Augmentation of 17–1A–Induced Antibody–Dependent Cellular Cytotoxicity by the Triple Cytokine Combination of Interferon-α, Interleukin-2, and Interleukin-12

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Abstract
Previously, interferon-α (IFN-α), interleukin-2 (IL-2), and interleukin-12 (IL-12) were shown to increase the antibody-dependent cellular cytotoxicity (ADCC) induced by the murine monoclonal antibody 17-1A, which recognizes the tumor-associated antigen EpCAM. In this study, the authors wanted to determine whether the combination of these three cytokines would yield greater cytotoxicity than the single cytokines. For cytotoxicity assessment, a new flow cytometric assay was used that allows the analysis of long-term ADCC exerted by macrophages. Peripheral blood mononuclear cells from healthy donors were used as effector cells against the colorectal carcinoma cell line HT29 at a low effector-to-target ratio of 4.5:1. With this test, the effectiveness of the combinations IL-2 and IFN-α, IL-2 and IL-12, and IL-12 and IFN-α were compared with each other. The combinations IL-2 plus IL-12 and IFN-α plus IL-12 were more potent at the concentrations tested. Furthermore, the triple cytokine combination of IFN-α, IL-2, and IL-12 revealed significantly greater ADCC than dual cytokine combinations. Next, CD14+, CD4+, and CD4− cells were isolated by paramagnetic beads and magnetic activated cell sorter (MACS) columns. The CD14+ and CD4− cell populations contained the ADCC effectors. The addition of CD4+ cells to CD14+ or CD4− cells resulted in augmented ADCC, indicating that cooperation between immune cells occurs. These results suggest that multiple cytokine combinations with monoclonal antibodies may be more effective for cancer immunotherapy.

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