Dual-Target CAR-NK Cells Targeting MSLN, EGFR, or HER2 in Advanced NSCLC
A Phase 1/2, Open-label, Biomarker-guided Study of Dual-target Chimeric Antigen Receptor Natural Killer (CAR-NK) Cells Targeting Mesothelin (MSLN) With EGFR or HER2/ERBB2, or EGFR With HER2/ERBB2, in Participants With Advanced/Metastatic Non-small Cell Lung Cancer (NSCLC)
Beijing Biotech
60 participants
Mar 2, 2026
INTERVENTIONAL
Conditions
Summary
This is a two-part, biomarker-guided Phase 1/2 study evaluating the safety, feasibility, and preliminary anti-tumor activity of off-the-shelf dual-target CAR-NK cells in participants with advanced or metastatic NSCLC whose tumors co-express at least two of the following antigens: Mesothelin (MSLN), EGFR, and HER2/ERBB2. Participants will receive lymphodepleting chemotherapy followed by infusion of the CAR-NK product matched to their tumor antigen profile. A data-driven interim assessment will be used to select the most suitable construct for expansion.
Eligibility
Inclusion Criteria10
- Histologically or cytologically confirmed NSCLC that is unresectable Stage IIIB/IIIC or Stage IV, with radiographic progression on or after standard-of-care therapy (including platinum-based chemotherapy and immune checkpoint inhibitor when appropriate).
- At least one measurable lesion per RECIST v1.1.
- Archival tumor tissue available (or willingness to undergo a fresh biopsy) for antigen testing.
- Tumor co-expression of at least two of the following antigens at screening: MSLN, EGFR, HER2/ERBB2.
- Example thresholds: IHC ≥2+ in ≥50% of tumor cells for each required antigen (or an equivalent RNA expression threshold).
- ECOG performance status 0-1.
- Adequate organ function (hematologic, hepatic, renal) as defined by protocol laboratory limits.
- Life expectancy ≥12 weeks.
- Negative pregnancy test for individuals of childbearing potential; agreement to use effective contraception for the study-defined period.
- Ability to understand and willingness to sign written informed consent.
Exclusion Criteria10
- Active, uncontrolled central nervous system (CNS) metastases. Participants with previously treated/stable CNS disease may be eligible if clinically stable and off high-dose corticosteroids.
- Prior gene-modified cellular therapy (e.g., CAR-T, CAR-NK, TCR-T) within 3 months, or any prior therapy that in the investigator's judgment increases risk of severe toxicity.
- History of severe cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) with prior therapies.
- Clinically significant interstitial lung disease or pneumonitis requiring systemic steroids, or uncontrolled pulmonary comorbidity that would confound toxicity monitoring.
- Active autoimmune disease requiring systemic immunosuppression (physiologic steroid replacement permitted).
- Active uncontrolled infection, including uncontrolled HIV, active hepatitis B, or active hepatitis C infection.
- Significant cardiovascular disease (e.g., recent myocardial infarction, unstable angina, uncontrolled arrhythmia, or LVEF below institutional lower limit).
- Pregnant or breastfeeding.
- Concurrent anti-cancer therapy (chemotherapy, targeted therapy, immunotherapy) within protocol-defined washout periods.
- Any condition that, in the investigator's opinion, would interfere with participant safety or compliance
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Interventions
Allogeneic cord-blood-derived NK cells engineered to express a dual-target CAR (tandem OR-gate) and IL-15 for enhanced persistence; includes an inducible safety switch . Infused intravenously on Day 1
Fludarabine + Cyclophosphamide administered on Days -5, -4, and -3 prior to CAR-NK infusion
Premedication and management per institutional guidelines (e.g., acetaminophen/antihistamine pre-infusion; tocilizumab and corticosteroids per CRS/ICANS management algorithm).
Locations(1)
View Full Details on ClinicalTrials.gov
For the most up-to-date information, visit the official listing.
NCT07641023