Cytheris Announces Publication of Preclinical Study in Journal of Immunology Showing Interleukin-7 PromotesT Cell Viability, Trafficking, and Functionality While Improving Survival in Sepsis
Study indicates rhIL-7 blocks sepsis-induced depletion of CD4 and CD8 T cells, enhances lymphocyte recruitment and prevents sepsis-induced loss in immunity leading to improved survival
PARIS--(BUSINESS WIRE)--Mar 16, 2010 - Cytheris SA, a clinical stage biopharmaceutical company focused on research and development of new therapies for immune modulation, today announced publication of data from a preclinical study in a clinically relevant animal model of sepsis showing that recombinant human Interleukin-7 (rhIL-7) treatment not only restores T cell trafficking and function, but also translates into improved survival. Sepsis, a highly lethal disorder which occurs during severe overwhelming infection, is the most common cause of death in most intensive care units in developed countries, annually striking an estimated 750,000 people in the United States alone, resulting in the death of more than 220,000 people per year.
The paper entitled “IL-7 Promotes T Cell Viability, Trafficking, and Functionality and Improves Survival in Sepsis” is prepublished online in The Journal of Immunology, the journal of The American Association of Immunologists (Jacqueline Unsinger, Margaret McGlynn, Kevin R. Kasten, Andrew S. Hoekzema, Eizo Watanabe, Jared T. Muenzer, Jacquelyn S. McDonough, Johannes Tschoep, Thomas A. Ferguson, Jonathan E. McDunn, Michel Morre, David A. Hildeman, Charles C. Caldwell, and Richard S. Hotchkiss, March 3, 2010; doi:10.4049/jimmunol.0903151).
The study strongly supports the belief that rather than being an uncontrolled inflammatory response, sepsis is the result of extensive apoptosis-induced depletion of immune effector cells. This explains the failure of the numerous sepsis trials conducted with agents that block the inflammatory cascade, leading investigators to question whether death in patients with sepsis results from uncontrolled inflammation. Three autopsy studies of patients who died of sepsis have confirmed findings in animal models by showing massive loss of T and B lymphocytes and dendritic cells.
“Based on this study, rhIL-7 appears to be a particularly attractive therapy for this indication because it ameliorates many of the key pathophysiologic processes that are believed to be central to the lethality of sepsis,” said Richard S. Hotchkiss, MD, Department of Anesthesiology, Washington University School of Medicine and lead investigator on the study. “Specifically, rhIL-7 blocks sepsis-induced depletion of CD4 and CD8 cells, enhances lymphocyte recruitment, prevents the sepsis-induced loss in immunity as evidenced by preserved delayed-type hypersensitivity response, does not exacerbate the proinflammatory response in sepsis, and clearly improves survival.”
By demonstrating that treatment with IL-7 reverses fundamental immunologic defects in sepsis, this study is relevant to treatment approaches in other patient populations where acute lymphopenia is a critical symptom. As described in a seminal paper by Brenchley JM (2006)1, during HIV infection, just as in sepsis, amounts of microbial products and inflammatory cytokines are increased in the patient's bloodstream due to gut bacterial “seepage” from a compromised GI tract. In addition to direct viral damage, this condition is associated with systemic immune activation, which induces T cell dysfunction contributing to the apoptotic effects and accompanying marked decline in CD4 T cell numbers during HIV infection. This is a strong argument for therapeutic strategies aimed at repairing the gut mucosal damage and preventing microbial translocation and hyperimmune activation in the treatment of both HIV and sepsis patients.
“In their rationale for the use of IL-7 in treatment of sepsis, Unsinger J et al reinforce the same key pathogenesis mechanism supporting T cell activation in HIV-infected, HAART treated, Immune Non Responding (INR) patients who have been the subject of ongoing clinical investigations utilizing rhIL-7,” said Michel Morre, DVM, President and CEO of Cytheris. “This mechanism is directly linked to the persistent mini sepsis originating in the T cell depleted gut mucosa of the INR population and the fact that IL-7 not only repopulates the mucosa, but also blocks a massive acute sepsis model as shown in the Journal of Immunology study, may help to explain a crucial element in the clinical outcome in this specific HIV patient subpopulation.”
