New protocol developed

This Phase 2 study tests whether adding two immune therapies - nogapendekin alfa-inbakicept (NAI) and off-the-shelf iNKT cell infusions - to standard care can safely help critically ill adults with severe community-acquired pneumonia (CAP) (with or without sepsis/ARDS) recover. The study will give NAI by subcutaneous injection (Days 1 and 10) and one IV dose of iNKT cells (Day 3), then follow participants for 90 days.

Phase 2, single-arm study in up to 20 critically ill adults with severe community-acquired pneumonia (CAP) (with or without sepsis/ARDS) and lymphopenia (ALC <1,500/µL). The study evaluates the safety, tolerability, and preliminary efficacy of combining an IL-15 superagonist (nogapendekin alfa-inbakicept, NAI) with an allogeneic invariant natural killer T cell product (iNKT cells) added to standard ICU care.

Key elements

Population: Adults (≥18) admitted to ICU for severe CAP within 72 hours, meeting IDSA/ATS severe CAP criteria (≥1 major or ≥3 minor) and on antibiotics.

Planned enrollment: up to 20 participants (≈40 screened).

Intervention schedule:

Day 1: NAI subcutaneous (≤50 kg → 15 µg/kg; >50 kg → fixed 1 mg). Day 3: Single IV infusion of iNKT cells (1 × 10^9 cells). Day 10: Second NAI subcutaneous dose (same dosing as Day 1). Concomitant care: all participants receive guideline-based standard of care for CAP/sepsis/ARDS (antibiotics, organ support, lung-protective ventilation, vasopressors, low-dose steroids as indicated, etc.).

Safety oversight: continuous ICU monitoring; Sponsor Drug Safety review of SAEs; Safety Review Committee (SRC) reviews safety after first 5 participants and oversees stopping rules. Predefined toxicity rules and management algorithms for infusion reactions, CRS, and ICANS are specified.

Primary endpoints: safety/tolerability (TEAEs, SAEs, grade ≥3 AEs) and 28-day all-cause mortality.

Secondary endpoints: absolute lymphocyte count recovery, ventilator-free days, ICU-free days, antibiotic-free days, days free from organ support, time to ICU/hospital discharge, incidence of secondary infections through Day 28, and 90-day mortality.

Exploratory endpoints: serum cytokines, NK and T-cell expansion and activation/exhaustion markers, monocyte HLA-DR, quantification and persistence of donor iNKT cells (Days 1, 7, 14, 28).

Duration per participant: treatment up to 10 days; follow-up to 90 days after first dose.

Stopping/discontinuation: specified criteria for permanent discontinuation (e.g., drug-related Grade ≥3 organ toxicity, Grade ≥3 CRS/ICANS, intolerable infusion reactions), SRC stopping rules (including treatment-related death or clustered severe toxicities).

Objective: determine whether the NAI + iNKT combination can be given safely in this population and provide signals of reduced 28-day mortality and immune recovery (reversal of lymphopenia) to justify further study.

Sites will collect clinical outcomes, safety data, laboratory panels (CBC/CMP/coagulation), and samples for immune monitoring per protocol schedule.

Inclusion Criteria-

1. Age ≥ 18 years.

2. Critically ill adult requiring ICU admission due to severe community acquired pneumonia (CAP), defined by ≥1 major criterion or ≥3 minor criteria (IDSA/ATS):

   • Major: respiratory failure requiring mechanical ventilation OR septic shock requiring vasopressors.
   • Minor: tachypnea (RR ≥ 30), PaO2/FiO2 ≤ 200, multilobar infiltrates, new confusion/disorientation, BUN ≥ 20 mg/dL, platelet count < 100,000/µL, core temperature < 36.0°C, hypotension requiring aggressive fluid resuscitation.

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

4. Lymphopenia: absolute lymphocyte count (ALC) < 1,500/µL (not secondary to chemotherapy).

5. Receiving antibiotics for CAP (at least one dose since ICU admission).

6. Informed consent obtainable from participant or legally authorized representative.

Exclusion Criteria-

1. Hematologic malignancy (e.g., active leukemia or lymphoma not in remission).
2. Post CAR T therapy or hematopoietic cell transplant for ALL, NHL, or multiple myeloma < 3 months prior to enrollment.
3. Current diagnosis of cytokine release syndrome.
4. Receiving colony stimulating factors (e.g., G CSF).
5. Clinical history or imaging suggesting aspiration of gastric contents.
6. Advanced dementia or prolonged bedridden status.
7. Pregnancy or breastfeeding.
8. High dose immunosuppressive therapy at baseline (e.g., > 0.5 mg/kg prednisone or equivalent). (Low dose corticosteroids for septic shock/ARDS per SOC permitted.)
9. Uncontrolled autoimmune or inflammatory disease requiring immunosuppressive therapies.
10. Life expectancy < 24-48 hours or moribund condition despite care (investigator judgment).
11. Active uncontrolled bleeding or intracerebral hemorrhage.
12. Known hypersensitivity to ingredients used in the cell product formulation (e.g., DMSO).
13. Treated by antibiotics for the current respiratory infection for more than seven days at time of hospitalization (unless culture/sensitivity indicates resistant organism to administered antibiotics).
14. Known active viral hepatitis A, B, or C.
15. Investigator judgment that participation is not in the participant's best interest or participant is unsuitable for enrollment.