Interleukin-7 restores lymphocytes in septic shock: the IRIS-7 randomized clinical trial
Bruno Francois, Robin Jeannet, Thomas Daix, Andrew H. Walton, Matthew S. Shotwell, Jacqueline Unsinger, Guillaume Monneret, Thomas Rimmelé, Teresa Blood, Michel Morre, Anne Gregoire, Gail A. Mayo, Jane Blood, Scott K. Durum, Edward R. Sherwood, Richard S. Hotchkiss
Bruno Francois, Robin Jeannet, Thomas Daix, Andrew H. Walton, Matthew S. Shotwell, Jacqueline Unsinger, Guillaume Monneret, Thomas Rimmelé, Teresa Blood, Michel Morre, Anne Gregoire, Gail A. Mayo, Jane Blood, Scott K. Durum, Edward R. Sherwood, Richard S. Hotchkiss
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Clinical Research and Public Health Immunology

Interleukin-7 restores lymphocytes in septic shock: the IRIS-7 randomized clinical trial

Abstract

BACKGROUND. A defining pathophysiologic feature of sepsis is profound apoptosis-induced death and depletion of CD4+ and CD8+ T cells. Interleukin-7 (IL-7) is an antiapoptotic common γ-chain cytokine that is essential for lymphocyte proliferation and survival. Clinical trials of IL-7 in over 390 oncologic and lymphopenic patients showed that IL-7 was safe, invariably increased CD4+ and CD8+ lymphocyte counts, and improved immunity. METHODS. We conducted a prospective, randomized, double-blind, placebo-controlled trial of recombinant human IL-7 (CYT107) in patients with septic shock and severe lymphopenia. Twenty-seven patients at academic sites in France and the United States received CYT107 or placebo for 4 weeks. Primary aims were to determine the safety of CYT107 in sepsis and its ability to reverse lymphopenia. RESULTS. CYT107 was well tolerated without evidence of inducing cytokine storm or worsening inflammation or organ dysfunction. CYT107 caused a 3- to 4-fold increase in absolute lymphocyte counts and in circulating CD4+ and CD8+ T cells that persisted for weeks after drug administration. CYT107 also increased T cell proliferation and activation. CONCLUSIONS. This is the first trial of an immunoadjuvant therapy targeting defects in adaptive immunity in patients with sepsis. CYT107 reversed the marked loss of CD4+ and CD8+ immune effector cells, a hallmark of sepsis and a likely key mechanism in its morbidity and mortality. CYT107 represents a potential new way forward in the treatment of patients with sepsis by restoring adaptive immunity. Such immune-based therapy should be broadly protective against diverse pathogens including multidrug resistant bacteria that preferentially target patients with impaired immunity. TRIAL REGISTRATION. Trials registered at clinicaltrials.gov: NCT02640807 and NCT02797431. FUNDING. Revimmune, NIH National Institute of General Medical Sciences GM44118.

Authors

Bruno Francois, Robin Jeannet, Thomas Daix, Andrew H. Walton, Matthew S. Shotwell, Jacqueline Unsinger, Guillaume Monneret, Thomas Rimmelé, Teresa Blood, Michel Morre, Anne Gregoire, Gail A. Mayo, Jane Blood, Scott K. Durum, Edward R. Sherwood, Richard S. Hotchkiss

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Figure 2

CYT107 increases absolute lymphocyte counts.

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CYT107 increases absolute lymphocyte counts. (A) Patients were treated w...
(A) Patients were treated with 10 μg/kg CYT107, a recombinant human interleukin-7 (IL-7) using 2 different dosing regimens. Both CYT107-treated groups received CYT107 twice a week for the first week. Thereafter, one group was treated with CYT107 once a week (low frequency) while the second CYT107 treated group was treated with CYT107 twice a week (high frequency). Therapy with CYT107 was continued for a total of 4 weeks or until the patient was discharged from the hospital. The maximum number of doses of CYT107 that a patient could receive was 5 or 8 doses respectively for the low- and high-dose regimens of CYT107. All patients received injections twice a week. (B) The CYT107 treatment effect on average absolute lymphocyte counts (ALCs) was significant for both high- and low-frequency treatment regimens. The gray-shaded region represents the upper and lower limit of normal for ALCs. The CYT107 low-frequency group (red color) was greater than the placebo-treated group at days 15 and 42, and the CYT107 high-frequency group (blue color) was greater than placebo-treated at days 22 and 29. *P < 0.05, **P < 0.01, ***P < 0.001. Statistical tests were conducted using a Wald-type multiple-degree-of-freedom method. Dark arrowhead represents the last day of treatment. Values reported are mean ± SEM. n = 10, 8, and 9 for placebo, low-frequency CYT107-treated, and high-frequency CYT107-treated patients, respectively. (C) The CYT107 treatment effect on ALCs is displayed for each patient over the study duration.