Acute Respiratory Distress Syndrome, Lymphopenia / Immunoparalysis in Critically Ill Adults, Sepsis, Severe Community-Acquired Pneum
Conditions
Keywords
nogapendekin alfa-inbakicept, NAI, ANKTIVA, iNKT cells, AgenT-797, IL-15 superagonist, cell therapy, immunotherapy, community-acquired pneumonia, CAP, sepsis, sepsis shock, acute respiratory distress syndrome, ARDS, lymphopenia, immunoparalysis, intensive care unit, ICU, critical care, ventilator-free days, immune monitoring
Brief summary
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.
Detailed description
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.
Interventions
DRUGAllogeneic invariant Natural Killer T (iNKT) Cells (AgenT-797)
Allogeneic invariant Natural Killer T (iNKT) Cells (AgenT-797) - cryopreserved, GMP-manufactured off-the-shelf donor iNKT cell product administered as a single intravenous infusion (1 × 10\^9 cells on Day 3) intended to provide immediate effector function and immunomodulation; cell product thawed and infused per cell-therapy procedures with premedication as indicated.
DRUGNogapendekin Alfa-Inbakicept (NAI)
Nogapendekin alfa-inbakicept (NAI) - a recombinant IL-15 superagonist complex (IL-15N72D:IL-15RαSu/IgG1 Fc) administered subcutaneously (Day 1 and Day 10; weight-based 15 µg/kg if ≤50 kg or fixed 1 mg if \>50 kg) to stimulate NK and CD8+ T-cell proliferation and function.
Sponsors
ImmunityBio, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open-label, single-arm study in which all enrolled participants receive nogapendekin alfa-inbakicept (NAI) plus a single IV infusion of allogeneic iNKT cells added to standard of care. Participants receive NAI on Days 1 and 10 and iNKT cells on Day 3; safety review by the SRC after the first 5 participants. Up to 20 participants will be treated and followed for 90 days.
Eligibility
Sex/Gender
ALL
Age
18 Years to 105 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 28-day all-cause mortality | Day 28 (28 days after first dose) | Proportion of participants who die from any cause within 28 days of first study drug administration. |
| Treatment Emergent Adverse Events (TEAEs) | From first study treatment to 30 days after the participant's last study dose. | Any new or worsening medical event beginning after the first dose through 30 days post-last dose, collected to characterize overall tolerability. |
| Severe Adverse Events (SAEs) | From first study treatment to 30 days after the participant's last study dose (SAEs related to study product reported regardless of last dose date). | Events meeting regulatory seriousness criteria (death, life-threatening, hospitalization, disability, congenital anomaly or other medically important events) reported to evaluate major safety risks. |
| Grade ≥3 TEAEs | From first study treatment to 30 days after the participant's last study dose. | Adverse events of CTCAE severity grade 3 or higher that emerge after first dose, used to quantify severe toxicity burden. |
| Safety laboratory tests | From baseline (pre-dose) through 30 days after the participant's last study dose. | Routine clinical labs (CBC, chemistry, coagulation, etc.) collected serially to detect clinically meaningful laboratory abnormalities attributable to treatment. |
| Temperature | Baseline (pre-dose) through End of ICU stay; intensified monitoring for 24 hours after iNKT infusion (vitals every ≥4 hours; continuous telemetry as indicated). | Serial core body temperature measured in degrees Celsius. Report baseline, maximum post-dose within 24 hours, and incidence of fever \>39.0°C. |
| Heart rate | Baseline (pre-dose); maximum post-dose within 24 hours after iNKT infusion (intensified monitoring during this 24-hour window); overall reporting through End of ICU stay (up to 28 days). | Serial heart rate (bpm). Report baseline, peak within 24 hours post-infusion, and incidence of new clinically significant tachycardia (\>120 bpm) requiring intervention. |
| Blood pressure | Baseline (pre-dose); maximum post-dose within 24 hours after iNKT infusion (intensified monitoring during this 24-hour window); overall reporting through End of ICU stay (up to 28 days). | Serial systolic/diastolic blood pressure (mmHg). Report baseline, nadir within 24 hours post-infusion, and incidence of new hypotension (MAP \<65 mmHg or need for new/increased vasopressor) temporally related to infusion. |
| Respiratory rate | Baseline (pre-dose); maximum post-dose within 24 hours after iNKT infusion (intensified monitoring during this 24-hour window); overall reporting through End of ICU stay (up to 28 days). | Serial RR (breaths/min). Report baseline, worst value within 24 hours post-infusion, and incidence of clinically significant tachypnea (RR ≥30) or new respiratory deterioration requiring escalation. |
| Oxygen saturation | Baseline through End of ICU stay; intensified monitoring for 24 hours after iNKT infusion. | Serial peripheral oxygen saturation (%). Report baseline, nadir within 24 hours post-infusion, and incidence of new hypoxemia (SpO2 \<90% on prior baseline support or increase in FiO2/ventilatory support). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Lymphocyte Count (ALC) | Assessed at baseline and summarized at Days 7, 14, 21, and 28 after first dose. | Peripheral ALC measured over time to evaluate reversal of lymphopenia and quantitative immune recovery after treatment. |
| Ventilator-free days (VFD) through Day 28 | Number of days within the 28-day window the participant is alive and free from mechanical ventilation, with death or ventilator dependence to Day 28 scored as zero. | From first study treatment through Day 28 after first dose. |
| ICU-free days through Day 28 | From first study treatment through Day 28 after first dose. | Number of days within 28 days the participant is alive and not in ICU, reflecting time free from intensive care support. |
| Antibiotic-free days through Day 28 | From first study treatment through Day 28 after first dose. | Number of days within 28 days the participant is alive and not receiving systemic antibiotics for respiratory infection, as a proxy for infection control and clinical recovery. |
| Days alive and free of other organ support through Day 28 | From first study treatment through Day 28 after first dose. | Count of days within 28 days the participant is alive and not requiring non-respiratory organ supports (eg, vasopressors, renal replacement therapy), reflecting multi-organ recovery. |
| Time to ICU discharge | From first study treatment (Day 1) through Day 28 - time to ICU discharge will be reported as days from first dose to date/time of ICU discharge; participants not discharged by Day 28 will be censored at Day 28. | Interval from first dose to date/time participant leaves ICU, used to assess speed of clinical improvement sufficient for lower-level care. |
| Time to hospital discharge | From first study treatment (Day 1) through Day 28 - time to hospital discharge will be reported as days from first dose to date of hospital discharge; participants not discharged by Day 28 will be censored at Day 28. | From first study treatment until hospital discharge (if occurs). |
| Number of secondary infections through Day 28 | From first study treatment through Day 28 after first dose. | Incidence and timing of new clinically documented infections (eg, ventilator-associated pneumonia, bloodstream infection) occurring within 28 days, to evaluate infection risk post-treatment. |
| Number of secondary infections through participant follow-up | Incidence of new clinically documented infections up to 90 days to capture later-onset infectious complications. | From first study treatment through 90 days after first dose. |
| 90-day all-cause mortality | From first study treatment to Day 90 after first dose. | Death from any cause occurring within 90 days of first treatment to evaluate longer-term survival. |
Outcome results
None listed