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Cancer Therapy: Clinical |
Authors' Affiliations: 1 Division of Hematology/Oncology, Department of Internal Medicine; 2 Integrated Biomedical Sciences Program; 3 Department of Epidemiology and Biometrics; and 4 The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; 5 The AIDS Malignancy Consortium; 6 Beth Israel Deaconess Medical Center, Boston, Massachusetts; 7 Roswell Park Cancer Institute, Buffalo, New York; and 8 The Cancer and Leukemia Group B, Chicago, Illinois
Requests for reprints: Manisha A. Shah, The Ohio State University Comprehensive Cancer Center, A438 Starling-Loving Hall, 320 West 10th Avenue, Columbus, OH 43210. Phone: 614-293-7521; Fax: 614-293-7522; E-mail: manisha.shah{at}osumc.edu.
Purpose: Ultra low doses of interleukin-2 (IL-2) can activate the high-affinity IL-2 receptor constitutively expressed on CD56bright 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 CD56bright 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 µg/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 µg/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.
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