A Study of IL-7 to Restore Absolute Lymphocyte Counts in Sepsis Patients

Sepsis is the leading cause of death in critically ill patients in most intensive care units
in Europe and the US. Recently, evidence has accumulated that sepsis progresses from a state
of hyper-inflammation to a state of immunosuppression. This immunosuppressive phase is
characterized by increased incidence of secondary infections often with relatively avirulent
opportunistic type pathogens. Currently, new therapeutic approaches to sepsis are occurring
using immuno-adjuvants that boost host immunity. One of the most promising agents
Interleukin-7 is an essential, non-redundant, pluripotent cytokine produced mainly by bone
marrow and thymic stromal cells that is required for T-cell survival.In addition to its
anti-apoptotic properties, IL-7 induces potent proliferation of naïve and memory T-cells
potentially supporting replenishment of the peripheral T-cell pool which is severely depleted
during sepsis. These effects were confirmed in clinical trials at the National Cancer
Institute and in HIV+ patients.

This clinical study will test the ability of IL-7 to restore the absolute lymphocyte counts
in septic patients who have markedly reduced levels of circulating lymphocytes. An effect
already confirmed in preclinical models of sepsis.

Inclusion Criteria:

1. Patients of age ≥ 18 yrs and older but < 80 yrs

2. Patients with persistent suspected sepsis at 48-120 hrs after admission

3. Two or more criteria for the systemic inflammatory response syndrome (SIRS) (see
reference #19 for SIRS criteria) and a clinically or microbiologically suspected
infection.

4. At least one organ failure as defined by a SOFA (Sepsis-related organ failure
assessment) score of ≥2 at any time point during the 48-120 hrs after admission to the
ICU

5. Requirement of vasopressor treatment as follows: i) epinephrine or norepinephrine at ≥
0.05 µg/kg/min ideal body weight; ii) vasopressin, or iii) dopamine at ≥ 4-5 μg/kg/min
ideal body weight, continuously for 4 hrs or more, provided that at least 20 ml/kg of
ideal body weight of crystalloid or an equivalent volume of colloid was administered
during the 24-hour interval surrounding the start of vasopressor treatment, to
maintain systolic pressure ≥ 90 mmHg or a mean arterial pressure ≥ 60 mmHg at any time
point during their sepsis course preceding enrollment into the IL-7 study.

6. Lymphopenia with an absolute lymphocyte count ≤ 900 cells/mm3 at either the day of
consent or the day prior to consent during their ICU stay.

7. Predicted length of stay in the ICU of up to two weeks after starting drug therapy
treatment in the trial (ICU may also include a close medical ward on the same study
site where the patient will remain under medical control of the Investigator).

8. Ability to obtain a signed informed consent from patient or LAR (Legally Authorized
Representative) consent.

Exclusion Criteria:

1. Cancer with current chemotherapy or radiotherapy and/or .receipt of chemotherapy or
radiotherapy within the last 6 weeks

2. Cardiopulmonary resuscitation within the previous 4 weeks without objective evidence
of full neurologic recovery) or patients who have minimal chance of survival and are
not expected to live > 3-5 days as defined by an APACHE II score of ≥ 35 at time of
consideration for study eligibility

3. Patients with a history of or who currently have evidence of autoimmune disease
including for example: myasthenia gravis, Guillain Barre syndrome, systemic lupus
erythematosis, multiple sclerosis, scleroderma, ulcerative colitis, Crohn's disease,
autoimmune hepatitis, Wegener's etc.

4. Patients who have received solid organ transplant or bone marrow transplant

5. Patients with active or a history of acute or chronic lymphocytic leukemia

6. AIDS-defining illness (category C) diagnosed within the last 12 months prior to study
entry

7. History of splenectomy

8. Any hematologic disease associated with hypersplenism, such as thalassemia, hereditary
spherocytosis, Gaucher's Disease, and autoimmune hemolytic anemia

9. Pregnant or lactating women

10. Participation in another investigational interventional study within the last 6 months
prior to study entry, with the exception of studies aimed at testing sedation products
belonging to standard of care such as Propofol, Dexmedetomidine, Midazolam.

11. Patients receiving immunosuppressive drugs, e.g., TNF-alpha inhibitors, for rheumatoid
arthritis, inflammatory bowel disease or any other reason, or systemic corticosteroids
other than hydrocortisone at a dose of 300 mg/day

12. Patients receiving concurrent immunotherapy or biologic agents including: growth
factors, cytokines and interleukins, (other than the study medication); for example
IL-2,growth factors, interferons, HIV vaccines, immunosuppressive drugs, hydroxyurea,
immunoglobulins, adoptive cell therapy

13. Prisoners