Overview
This Phase 1/2, open-label, biomarker-guided platform study evaluates the safety, tolerability, and preliminary anti-tumor activity of banked allogeneic donor-derived chimeric antigen receptor natural killer (CAR-NK) cells in adults with advanced solid tumors. During screening, tumor antigen profiling is performed using tissue biopsy and/or liquid biopsy (circulating tumor DNA and/or circulating tumor cells).
Participants are assigned to receive either a single-target CAR-NK product (matched to the dominant tumor antigen) or a dual-target CAR-NK product (matched to two co-expressed antigens) to reduce the risk of antigen escape.
Description
This example trial is designed to reflect common elements of early-phase CAR-NK studies in solid tumors, including dose escalation followed by expansion cohorts, open-label safety monitoring, and response assessment using standard radiologic criteria. Similar solid-tumor CAR-NK studies on ClinicalTrials.gov include trials targeting TROP2 (NCT06066424), NKG2D ligands (NCT03415100), and multi-target CAR-NK platforms that evaluate different antigens such as CLDN6, GPC3, mesothelin, or AXL (NCT05410717).
Antigen selection workflow (precision matching):
- Obtain tumor tissue biopsy (preferred) and/or blood for liquid biopsy at screening.
- Assess antigen expression using a prespecified panel (example panel: mesothelin, TROP2, HER2, MUC1, CLDN18.2, B7-H3/CD276, AXL, GPC3, CLDN6, EGFR).
- Assign participant to: (a) single-target cohort if one antigen meets the threshold; or (b) dual-target cohort if two antigens meet thresholds or if the investigator judges high risk of antigen heterogeneity.
- Select the matched cryopreserved allogeneic donor-derived CAR-NK product from a manufacturing bank and schedule treatment. Treatment overview: Participants receive lymphodepleting chemotherapy (e.g., fludarabine/cyclophosphamide) followed by one or more infusions of CAR-NK cells. Cytokine support (e.g., low-dose IL-2 or IL-15 agonist per institutional practice) may be given to promote CAR-NK persistence. Participants are monitored closely for cytokine release syndrome (CRS), neurotoxicity, infusion reactions, and other adverse events. Tumor imaging is performed at prespecified intervals during the first 6 months and then less frequently during follow-up.
Eligibility
Inclusion Criteria:
- Age 18 to 75 years at the time of consent.
- Histologically or cytologically confirmed advanced or metastatic solid tumor that is refractory to, relapsed after, or intolerant of standard therapy, or for which no standard therapy exists.
- At least 1 measurable lesion per RECIST v1.1.
- Tumor antigen positivity documented by tissue biopsy and/or liquid biopsy using a protocol-specified assay; for dual-target cohort: co-expression of both antigens above threshold.
- ECOG performance status 0-1.
- Adequate organ function (hematologic, renal, hepatic) as defined by protocol labs.
- Ability to undergo lymphodepleting chemotherapy (if required) and receive IV cell infusion.
- Negative pregnancy test for individuals of childbearing potential; agreement to use effective contraception during study participation and for a protocol-defined period after infusion.
- Willingness to provide baseline blood samples and, when feasible, tumor biopsy for biomarker analyses.
Exclusion Criteria:
- Active, uncontrolled infection, including uncontrolled bacterial, fungal, or viral infection.
- Known uncontrolled HIV infection; active hepatitis B or hepatitis C with evidence of active replication (per local testing).
- Clinically significant cardiovascular disease (e.g., recent myocardial infarction, uncontrolled arrhythmia) that would increase risk from lymphodepletion or infusion.
- Active central nervous system (CNS) metastases that are symptomatic or require escalating steroids.
(Stable treated CNS disease may be allowed per protocol.)
- Current systemic immunosuppressive therapy (e.g., \>10 mg/day prednisone equivalent) within a protocol-defined window prior to lymphodepletion.
- Prior gene-modified cellular therapy within 3 months or any prior therapy that, in the investigator's judgment, would confound safety evaluation.
- Prior allogeneic hematopoietic stem cell transplant within 6 months, or active graft-versus-host disease.
- Pregnant or breastfeeding.
- Any condition that, in the investigator's opinion, would interfere with study participation, compliance, or interpretation of results.
