Advanced/Metastatic, Non-Small Cell Lung Cancer
Conditions
Keywords
CAR-NK, Dual-target, Bispecific, Adoptive cell therapy, Solid tumor, Immunotherapy, Biomarker-guided, Mesothelin, EGFR, HER2, Dose escalation
Brief 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.
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
BIOLOGICALDual-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
Fludarabine + Cyclophosphamide administered on Days -5, -4, and -3 prior to CAR-NK infusion
OTHERSupportive care
Premedication and management per institutional guidelines (e.g., acetaminophen/antihistamine pre-infusion; tocilizumab and corticosteroids per CRS/ICANS management algorithm).
Sponsors
Beijing Biotech
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Open-label due to early-phase safety monitoring and individualized product assignment
Intervention model description
Participants are assigned to a construct based on tumor antigen co-expression. Each construct undergoes dose escalation (3+3) to determine RP2D, followed by expansion; an interim assessment may select one construct for larger expansion.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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 |
Secondary
| Measure | Time frame |
|---|---|
| Duration of response | 12 months |
| Disease control rate | 6 months |
| Progression-free survival | 12 months |
Countries
China
Contacts
CONTACTshan S Lu, Phd
Outcome results
None listed