Exploratory Clinical Study of Claudin18.2-Targeted CAR-DC and CAR-T Therapy in Advanced Colorectal Cancer

Exploratory Clinical Study of Combined Claudin18.2-Targeted CAR-DC and CAR-T Therapy in Patients With Advanced Colorectal Cancer

This is an open-label, single-arm clinical study designed to evaluate the safety and preliminary efficacy of Claudin18.2-targeted CAR-DC combined with CAR-T cell therapy in patients with advanced colorectal cancer.

Main purpose:

To evaluate the safety of Claudin18.2-targeted CAR-T cells in combination with CAR-DCs in patients with advanced colorectal cancer during the dose-escalation phase.

To determine the maximum tolerated dose of Claudin18.2-targeted CAR-DCs when administered in combination with CAR-T cells.

Secondary purpose:

To assess the overall response rate (ORR), including complete response (CR) and partial response (PR), as well as overall survival (OS) and disease-free survival (DFS) in patients receiving the combination therapy.

To evaluate the in vivo persistence, immunophenotype, and functional activity of CAR-T cells and CAR-DCs following infusion.

Inclusion Criteria:

1. Participants must have a histologically or cytologically confirmed diagnosis of colonic or rectal adenocarcinoma, with at least one measurable lesion meeting RECIST v1.1 criteria (i.e., a target lesion with a longest diameter ≥10 mm on spiral CT scan, or a lymph node with a short axis ≥15 mm).

2. Claudin18.2 expression must be confirmed as positive in tumor tissue by immunohistochemistry (IHC).

3. Disease progression following standard treatments, including prior administration of fluoropyrimidines, irinotecan, and oxaliplatin. Disease progression may occur during or after treatment. Prior molecular targeted therapies are allowed.

4. ECOG performance status of 0 to 1.

5. Expected survival of at least 6 months.

6. Toxicities related to prior antitumor treatments must have resolved to baseline or ≤ Grade 1 (except for residual alopecia); peripheral neurotoxicity ≤ Grade 2 is acceptable. The minimum washout period is 4 weeks for chemotherapy and immunotherapy, and 2 weeks for targeted therapy.

7. Adequate organ function, defined as follows:

   • Hematologic function: Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L, platelet count ≥ 75 × 10^9/L, and hemoglobin ≥ 9 g/dL. No blood transfusions, granulocyte colony-stimulating factor (G-CSF), thrombopoietin (TPO), or erythropoietin (EPO) allowed within 14 days prior to hematology testing.
   • Hepatic function: Total bilirubin (TBIL) < 1.5 × upper limit of normal (ULN); AST and ALT < 2.5 × ULN. For patients with Gilbert's syndrome, TBIL < 2 × ULN. For patients with liver metastases, AST and ALT must be < 5 × ULN.
   • Renal function: Serum creatinine ≤ 1.5 × ULN; or if > 1.5 × ULN, creatinine clearance (CrCl) ≥ 60 mL/min as calculated by the Cockcroft-Gault formula.
   • Coagulation function: Prothrombin time (PT) and activated partial thromboplastin time (APTT) < 1.5 × ULN; international normalized ratio (INR) < 1.5 or within the therapeutic range if on anticoagulation therapy.

8. Participants of childbearing potential must agree to use effective contraception during the study period.

9. Participants must have adequate comprehension and voluntarily sign the informed consent form.

10. Willingness to comply with all study-related procedures, including scheduled visits, drug administration, laboratory assessments, and other protocol requirements.

Exclusion Criteria:

1. Tumor-related emergencies requiring immediate intervention, such as malignant pericardial effusion or cardiac tamponade, superior vena cava syndrome, or spinal cord compression.

2. Clinically significant cardiovascular disease, including:

   • Documented cardiovascular events within the past 6 months, such as myocardial infarction, angina, heart failure, severe arrhythmias, or history of angioplasty, stent implantation, or coronary artery bypass grafting (CABG);
   • Prolonged QT/QTcF interval with clinical significance (QT/QTcF > 470 ms in females or > 450 ms in males).

3. Clinically significant bleeding disorders or coagulopathies, such as hemophilia.

4. Active infections including HIV, syphilis, or active hepatitis B or C:

   • Hepatitis B: HBV-DNA ≥ 1000 IU/mL;
   • Hepatitis C: Positive HCV RNA with abnormal liver function.

5. History of involuntary psychiatric hospitalization due to mental illness or other psychiatric disorders deemed unsuitable for treatment by the investigator.

6. Presence of autoimmune diseases or chronic use of immunosuppressive agents or corticosteroids.

7. Poor medication compliance or inability to adhere to the treatment protocol.

8. Any other condition that, in the opinion of the investigator, warrants exclusion from the study.