Intravenously administered interleukin-7 to reverse lymphopenia in patients with septic shock: a double-blind, randomized, placebo-controlled trial

Thomas Daix; Armelle Mathonnet; Scott Brakenridge; Pierre-François Dequin; Jean-Paul Mira; Frederique Berbille; Michel Morre; Robin Jeannet; Teresa Blood; Jacqueline Unsinger; Jane Blood; Andrew Walton; Lyle L Moldawer; Richard Hotchkiss; Bruno François

doi:10.1186/s13613-023-01109-w

Intravenously administered interleukin-7 to reverse lymphopenia in patients with septic shock: a double-blind, randomized, placebo-controlled trial

Ann Intensive Care. 2023 Mar 12;13(1):17. doi: 10.1186/s13613-023-01109-w.

Authors

Affiliations

¹ Réanimation Polyvalente, INSERM CIC 1435 and UMR 1092, CHU Limoges, Limoges, France.
² Médecine Intensive Réanimation, CH Orléans, Orléans, France.
³ Department of Surgery, Sepsis and Critical Illness Research Center, University of Florida College of Medicine, Gainesville, FL, USA.
⁴ Department of Surgery, Harborview Medical Center, University of Washington, Seattle, WA, USA.
⁵ Médecine Intensive Réanimation, INSERM U1100 Centre d'Étude des Pathologies Respiratoires and INSERM CIC 1415, CHRU Tours and Université de Tours, Tours, France.
⁶ Réanimation Médicale, Assistance Publique des Hôpitaux de Paris, Groupe Hospitalier Universitaire de Paris Centre, Hôpital Cochin, and Faculté de Médecine, Université Paris Descartes, Paris, France.
⁷ RevImmune, Bethesda, MD, USA.
⁸ INSERM CIC 1435 and UMR CNRS 7276, INSERM 1262, CHU Limoges and Faculté de Médecine, Université de Limoges, Limoges, France.
⁹ Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, USA.
¹⁰ Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, USA. richardshotchkiss@wustl.edu.
¹¹ Réanimation Polyvalente, INSERM CIC 1435 and UMR 1092, CHU Limoges, Limoges, France. b.francois@unilim.fr.

Abstract

Background: Profound lymphopenia is an independent predictor of adverse clinical outcomes in sepsis. Interleukin-7 (IL-7) is essential for lymphocyte proliferation and survival. A previous phase II study showed that CYT107, a glycosylated recombinant human IL-7, administered intramuscularly reversed sepsis-induced lymphopenia and improved lymphocyte function. Thepresent study evaluated intravenous administration of CYT107. This prospective, double-blinded, placebo-controlled trial was designed to enroll 40 sepsis patients, randomized 3:1 to CYT107 (10 µg/kg) or placebo, for up to 90 days.

Results: Twenty-one patients were enrolled (fifteen CYT107 group, six placebo group) at eight French and two US sites. The study was halted early because three of fifteen patients receiving intravenous CYT107 developed fever and respiratory distress approximately 5-8 h after drug administration. Intravenous administration of CYT107 resulted in a two-threefold increase in absolute lymphocyte counts (including in both CD4⁺ and CD8⁺ T cells (all p < 0.05)) compared to placebo. This increase was similar to that seen with intramuscular administration of CYT107, was maintained throughout follow-up, reversed severe lymphopenia and was associated with increase in organ support free days (OSFD). However, intravenous CYT107 produced an approximately 100-fold increase in CYT107 blood concentration compared with intramuscular CYT107. No cytokine storm and no formation of antibodies to CYT107 were observed.

Conclusion: Intravenous CYT107 reversed sepsis-induced lymphopenia. However, compared to intramuscular CYT107 administration, it was associated with transient respiratory distress without long-term sequelae. Because of equivalent positive laboratory and clinical responses, more favorable pharmacokinetics, and better patient tolerability, intramuscular administration of CYT107 is preferable.

Trial registration: Clinicaltrials.gov, NCT03821038. Registered 29 January 2019, https://clinicaltrials.gov/ct2/show/NCT03821038?term=NCT03821038&draw=2&rank=1 .

Keywords: Immune restoration; Interleukin-7; Lymphocyte; Sepsis.

Associated data

ClinicalTrials.gov/NCT03821038