Target-Selected CAR-NK Cells (CD30, CD5, or Mesothelin) for Relapsed/Refractory B2 Thymoma or Thymic Carcinoma

This is a first-in-indication, open-label, non-randomized, multi-center Phase 1/2 study with biomarker-driven cohort assignment. Phase 1 (dose escalation): Within each target cohort, a standard 3+3 dose-escalation design evaluates up to three dose levels of the assigned CAR-NK product to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D). Dose-limiting toxicities (DLTs) are assessed from Day 0 through Day 28 after the first CAR-NK infusion. Phase 2 (dose expansion): After an RP2D is identified in a cohort, an expansion stage enrolls additional participants in that cohort to further characterize safety and estimate preliminary antitumor activity. CAR-NK product: Off-the-shelf, allogeneic cord blood-derived NK cells are genetically modified to express a single-target CAR (anti-CD30, anti-CD5, or anti-mesothelin). The construct includes an IL-15 support element to enhance persistence and an inducible caspase-9 (iCasp9) safety switch for rapid elimination of CAR-NK cells if clinically indicated. Correlative studies: Serial blood and (when feasible) tumor sampling will evaluate CAR-NK persistence, immune activation markers, cytokines, tumor antigen modulation, and exploratory biomarkers of response and resistance. Long-term follow-up: Participants will be followed for delayed adverse events and survival; participants receiving gene-modified cells will also be invited to long-term follow-up consistent with applicable gene therapy guidance.

Inclusion criteria

• Age 18 to 75 years at the time of consent.
• Histologically confirmed B2 thymoma or thymic carcinoma that is unresectable, metastatic, or recurrent.
• Relapsed or refractory after at least 1 prior systemic therapy (including a platinum-based regimen for thymic carcinoma when appropriate) or no standard curative option available.
• Tumor antigen positivity for at least one of the following by central laboratory assessment: CD30, CD5, or mesothelin. Cohort assignment is based on the dominant target (pre-specified algorithm) and feasibility of manufacturing/availability.
• Measurable disease per RECIST v1.1 (or evaluable disease if measurable disease is not feasible; to be specified).
• ECOG performance status 0-1 (0-2 may be permitted in expansion at investigator discretion).
• Adequate organ function: ANC ≥ 1.0 x 10^9/L, platelets ≥ 75 x 10^9/L, hemoglobin ≥ 8 g/dL (transfusions allowed), AST/ALT ≤ 3 x ULN (≤ 5 x ULN with liver involvement), total bilirubin ≤ 1.5 x ULN (except Gilbert's), creatinine clearance ≥ 50 mL/min.
• Negative pregnancy test for participants of childbearing potential; agreement to use effective contraception.
• Ability to understand and sign informed consent.

Exclusion criteria

• Active central nervous system involvement by malignancy requiring immediate therapy.
• Prior gene-modified cellular therapy (e.g., CAR-T, CAR-NK) within 90 days or unresolved ≥Grade 2 toxicity from prior cellular therapy.
• Uncontrolled infection, including active tuberculosis, or uncontrolled hepatitis B or C infection; known uncontrolled HIV infection.
• Clinically significant autoimmune disease requiring systemic immunosuppression (e.g., >10 mg/day prednisone equivalent) within 14 days of conditioning, except for stable endocrine replacement.
• Prior allogeneic hematopoietic stem cell transplant with active graft-versus-host disease or ongoing immunosuppression.
• Significant cardiovascular disease (e.g., NYHA class III/IV heart failure, recent myocardial infarction), uncontrolled arrhythmia, or QTc prolongation felt to increase risk.
• Pregnancy or breastfeeding.
• Concurrent participation in another interventional trial with an investigational anticancer agent within 21 days (washout required).
• Any condition that, in the investigator's judgment, would interfere with safe participation or interpretation of results.