About the Study
Sepsis is a highly lethal disorder characterized by widespread apoptosis-induced depletion of immune cells and the development of a profound immunosuppressive state. There is compelling evidence from animal models that the apoptosis-induced loss of immune cells is a critical factor in the immunosuppression and subsequent mortality frequently associated with the condition. The assertion that apoptosis is decisive in sepsis-induced mortality is supported by work showing that a variety of antiapoptotic strategies improve overall animal survival in this lethal disorder.
In this study, recombinant human IL-7 (rhIL-7) efficacy and potential mechanisms of action were tested in a murine peritonitis model. Studies at two independent laboratories showed that rhIL-7 markedly improved host survival, blocked apoptosis of CD4 and CD8 T cells, restored IFN-Î³ production, and improved immune effector cell recruitment to the infected site. Importantly, rhIL-7 also prevented a hallmark of sepsis (i.e., the loss of delayed-type hypersensitivity), which is an IFN-Î³– and T cell-dependent response. Mechanistically, rhIL-7 significantly increased the expression of the leukocyte adhesion markers LFA-1 and VLA-4, consistent with its ability to improve leukocyte function and trafficking to the infectious focus. rhIL-7 also increased the expression of CD8. The potent antiapoptotic effect of rhIL-7 was due to increased Bcl-2, as well as to a dramatic decrease in sepsis-induced PUMA, a heretofore unreported effect of IL-7.
Sepsis is defined as a clinical syndrome characterized by the presence of both infection and a systemic inflammatory response. The patient populations most susceptible to sepsis include those with the following characteristics: age younger than 1 year or older than 65 years, chronic illness, immunosuppression, broad-spectrum antibiotic use, and exposure to infection associated with surgical and invasive procedures.
The treatment of sepsis is often focused on supporting failing organ systems with interventions including fluid replacement, airway management, antibiotic therapy, and use of vasopressors. Current clinical advances in the treatment of sepsis include therapy with activated protein C in select subsets of patients, control of blood glucose, and early goal-directed therapy to treat the cellular oxygen deficit.
Between the US and the EU there are estimated to be more that 1.5 million episodes of sepsis per year with a 25-30% mortality rate and an annual cost to western economies of ‚¬45B. In fact, severe sepsis takes more lives than breast, colon/rectal, pancreatic, and prostate cancer combined.
About Interleukin-7 (CYT107)
Recombinant human interleukin-7 (CYT107) is a critical immune-modulator for immune T-cell recovery and enhancement. As a growth factor and cytokine physiologically produced by marrow or thymic stromal cells and other epithelia, IL-7 has a critical and, at some steps, a non-redundant stimulating effect on T lymphocyte development, notably on thymopoïesis and, downstream from the thymus, on homeostatic expansion of peripheral T-cells.
A first-generation form of rhIL-7 was shown in pre-clinical and Phase I studies in oncology and HIV-infected patients to be well tolerated in repeated dose trials, with long-lasting increases in both CD4 and CD8 T cells. CYT107 is a second-generation rhIL-7 product made by Cytheris via a recombinant mammalian cell culture system.
Clinical trials conducted on more than 140 patients in Europe, North America and Taiwan have demonstrated the potential of IL-7 to expand and protect CD4+ and CD8+ T-cells.
Currently, Cytheris is conducting multiple international investigations of IL-7 in HIV, HBV, HCV, idiopathic CD4 lymphocytopenia (sponsored by NIAID/NIH) and cancer, the latter including an NCI/NIH-sponsored study of IL-7 in combination with dendritic cell vaccines in a pilot study of tumor vaccination in children, and a study designed to restore CD4+ and CD8+ counts following T-cell depletion due to bone marrow or peripheral blood stem cell transplant (being conducted at the Memorial Sloan-Kettering Cancer Center in New York City).
About Cytheris – www.cytheris.com
Cytheris SA is a privately held clinical-stage biopharmaceutical company focused on research and development of new therapies for immune modulation. These drugs aim at reconstituting and enhancing the immune system of patients suffering from cancer, chronic viral or bacterial infections such as HCV, HBV and HIV, or lympho-depleting treatments such as chemotherapy, radiotherapy, bone marrow transplantation (BMT) and hematopoietic cell transplantation (HCT). The company operates from its headquarters and laboratories in Issy-les-Moulineaux, a suburb of Paris, and its U.S. subsidiary in Rockville, Maryland.
(1) Brenchley JM, et al. 2006. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 12 (12) Dec 1365-1371.
Posted: March 2010