Off-the-shelf dual-target CAR-NK cell therapy for advanced non-small cell lung cancer targeting MSLN with EGFR or HER2

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)

This study tests off-the-shelf CAR-NK cells matched to tumors that express two of MSLN, EGFR, or HER2 in people with advanced or metastatic non-small cell lung cancer.

Quick facts

• Phase: PHASE1; PHASE2
• Study type: Interventional
• Enrollment: 48 (estimated)
• Ages: 18 Years to 75 Years
• Sex: All
• Sponsor: Beijing Biotech (industry)
• Drugs / interventions: CAR-T, chemotherapy
• Locations: 1 site (Shenzhen, Guangdong)
• Trial ID: NCT07467863 on ClinicalTrials.gov

What this trial studies

This two-part Phase 1/2 program gives lymphodepleting chemotherapy followed by infusion of one of three off-the-shelf dual-target CAR-NK products selected according to the tumor's antigen profile (MSLN/EGFR, MSLN/HER2, or EGFR/HER2). Part A uses a 3+3 dose-escalation design within each construct to find a recommended Phase 2 dose, and Part B expands at that dose with adaptive prioritization of the construct showing the best early benefit-risk profile. Tumor antigen status is determined by IHC and/or RNA profiling, and a data-driven interim assessment may select the construct to advance. Exploratory objectives include CAR-NK persistence, immune pharmacodynamics, cytokine profiling, and correlations between antigen density and clinical outcomes.

Who should consider this trial

Good fit: Ideal candidates are adults with unresectable Stage IIIB/IIIC or Stage IV NSCLC that has progressed after standard treatments and whose tumors co-express at least two of MSLN, EGFR, and HER2.

Not a fit: Patients whose tumors express only one or none of the target antigens, those with poor performance status, or those with significant organ dysfunction are unlikely to benefit from this therapy.

Why it matters

Potential benefit: If successful, this approach could shrink tumors or slow disease progression in patients whose tumors express the targeted antigen pairs and provide an off-the-shelf cellular therapy option.

How similar studies have performed: CAR-NK and CAR-T therapies have produced strong responses in some hematologic cancers, but results in solid tumors have been limited and mixed, making dual-target CAR-NK for NSCLC a relatively novel approach with limited prior clinical proof.

Eligibility criteria

Inclusion Criteria:

* 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 Criteria:

* 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.

Where this trial is running

Shenzhen, Guangdong

• Peking University Shenzhen Hospital — Shenzhen, Guangdong, China (RECRUITING)

Study contacts

• Study coordinator: Seni S Lu, Phd

Conditions: Non-Small Cell Lung Cancer, Advanced/Metastatic NSCLC, CAR-NK, dual-target, bispecific, Mesothelin, MSLN, EGFR