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

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 C D56(+) natural killer cells expressing intermediate-affinity IL-2 rece ptor py, complexes. Because IL-15 activates cells via these same py, r eceptors, we hypothesized that IL-15 would also activate lymphocytes f rom patients treated with in vivo 1L-2 therapy and therefore that IL-1 5 might potentially be useful as an immunotherapeutic agent alone or i n combination with IL-2, We report here that peripheral blood mononucl ear cells (PBMCs) from patients receiving in vivo IL-2 therapy do prol iferate in response to IL-15, However, a greater dose of IL-15 is need ed to reach the same level of proliferation stimulated by IL-2, The EC 50 for IL-2 is 0.21 a 0.01 nM (mean +/- SE; n = 18), whereas the EC50 for IL-15-slimulated proliferation is 1.16 +/- 0.16 nM (n = 18). In co ntrast to the proliferative response, equivalent doses of IL-2 and IL- 15 stimulate patient PBMCs to mediate similar levels of cytotoxicity a gainst Daudi, K562, and LA-N-5 tumor targets. Notably, low concentrati ons of IL-15 that do not stimulate a substantial proliferative respons e (e.g. 1.0 ng/ml) do boost PBMCs to mediate cytotoxicity against thes e tumor targets. These distinct dose-response curves for proliferation compared to cytotoxicity suggest that IL-15 should be evaluated for i ts potential as an immunotherapeutic agent to treat cancer, particular ly in regimens providing doses that might minimize the proliferative r esponse (associated with cytokine release and toxic side effects) whil e maintaining the cytolytic antitumor response.