performed gastrointestinal biopsies; D

performed gastrointestinal biopsies; D.R.M. recombinant individual IL-7 (rhIL-7) per week in patients with ICL who were at risk of disease progression. The primary objectives of the study were to assess safety and the immunomodulatory effects of rhIL-7 in ICL patients. Injection site reactions were the most frequently reported adverse events. One patient experienced a hypersensitivity reaction and designed non-neutralizing anti-IL-7 antibodies. Patients with autoimmune diseases that required systemic therapy at screening were excluded from the study; however, 1 participant developed systemic lupus erythematosus while on study and was excluded from further rhIL-7 dosing. Quantitatively, rhIL-7 led to an increase in the number of circulating CD4 and CD8 T cells and tissue-resident CD3 T cells in the gut mucosa and bone marrow. Functionally, these T cells were capable of producing cytokines after mitogenic stimulation. rhIL-7 was well tolerated at biologically active doses and may represent a promising therapeutic intervention in ICL. This trial was registered at www.clinicaltrials.gov as #”type”:”clinical-trial”,”attrs”:”text”:”NCT00839436″,”term_id”:”NCT00839436″NCT00839436. Introduction Idiopathic CD4 lymphopenia (ICL) is a rare syndrome characterized by consistently low CD4 T-cell counts (<300/L) in the absence of HIV contamination or other known immunodeficiency and susceptibility Rabbit Polyclonal to XRCC5 to opportunistic infections typically associated with AIDS.1-3 Twenty-five years have elapsed since the first reports of ICL and yet the etiology, pathogenesis, and management remain CYC116 (CYC-116) unclear. Infectious complications of ICL are largely managed and prevented with antimicrobials based on guidelines for HIV/AIDS patients; however, no confirmed therapies exist for ICL immunodeficiency. Interleukin-7 (IL-7) is a cytokine produced by epithelial, stromal, and endothelial cells in the bone marrow, thymus, and lymph nodes and is essential for thymopoiesis, T-cell homeostasis, and survival.4,5 IL-7 can also enhance the killing capacity of cytotoxic CD8 T lymphocytes6 and the reactivity of antigen-specific T cells,7 thus providing the rationale for exploring a potential therapeutic role of exogenous administration of recombinant human IL-7 (rhIL-7) as treatment for ICL. In addition, previous clinical trials of rhIL-7 administration in patients with HIV8-10 and cancer,11 as well as stem cell transplant recipients,12 have established a CYC116 (CYC-116) favorable safety profile and biologic activity of this cytokine in immunocompromised patients. We hypothesized that rhIL-7 would be safe and would lead to improved T-cell proliferation and survival in ICL patients. We report here the results of the Interleukin-7 (CYT107) Treatment of Idiopathic CD4 Lymphocytopenia: Growth of CYC116 (CYC-116) CD4 T Cells (ICICLE) study, which was designed to evaluate the safety, pharmacokinetic, and immunologic effects of rhIL-7 in ICL patients. Methods Study design and objectives ICICLE was an open-label phase 1/2A, dose-escalation study of rhIL-7 administered in patients with confirmed ICL. The study was approved by the Institutional Review Board of the National Institute of Allergy and Infectious Diseases, and written informed consent was obtained from all participants prior to any study procedures and in accordance with the Declaration of Helsinki. Eligible participants were adults with confirmed ICL (CD4 T-cell count <300/L at screening and on at least 2 occasions at least 6 weeks apart in the absence of any illness, treatment, or condition accounting for CD4 lymphopenia) and increased risk for disease progression (history of opportunistic contamination or CD8 cells <180/L).3 Patients deemed to be at higher risk of untoward consequences of immune restoration as a result of ongoing uncontrolled infection, lymphoid malignancy, CYC116 (CYC-116) or autoimmune disease requiring systemic therapy were excluded. Healthy controls (HCs) were recruited under individual protocols approved by the institutional review board. The primary objective was to evaluate the safety of a biologically active dose of rhIL-7 in the treatment of ICL patients. Secondary objectives included assessing the immunomodulatory effects of rhIL-7 on peripheral blood mononuclear cells (PBMCs) and tissue distribution of lymphocytes via optional rectosigmoid and bone marrow biopsies. The protocol was designed to study escalating doses of subcutaneous rhIL-7 administered once per week for 3 consecutive weeks at 3 g/kg (first 3 patients), 10 g/kg (subsequent 5 patients), and 20 g/kg (subsequent 5 patients). Administration of rhIL-7 (3 additional injections once per week at the same dose) was repeated at week 24, and follow-up was continued until week 48. The study team and the National Institute of Allergy and Infectious Diseases Data Safety Monitoring Board reviewed safety data until week 8 before escalation to the next dose. The protocol was later amended to allow for additional administration of rhIL-7 in patients with CD4 count remaining at <350/L at the highest rhIL-7 dose deemed safe after safety evaluation by the DMSB. rhIL-7 study drug The rhIL-7 used in this study, CYT107, was supplied by Cytheris, Inc. It is a purified glycosylated 152-amino-acid rhIL-7 expressed in a Chinese hamster ovary cell line. The molecular formula for the nonglycosylated peptidic sequence is usually C762H1241N213O228S11. Immunophenotyping of PBMCs Immunophenotyping of peripheral blood drawn.