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

• 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).
• Claudin18.2 expression must be confirmed as positive in tumor tissue by immunohistochemistry (IHC).
• 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.
• ECOG performance status of 0 to 1.
• Expected survival of at least 6 months.
• 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.
• 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.
• Participants of childbearing potential must agree to use effective contraception during the study period.
• Participants must have adequate comprehension and voluntarily sign the informed consent form.
• Willingness to comply with all study-related procedures, including scheduled visits, drug administration, laboratory assessments, and other protocol requirements.

Exclusion criteria

• Tumor-related emergencies requiring immediate intervention, such as malignant pericardial effusion or cardiac tamponade, superior vena cava syndrome, or spinal cord compression.
• 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).
• Clinically significant bleeding disorders or coagulopathies, such as hemophilia.
• 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.
• History of involuntary psychiatric hospitalization due to mental illness or other psychiatric disorders deemed unsuitable for treatment by the investigator.
• Presence of autoimmune diseases or chronic use of immunosuppressive agents or corticosteroids.
• Poor medication compliance or inability to adhere to the treatment protocol.
• Any other condition that, in the opinion of the investigator, warrants exclusion from the study.