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

Official title

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)

Overview

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.

Detailed description

The study includes Part A (dose escalation) and Part B (dose expansion). In Part A, participants are assigned to one of three dual-target CAR-NK constructs based on tumor antigen co-expression (IHC and/or RNA profiling): MSLN/EGFR, MSLN/HER2, or EGFR/HER2. Dose escalation within each construct follows a standard 3+3 design to identify a recommended Phase 2 dose (RP2D).

In Part B, the study expands at the RP2D and may adaptively prioritize the construct demonstrating the most favorable benefit-risk profile .

Key exploratory objectives include CAR-NK persistence, immune pharmacodynamics, cytokine profiling, and correlations between antigen density and clinical outcomes.

Interventions

• Biological Dual-target CAR-NK cells
  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
• Drug Lymphodepleting chemotherapy
  Fludarabine + Cyclophosphamide administered on Days -5, -4, and -3 prior to CAR-NK infusion
• Other Supportive care
  Premedication and management per institutional guidelines (e.g., acetaminophen/antihistamine pre-infusion; tocilizumab and corticosteroids per CRS/ICANS management algorithm).

Primary outcome measures

• Incidence of dose-limiting toxicities (DLTs) [Time frame: 28 days]
• Recommended Phase 2 dose (RP2D) [Time frame: 28 days]
• Objective response rate (ORR) per RECIST v1.1 [Time frame: 6 months]

Secondary outcome measures (3)

• Duration of response [Time frame: 12 months]
• Disease control rate [Time frame: 6 months]
• Progression-free survival [Time frame: 12 months]

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.
• 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Peking University Shenzhen Hospital — Shenzhen

Identifiers

NCT: NCT07641023 · EB-CARNK-NSCLC-013

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