A Clinical Study of CEA-targeted CAR-T in the Treatment of CEA-positive Advanced Malignant Solid Tumors

A Phase I Clinical Study of Anti-CEA CAR-T Therapy in the Treatment of CEA-positive Advanced Malignant Solid Tumors

This is a phase I clinical study to evaluate the safety and tolerability of CAR-T in patients with CEA-positive advanced malignant solid tumors, and to obtain the maximum tolerated dose of CAR-T and phase II Recommended dose.

This is a single-center, open-label, dose-escalation study consisting of three distinct treatment cohorts for patients with CEA-positive advanced malignant solid tumors:

Cohort 1 (Intravenous infusion): A dose-escalating (3+3 design) study with 4 dose levels,: 1.0×106, 3.0×106, 5.0×106 CAR+ cells/kg and 7.0×106 CAR+ cells/kg.

Cohort 2 (Intraperitoneal injection): A dose-escalating (3+3 design) study with 3 dose levels：1.0×106, 3.0×106,and 5.0×106 CAR+ cells/kg.

Cohort 3 (FAST CAR-T Intraperitoneal infusion): A dose-escalating study (3+3 design) with 4 dose levels: 2.0×10⁵, 3.0×10⁵, 4.0×10⁵, and 5.0×10⁵ CAR+ cells/kg.

Inclusion Criteria:

1. Age ≥18 years old, male or female;

2. Advanced, metastatic or recurrent malignant tumors diagnosed by histology or pathology, mainly colorectal cancer;

3. After receiving at least second-line standard treatment and failing (disease progression or intolerance, such as surgery, chemotherapy, radiotherapy, etc.) or lack of effective treatment methods;

4. Immunohistochemical staining of tumor samples within 3 months confirmed that the tumor was CEA positive (clear membrane staining, positive rate ≥ 10%); If over 3 months, the patient's serum CEA should exceed 10ug/L.

5. At least one assessable lesion according to RECIST 1.1 criteria;

6. ECOG score 0-2 points;

7. No serious mental disorder;

8. Unless otherwise specified, the function of the vital organs of the subject shall meet the following conditions:

   1. Blood routine: white blood cells>2.0×109/L, neutrophils>0.8×109/L, lymphocytes cells>0.5×109/L, platelets>50×109/L, hemoglobin>90g/L;
   2. Cardiac function: echocardiography showed cardiac ejection fraction ≥50%, and no obvious abnormality was found on electrocardiogram;
   3. Renal function: serum creatinine≤2.0×ULN;
   4. Liver function: ALT and AST ≤3.0×ULN (for those with liver tumor infiltration, it can be relaxed to≤5.0×ULN);
   5. Total bilirubin≤2.0×ULN;
   6. Oxygen saturation > 92% in non-oxygen state.

9. Have apheresis or venous blood collection standards, and have no other contraindications for cell collection;

10. Subjects agree to use reliable and effective contraceptive methods for contraception within 1 year after signing the informed consent form to receiving CAR-T cell infusion (excluding rhythm contraception);

11. The patients themselves or their guardians agree to participate in this clinical trial and sign the ICF, indicating that they understand the purpose and procedures of this clinical trial and are willing to participate in the research.

Exclusion Criteria:

1. CNS metastases or meningeal metastases with clinical symptoms at the time of screening, or there is other evidence that the patient's central nervous system metastases or meningeal metastases have not been controlled, and are judged by the investigator to be unsuitable for inclusion;

2. Participated in other clinical studies within 1 month before screening;

3. vaccinated with live attenuated vaccine within 4 weeks before screening;

4. Received the following anti-tumor treatments before screening: Received chemotherapy, targeted therapy or other experimental drug treatments within 14 days or at least 5 half-lives (whichever is shorter);

5. Active infection or uncontrollable infection requiring systemic treatment;

6. Patients with intestinal obstruction, active gastrointestinal bleeding, or a history of gastrointestinal bleeding within 3 months;

7. Except for alopecia or peripheral neuropathy, the toxicity of previous anti-tumor therapy has not improved to the baseline level or ≤ grade 1;

8. Suffering from any of the following heart diseases:

   1. New York Heart Association (NYHA) stage III or IV congestive heart failure;
   2. Myocardial infarction or coronary artery bypass grafting (CABG) within 6 months before enrollment;
   3. Clinically significant ventricular arrhythmia, or history of syncope of unknown origin (caused by vasovagal except those caused by neurosis or dehydration);
   4. History of severe non-ischemic cardiomyopathy;

9. Patients with active autoimmune disease, or other patients requiring long-term immunosuppressive therapy;

10. Suffering from other uncured malignant tumors in the past 3 years or at the same time, except cervical carcinoma in situ and basal cell carcinoma of the skin;

11. Hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) positive and peripheral blood hepatitis B virus (HBV) DNA titer is greater than the normal range; hepatitis C virus (HCV) antibody positive and peripheral blood hepatitis C Virus (HCV) RNA test is greater than the normal range; human immunodeficiency virus (HIV) antibody positive; syphilis test positive;

12. Women who are pregnant or breastfeeding;

13. Other investigators deem it unsuitable to participate in the study.