CELL INTELLIGENCE · 肿瘤细胞治疗研究

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.
* 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

主要终点：Incidence of dose-limiting toxicities (DLTs) · 28 days；Recommended Phase 2 dose (RP2D) · 28 days；Objective response rate (ORR) per RECIST v1.1 · 6 months
次要终点：Duration of response；Disease control rate；Progression-free survival

• EB-DuoNK-MSLN/EGFR · EXPERIMENTAL · Participants with tumors co-expressing MSLN and EGFR (meeting screening thresholds) receive lymphodepletion followed by EB-DuoNK-MSLN/EGFR infusion at the assigned dose leve
• EB-DuoNK-MSLN/HER2 · EXPERIMENTAL · Participants with tumors co-expressing MSLN and HER2/ERBB2 receive lymphodepletion followed by EB-DuoNK-MSLN/HER2 infusion at the assigned dose level.
• EB-DuoNK-EGFR/HER2 · EXPERIMENTAL · Participants with tumors co-expressing EGFR and HER2/ERBB2 receive lymphodepletion followed by EB-DuoNK-EGFR/HER2 infusion at the assigned dose level.

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.