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Phase I Studies of Interleukin (IL)-2 and Rituximab in B-Cell Non-Hodgkin’s Lymphoma

2004; American Association for Cancer Research; Volume: 10; Issue: 7 Linguagem: Inglês

10.1158/1078-0432.ccr-1087-3

1557-3265

William Larry Gluck, Deborah Hurst, Alan R. Yuen, Alexandra M. Levine, Mark A. Dayton, Jon P. Gockerman, Jennifer B. Lucas, Kimberly Denis-Mize, Barbara Tong, Dawn Navis, A. DiFrancesco, Sandra Milan, Susan E. Wilson, Maurice J. Wolin,

CAR-T cell therapy research

Abstract Purpose: Expansion and activation of natural killer (NK) cells with interleukin-2 (IL-2) may enhance antibody-dependent cellular cytotoxicity (ADCC), an important mechanism of rituximab activity. Two parallel Phase I studies evaluated combination therapy with rituximab and IL-2 in relapsed or refractory B-cell non-Hodgkin’s lymphoma (NHL). Experimental Design: Thirty-four patients with advanced NHL received rituximab (375 mg/m2 i.v. weekly, weeks 1–4) and escalating doses of s.c. IL-2 [2–7.5 MIU daily (n = 19) or 4.5–14 million international units three times weekly (n = 15), weeks 2–5]. Safety, tolerability, clinical responses, NK cell counts, and ADCC activity were evaluated. Results: Maximally tolerated doses (MTD) of IL-2 were 6 MIU daily and 14 million international units thrice weekly. The most common adverse events were fever, chills, and injection site reactions. Dose-limiting toxicities were fatigue and reversible liver enzyme test elevations. Of the 9 patients enrolled at the daily schedule MTD, 5 showed clinical response. On the thrice-weekly schedule at the MTD, 4 of 5 patients responded. Responders showed median time to progression of 14.9 and 16.1 months, respectively, for the two studies. For the same total weekly dose, thrice-weekly IL-2 administration induced greater increases in NK cell counts than daily dosing, and NK cells correlated with clinical response on the thrice-weekly regimen. ADCC activity was increased and maintained after IL-2 therapy in responding and stable disease patients. Conclusions: Addition of IL-2 to rituximab therapy is safe and, using thrice-weekly IL-2 dosing, results in NK cell expansion that correlates with response. This combination treatment regimen merits additional evaluation in a randomized clinical trial.