of the study, should include limiting missing data as one of its goals; (d) missing-data procedures should be discussed explicitly in the clinical trial protocol; (e) clinical trial conduct should take steps to limit the extent of missing data; (f) there is no universal method for handling missing data in the analysis of clinical trials – methods should be justified on the plausibility of the underlying scientific assumptions; and (g) when alternative assumptions are plausible, sensitivity analysis should be conducted to assess robustness of findings to these alternatives. This article focuses on the panel’s recommendations on the design and conduct of clinical trials to limit missing data. A companion paper addresses the panel’s findings on analysis methods.