Differential quantitative effects of interleukin (IL)-2 and IL-15 on cytotoxic activity and proliferation by lymphocytes from patients receiving in vivo IL-2 therapy

• Published in: Clinical cancer research Vol. 4; no. 5; pp. 1287 - 1296
• Main Authors: DE JONG, J. L. O, FARNER, N. L, JAVORSKY, B. R, LINDSTROM, M. J, HANK, J. A, SONDEL, P. M
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.05.1998
• Subjects: Antigens, CD - metabolism; Antigens, Differentiation, T-Lymphocyte - metabolism; Antineoplastic agents; Biological and medical sciences; CD56 Antigen - metabolism; Cell Division - drug effects; Dose-Response Relationship, Drug; Humans; Immunotherapy; Interleukin-15 - pharmacology; Interleukin-2 - pharmacology; Interleukin-2 - therapeutic use; Killer Cells, Natural - cytology; Killer Cells, Natural - drug effects; Lectins, C-Type; Leukocytes, Mononuclear - cytology; Leukocytes, Mononuclear - drug effects; Lymphocyte Subsets - cytology; Lymphocyte Subsets - drug effects; Medical sciences; Melanoma - drug therapy; Melanoma - immunology; Pharmacology. Drug treatments; Tumor Cells, Cultured; Antineoplastic agent; Human; Cell proliferation; Cytokine; Cytotoxicity; Stimulation; Interleukin 15; In vitro; Biological activity; Immunomodulator; Treatment; Interleukin 2; Immunotherapy; Lymphocyte
• ISSN: 1078-0432; 1557-3265

Lymphocytes from patients receiving in vivo interleukin (IL)-2 therapy possess enhanced in vitro proliferative and cytotoxic responses to IL-2. The cells from these patients that respond to exogenous IL-2 are CD56+ natural killer cells expressing intermediate-affinity IL-2 receptor betagamma(c) complexes. Because IL-15 activates cells via these same betagamma(c) receptors, we hypothesized that IL-15 would also activate lymphocytes from patients treated with in vivo IL-2 therapy and therefore that IL-15 might potentially be useful as an immunotherapeutic agent alone or in combination with IL-2. We report here that peripheral blood mononuclear cells (PBMCs) from patients receiving in vivo IL-2 therapy do proliferate in response to IL-15. However, a greater dose of IL-15 is needed to reach the same level of proliferation stimulated by IL-2. The EC50 for IL-2 is 0.21 +/- 0.04 nM (mean +/- SE; n = 18), whereas the EC50 for IL-15-stimulated proliferation is 1.16 +/- 0.16 nM (n = 18). In contrast to the proliferative response, equivalent doses of IL-2 and IL-15 stimulate patient PBMCs to mediate similar levels of cytotoxicity against Daudi, K562, and LA-N-5 tumor targets. Notably, low concentrations of IL-15 that do not stimulate a substantial proliferative response (e.g., 1.0 ng/ml) do boost PBMCs to mediate cytotoxicity against these tumor targets. These distinct dose-response curves for proliferation compared to cytotoxicity suggest that IL-15 should be evaluated for its potential as an immunotherapeutic agent to treat cancer, particularly in regimens providing doses that might minimize the proliferative response (associated with cytokine release and toxic side effects) while maintaining the cytolytic antitumor response.