Study of CEA Targeting CAR-T in the Treatment of CEA-Positive Advanced Malignant Solid Tumors

This is a phase I clinical study to evaluate the safety and tolerability of FAST targeted chimeric antigen receptor (CAR)-T cells in patients with carcinoembryonic antigen (CEA)-positive advanced malignant solid tumors, and to obtain the maximum tolerated dose of FAST CAR-T and phase II Recommended dose.

This is a single-center, double-arm, open-label study. The study plans to set up 2 groups,Intravenous infusion group have 4 dose groups, adopting a dose-escalating 3+3 design, and plan to recruit about 12-24 subjects with CEA-positive advanced malignant solid tumors.Intraperitoneal injection group have 4 dose groups, adopting a dose-escalating 3+3 design, and plan to recruit about 12-24 subjects with CEA-positive advanced malignant solid tumors.

Eligibility Criteria:
Inclusion Criteria:

Subjects must meet all the following criteria to be eligible for the study:

1. Age≥18 years, regardless of gender.
2. Diagnosed with advanced, metastatic, or recurrent malignant tumors confirmed by histology or pathology, primarily including colorectal cancer, esophageal cancer, gastric cancer, pancreatic cancer, lung cancer, or cholangiocarcinoma.
3. Failure of at least second-line standard therapy (due to disease progression or intolerance, such as surgery, chemotherapy, radiotherapy, etc.) or a lack of effective treatment options.
4. Immunohistochemical staining of tumor samples within 3 months confirming CEA positivity (distinct membrane staining with a positivity rate of≥10%); if the immunohistochemical result of the tumor sample is more than 3 months old at the time of screening (distinct membrane staining with a positivity rate of≥10%), the patient's serum CEA must exceed 10µg/L.
5. At least one evaluable lesion according to RECIST 1.1 criteria.
6. ECOG score of 0-2 (Appendix 2).
7. No severe psychiatric disorders.
8. Unless specifically stated otherwise, subjects' major organ functions must meet the following conditions:

   1. Blood routine: WBC\>2.0×109/L, neutrophils\>0.8×109/L, lymphocytes\>0.5×109/L, platelets\>50×109/L, hemoglobin\>90g/L;
   2. Cardiac function: Echocardiography indicating a left ventricular ejection fraction≥50%, and no significant abnormalities on electrocardiogram;
   3. Renal function: Serum creatinine≤2.0×ULN;
   4. Liver function: ALT and AST ≤3.0×ULN (may be relaxed to≤5.0×ULN if liver tumor infiltration is present);
   5. Total bilirubin≤2.0×ULN;
   6. Oxygen saturation\>92% without supplemental oxygen. 9. Eligible for apheresis or venous blood collection, with no contraindications for cell collection.

      10. Subjects agree to use reliable and effective contraceptive methods from signing the informed consent form until 1 year after receiving CAR-T cell infusion (excluding natural family planning methods).

      11. The patient or their guardian agree to participate in this clinical trial and signs the ICF, indicating an understanding of the trial's purpose and procedures and willingness to participate.

Exclusion Criteria:

Subjects meeting any of the following criteria will be excluded from the study:

1. Clinically symptomatic central nervous system or leptomeningeal metastasis at the time of screening, or other evidence suggesting that central nervous system or leptomeningeal metastases are not controlled, as judged unsuitable for inclusion by the investigator.
2. Participation in another clinical study within 1 month prior to screening.
3. Receipt of live attenuated vaccines within 4 weeks prior to screening.
4. Receipt of the following anti-tumor treatments before screening: Chemotherapy, targeted therapy, or other experimental drug treatments within 14 days or at least 5 half-lives (whichever is shorter).
5. Presence of active or uncontrolled infections requiring systemic treatment.
6. Patients with intestinal obstruction, active gastrointestinal bleeding, a history of major gastrointestinal bleeding within 3 months, severe gastroduodenal ulcers, or severe gastrointestinal inflammation such as ulcerative colitis.
7. Toxicity from previous anti-tumor therapy that has not improved to baseline levels or≤Grade 1, except for alopecia or peripheral neuropathy.
8. Presence of any of the following cardiac conditions:

   1. New York Heart Association (NYHA) Stage III or IV congestive heart failure;
   2. Myocardial infarction or coronary artery bypass graft (CABG) within 6 months prior to enrollment;
   3. Clinically significant ventricular arrhythmia or history of unexplained syncope (excluding vasovagal or dehydration-related causes);
   4. History of severe non-ischemic cardiomyopathy.
9. Presence of active autoimmune diseases or other conditions requiring long-term immunosuppressive therapy.
10. Diagnosis of another untreated malignancy within the past 3 years, except for in situ cervical cancer or basal cell carcinoma of the skin.
11. Positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) with peripheral blood hepatitis B virus (HBV) DNA levels exceeding the normal range; positive for hepatitis C virus (HCV) antibodies with peripheral blood HCV RNA levels exceeding the normal range; positive for human immunodeficiency virus (HIV) antibodies; or positive syphilis test.
12. Pregnant or breastfeeding women.
13. Any other conditions deemed unsuitable for participation in the study by the investigator.