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 3

CYT107 increased CD4+ and CD8+ T cell counts.

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CYT107 increased CD4+ and CD8+ T cell counts. (A) The effect of CYT107 o...
(A) The effect of CYT107 on the averaged CD4+ and CD8+ T cell counts, considered for study duration, was significant for both CD4+ and CD8+ T cells. The low-frequency regimen (red color) significantly increased CD4+ and the high-frequency regimen (blue color) increased CD8+ T cells compared with placebo. Low-frequency CYT107 therapy increased CD4+ T cells at days 8, 15, and 22. High-frequency CYT107 therapy increased CD8+ T cells at day 42. *P < 0.05, **P < 0.01. Statistical tests were conducted using a Wald-type multiple-degree-of-freedom method. Values reported are mean ± SEM. n = 10, 8, and 9 for placebo, low-frequency CYT107, and high-frequency CYT107-treated patients, respectively. (B) The effect of CYT107 on individual patient CD4+ and CD8+ T cell counts is presented. Note that the patients at US sites had quantification of CD4+ and CD8+ T cell counts for 6 weeks, while the patients at French sites had quantification out to 4 weeks only.