This Phase 1/2 study evaluates the safety, tolerability, and preliminary efficacy of target-selected CAR-natural killer (CAR-NK) cells in adults with relapsed or refractory B2 thymoma or thymic carcinoma. Participants undergo centralized tumor antigen assessment (CD30, CD5, and mesothelin). Based on the dominant and clinically actionable antigen expression profile, each participant is assigned to one of three parallel cohorts (CD30-CAR-NK, CD5-CAR-NK, or mesothelin-CAR-NK). All cohorts use the same lymphodepleting conditioning regimen followed by CAR-NK infusion(s).
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
36
lymphodepletion
lymphodepletion
CD30-targeted allogeneic CAR-NK cells
CD5-targeted allogeneic CAR-NK cells
Mesothelin-targeted allogeneic CAR-NK cells
ctivate the iCasp9 safety switch if clinically indicated
Peking University Shenzhen Hospital
Shenzhen, Guangdong, China
RECRUITINGIncidence of Dose-Limiting Toxicities (DLTs)
DLTs as defined in protocol, assessed during the DLT window after the first CAR-NK infusion. Includes severe infusion-related toxicity, Grade \>=3 organ toxicity attributable to CAR-NK cells, severe CRS or neurotoxicity, and treatment-related death.
Time frame: 28 Days
Recommended Phase 2 Dose
Determined separately for each cohort based on DLTs, overall safety, and pharmacodynamic data
Time frame: 28 Days
Objective Response Rate
Proportion of participants with complete response (CR) or partial response (PR) per RECIST v1.1 (or modified criteria appropriate for thymic tumors) in each cohort.
Time frame: 12 months
Disease Control Rate
Proportion of participants with CR, PR, or stable disease
Time frame: 12 months
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