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Induction of lymphokine-activated killing with reduced secretion of interleukin-1β, tumor necrosis factor-α, and interferon-γ by interleukin-2 analogs

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Abstract

Background: Interleukin-2 (IL-2)-based immunotherapy has been shown to effect clinical responses in 15–35% of patients with metastatic renal cell carcinoma or melanoma. Despite its clinical efficacy, many clinicians refrain from using IL-2 because of the associated toxicity. This toxicity is believed to be mediated by such secondary cytokines as IL-1, tumor necrosis factor (TNF), and interferon (IFN)-γ, which are produced by the patient's IL-2-stimulated peripheral blood mononuclear cells (PBMCs).

Methods: Human PBMCs were stimulated with 1 nM wild-type recombinant IL-2 (rIL-2) or IL-2 analogs (R38A or F42K) that preferentially bind to the intermediate affinity IL-2 receptor (IL-2R). PBMCs were activated for lymphokine-activated killer (LAK) activity in 4-h51Cr-release assays, using Daudi target cells. Cytokine content in the culture supernatants was determined by enzyme-linked immunosorbent assay.

Results: Both R38A and F42K were capable of generating substantial LAK activity. Maximal specific lysis was 54% for PBMCs activated by R38A and 52% for F42K-stimulated cells, in contrast to 64% for rIL-2. In addition, analog-stimulated PBMCs secreted 59% of the IL-1β, 25% of the TNF-α, and only 8% of the IFN-γ produced in response to rIL-2 (allp<0.01 compared with rIL-2-stimulated secretion; one-way ANOVA).

Conclusions: IL-2 analogs that preferentially bind the intermediate-affinity IL-2R retain the capacity to induce substantial LAK activity despite a greatly reduced secondary cytokine production. Therefore, such IL-2 analogs may provide an effective, yet less toxic means of cancer immunotherapy.

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Authors and Affiliations

  1. From the Department of Tumor Biology and General Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

    Keith M. Heaton MD &  Elizabeth A. Grimm PhD

  2. the Department of Inflammation/Autoimmune Diseases, Hoffmann-La Roche, Inc., Nutley, New Jersey, U.S.A.

    Grace Ju PhD

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  1. Keith M. Heaton MD
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  2. Grace Ju PhD
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  3. Elizabeth A. Grimm PhD
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Heaton, K.M., Ju, G. & Grimm, E.A. Induction of lymphokine-activated killing with reduced secretion of interleukin-1β, tumor necrosis factor-α, and interferon-γ by interleukin-2 analogs. Annals of Surgical Oncology 1, 198–203 (1994). https://doi.org/10.1007/BF02303524

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  • DOI: https://doi.org/10.1007/BF02303524

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