Dual-Target CAR-NK Cells Directed Against MSLN, EGFR, or HER2 in Advanced NSCLC

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 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.

Conditions4

Interventions2

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