New protocol developed

This is a Phase 3, randomized, blinded, and placebo-controlled clinical trial investigating a new combination treatment for critically ill adults who have severe community-acquired pneumonia, especially if they also have sepsis or acute respiratory distress syndrome.

The study aims to determine if adding the experimental agents, Nogapendekin Alfa Inbakicept and iNKT cells, to standard medical care can reduce the 28-day all-cause mortality rate compared to standard care alone with a placebo.

This multi-center, randomized, blinded, and placebo-controlled Phase 3 study aims to address the high mortality and complication rates associated with severe community-acquired pneumonia (CAP) in critically ill adults, particularly those experiencing immune deficiency like lymphopenia or immunoparalysis.

Current standard treatments for severe CAP focus on infection control and organ support but often do not directly restore the patient's compromised immune function. This trial investigates a novel immunotherapeutic approach using a combination of two agents:

1. Nogapendekin Alfa Inbakicept (NAI): An IL-15 receptor agonist designed to activate natural killer (NK) and CD8+ T-cells, aiming to enhance the body's immune competence.
2. iNKT Cells (invariant natural killer T cells): An allogeneic cell therapy intended to rapidly orchestrate both innate and adaptive immune responses.

The central hypothesis is that this combination therapy, when added to standard of care treatments, can reverse immune dysfunction, clear infections, regulate inflammation, and ultimately improve survival and reduce severe complications such as secondary infections and prolonged organ support requirements in this vulnerable patient population. The study will meticulously assess the safety and efficacy of this combined approach, building on promising signals from earlier research.

Inclusion Criteria:

1. Age ≥ 18 years, adult participants of any gender.

2. Critically ill adults requiring admission to an ICU-unit due to severe community acquired pneumonia.

   • Severe CAP is defined by the presence of one major criterion or at least three minor criteria:
   • Major Criteria (any one = severe CAP):
   • Respiratory failure requiring mechanical ventilation
   • Septic shock requiring vasopressors to maintain blood pressure
   • Minor Criteria (≥3 indicates severe CAP):
   • Tachypnea: Respiratory rate ≥ 30 breaths/min
   • Hypoxemia: PaO2/FiO2 ratio ≤ 200
   • Multilobar infiltrates on chest imaging
   • Confusion or disorientation (new onset mental status changes)
   • Uremia: Blood urea nitrogen (BUN) ≥ 20 mg/dL (7.1 mmol/L)
   • Thrombocytopenia: Platelet count < 100,000/μL
   • Hypothermia: Core temperature < 36.0 °C (96.8 °F)
   • Hypotension requiring aggressive fluid resuscitation

3. Hospital admission with a diagnosis of CAP within 72 hours.

4. Lymphopenia/ Absolute Lymphocyte Count (ALC): ALC < 1,500/μL (not secondary due to chemotherapy).

5. Participants already treated by antibiotics (at least one dose since admission to the ICU).

6. Informed consent: Ability to obtain informed consent from participant or legally authorized representative (given the incapacity of many ICU participants, consent via surrogate/Legally Authorized Representative is allowed per ethics approval).

Exclusion Criteria:

1. Hematologic malignancies (eg, active leukemia and lymphoma, not in remission).
2. Post CAR-T cells therapy or hematopoietic cell transplant for ALL, NHL or Multiple Myeloma less than 3 months prior to enrollment.
3. Participant diagnosed with cytokine release syndrome.
4. Participant receiving colony stimulating factors eg, G-CSF.
5. Clinical history or radiological imaging suggesting aspiration of gastric content.
6. Participant with advanced dementia or prolonged bedridden status.
7. Pregnancy or breastfeeding.
8. High-dose immunosuppressive therapy at baseline: eg, > 0.5 mg/kg prednisone (or equivalent). Note: Use of low-dose corticosteroids for septic shock or ARDS (eg, dexamethasone 6 mg/day for ARDS) is not an exclusion, as it is standard care such use will be recorded and balanced between arms.
9. Uncontrolled autoimmune or inflammatory disease requiring immunosuppressive therapies (to avoid confounding immune effects or exacerbation).
10. Life expectancy < 24-48 hours or moribund condition despite care (Investigator judgment that participant will not survive long enough to benefit or be evaluated).
11. Active uncontrolled bleeding or intracerebral hemorrhage (cell therapy infusion could transiently affect hemodynamics or coagulation; exclude if such conditions make the intervention risk unjustifiable).
12. Known hypersensitivity to ingredients used in cell product formulation such as DMSO.
13. Treated by antibiotics for a respiratory infection for more than seven days at the time of hospitalization (except if culture and sensitivities determine a resistant organism to the administered antibiotics).
14. Known active Viral Hepatitis A, B, or C.
15. History of human immunodeficiency virus (HIV) with current CD4+ T-cell count < 350 cells/µL and/or a detectable HIV viral load.
16. The Investigator believes that participating in the trial is not in the best interest of the participant, or the Investigator considers the participant unsuitable for enrollment (such as due to unpredictable risks or severe co-morbidities).

This is a double-blind study, meaning that participants, treating physicians, and most study personnel and sponsor staff are unaware of which treatment (active drug or placebo) a participant receives. Blinding is maintained through the use of identical-looking active drugs and placebos.