PURPOSE: Ultra low doses of interleukin-2 (IL-2) can activate the high-affinity IL-2 receptor constitutively expressed on CD56(bright) natural killer (NK) cells, the CD34+ NK cell precursor, and CD4+ CD25+ regulatory T cells (Tregs) in vivo. We have previously shown synergy between IL-2 and stem cell factor (SCF) in the generation of CD56(bright) NK cells from CD34+ hemopoietic progenitor cells in vitro and showed synergistic NK cell expansion in an in vivo preclinical model. To determine the safety, toxicity, and immune modulation of this combination of cytokines in vivo, we conducted a first-in-man phase I study. EXPERIMENTAL DESIGN: A phase I dose escalation study was conducted using IL-2 at 900,000 or 650,000 IU/m2/d for 8 weeks with 5 or 10 microg/kg/d of SCF given thrice a week for 8 weeks in patients with HIV infection and/or cancer. RESULTS: Ten of 13 patients completed therapy; four experienced the dose-limiting toxicities of grade 3 fatigue or urticaria. The maximum tolerated doses of IL-2 and SCF in combination is 650,000 IU/m2/d of IL-2 and 5 microg/kg/d thrice a week of SCF. NK cells were expanded over 2-fold on therapy; Tregs were expanded nearly 6-fold from baseline. CONCLUSIONS: Administration of IL-2 with SCF is safe and well tolerated and leads to expansion of lymphocyte subsets in patients with HIV or HIV and cancer; however, the changes in NK cell and Treg expansion seen with this cytokine combination were no different than those seen with a similar dose of IL-2 alone.
PURPOSE: Ultra low doses of interleukin-2 (IL-2) can activate the high-affinity IL-2 receptor constitutively expressed on CD56(bright) natural killer (NK) cells, the CD34+ NK cell precursor, and CD4+ CD25+ regulatory T cells (Tregs) in vivo. We have previously shown synergy between IL-2 and stem cell factor (SCF) in the generation of CD56(bright) NK cells from CD34+ hemopoietic progenitor cells in vitro and showed synergistic NK cell expansion in an in vivo preclinical model. To determine the safety, toxicity, and immune modulation of this combination of cytokines in vivo, we conducted a first-in-man phase I study. EXPERIMENTAL DESIGN: A phase I dose escalation study was conducted using IL-2 at 900,000 or 650,000 IU/m2/d for 8 weeks with 5 or 10 microg/kg/d of SCF given thrice a week for 8 weeks in patients with HIV infection and/or cancer. RESULTS: Ten of 13 patients completed therapy; four experienced the dose-limiting toxicities of grade 3 fatigue or urticaria. The maximum tolerated doses of IL-2 and SCF in combination is 650,000 IU/m2/d of IL-2 and 5 microg/kg/d thrice a week of SCF. NK cells were expanded over 2-fold on therapy; Tregs were expanded nearly 6-fold from baseline. CONCLUSIONS: Administration of IL-2 with SCF is safe and well tolerated and leads to expansion of lymphocyte subsets in patients with HIV or HIV and cancer; however, the changes in NK cell and Treg expansion seen with this cytokine combination were no different than those seen with a similar dose of IL-2 alone.
Authors: Robert J Lechleider; Philip M Arlen; Kwong-Yok Tsang; Seth M Steinberg; Junko Yokokawa; Vittore Cereda; Kevin Camphausen; Jeffrey Schlom; William L Dahut; James L Gulley Journal: Clin Cancer Res Date: 2008-08-15 Impact factor: 12.531
Authors: William H D Hallett; Erik Ames; Maite Álvarez; Isabel Barao; Patricia A Taylor; Bruce R Blazar; William J Murphy Journal: Biol Blood Marrow Transplant Date: 2008-10 Impact factor: 5.742
Authors: Michael J Robertson; Christopher W Stamatkin; David Pelloso; Jill Weisenbach; Nagendra K Prasad; Ahmad R Safa Journal: J Immunother Date: 2018-04 Impact factor: 4.456
Authors: A Aoyama; D Klarin; Y Yamada; S Boskovic; O Nadazdin; K Kawai; D Schoenfeld; J C Madsen; A B Cosimi; G Benichou; T Kawai Journal: Am J Transplant Date: 2012-06-08 Impact factor: 8.086
Authors: Michael J Robertson; Justin Kline; Herbert Struemper; Kevin M Koch; John W Bauman; Olivia S Gardner; Sharon C Murray; Fiona Germaschewski; Jill Weisenbach; Zdenka Jonak; John F Toso Journal: J Immunother Date: 2013 Jul-Aug Impact factor: 4.456
Authors: Alana A Kennedy-Nasser; Stephanie Ku; Paul Castillo-Caro; Yasmin Hazrat; Meng-Fen Wu; Hao Liu; Jos Melenhorst; A John Barrett; Sawa Ito; Aaron Foster; Barbara Savoldo; Eric Yvon; George Carrum; Carlos A Ramos; Robert A Krance; Kathryn Leung; Helen E Heslop; Malcolm K Brenner; Catherine M Bollard Journal: Clin Cancer Res Date: 2014-02-26 Impact factor: 12.531
Authors: Stephan A Grupp; Michael Verneris; Paul M Sondel; Laurence J N Cooper Journal: Biol Blood Marrow Transplant Date: 2008-01 Impact factor: 5.742