CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

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Participants must meet all of the following criteria to be eligible for enrollment:

1. Age ≥18 years, regardless of gender.
2. Histologically or cytologically confirmed advanced, metastatic, or recurrent lung cancer, including both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).
3. Disease progression or intolerance after receiving standard therapies (including but not limited to surgery, chemotherapy, radiotherapy, targeted therapy, immunotherapy):

   NSCLC: Disease progression or intolerance after at least second-line standard therapy.

   SCLC: Disease progression or intolerance after at least first-line standard therapy.
4. For patients with pleural effusion assigned to the intrapleural infusion group, the pleural effusion volume and characteristics must be accurately assessed by imaging (chest CT or X-ray) combined with cytology. Malignant pleural effusion must be confirmed by the presence of tumor cells in pleural fluid cytology.
5. Tumor CEA positivity confirmed by immunohistochemistry (IHC) within 3 months prior to screening, defined as distinct membranous staining with ≥10% positivity. If the tumor sample was assessed more than 3 months prior to screening, a serum CEA level \>10 µg/L is required.
6. At least one measurable lesion according to RECIST 1.1 criteria:

   Non-nodal lesions: longest diameter ≥10 mm. Lymph node lesions: short axis ≥15 mm.
7. ECOG performance status score of 0 to 2 .
8. Estimated life expectancy of more than 12 weeks.
9. No severe psychiatric disorders.
10. Adequate major organ function unless otherwise specified, defined as follows:

    Hematology: WBC \> 2.0 × 10⁹/L; Neutrophils \> 1.0 × 10⁹/L; Lymphocytes \> 0.5 × 10⁹/L; Platelets \> 50 × 10⁹/L; Hemoglobin \> 80 g/L.

    Cardiac function: LVEF ≥ 50% on echocardiogram; no significant abnormalities on ECG.

    Renal function: Serum creatinine ≤ 2.0 × ULN. Hepatic function: ALT and AST ≤ 3.0 × ULN (≤ 5.0 × ULN if there is hepatic tumor infiltration).

    Total bilirubin ≤ 2.0 × ULN. Peripheral oxygen saturation \>92% in room air.
11. Eligible for leukapheresis or venous blood collection, with no contraindications to cell collection.
12. Willing to use reliable and effective contraception methods (excluding rhythm method) from informed consent signing until one year after CAR-T cell infusion.
13. Participant or legally authorized representative has voluntarily signed the informed consent form (ICF), indicating understanding of the study objectives and procedures and willingness to participate in the clinical trial.

Exclusion Criteria:

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Participants who meet any of the following criteria will be excluded from the study:

1. Clinically symptomatic central nervous system (CNS) metastasis or meningeal metastasis at screening, or other evidence suggesting the presence of uncontrolled CNS or meningeal metastasis, as judged by the investigator.
2. Participation in any other clinical trial within 1 month prior to screening.
3. Vaccination with a live attenuated vaccine within 4 weeks prior to screening.
4. Receipt of the following anti-tumor treatments within 4 weeks prior to screening: chemotherapy, targeted therapy, or any experimental drug treatment within 14 days or at least 5 half-lives (whichever is shorter).
5. Active infection requiring systemic treatment or any uncontrolled infection.
6. Tumor compression of the trachea or major blood vessels, as determined by the investigator to carry a high risk.
7. History of the following cardiac conditions:

   NYHA Class III or IV congestive heart failure. Myocardial infarction or coronary artery bypass graft (CABG) surgery within 6 months prior to enrollment.

   Clinically significant ventricular arrhythmias or a history of unexplained syncope (except due to vasovagal or dehydration-related causes).

   History of severe non-ischemic cardiomyopathy.
8. Active autoimmune disease or any condition requiring long-term immunosuppressive therapy.
9. History of any other untreated malignancy within the past 3 years, except for carcinoma in situ of the cervix or basal cell carcinoma of the skin.
10. Positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) with peripheral blood HBV DNA levels above normal range; positive for hepatitis C antibody with peripheral blood HCV RNA levels above normal range; positive for human immunodeficiency virus (HIV) antibody; positive for syphilis test.
11. Pregnancy or breastfeeding women.
12. Any other condition that the investigator deems unsuitable for participation in the study.

主要终点：To evaluate the safety and tolerability of CAR T cell preparations in the treatment of CEA positive advanced lung cancer【safety】 · Adverse events and their proportion during the trial (assessed against the Common Terminology Standard for Adverse Events Version 5.0 (CTCAE 5.0) and ASTCT standards) · 28days
次要终点：To evaluate the disease control rate of CAR-T cell preparations in CEA positive advanced lung cancer【efficacy】；To evaluate the remission rate of CAR-T cell preparations in CEA positive advanced lung cancer【efficacy】；To evaluate the overall survival of CAR-T cell preparations in CEA-positive advanced lung cancer【efficacy】；To evaluate the duration of response of CAR-T cell preparations in CEA-positive advanced lung cancer【efficacy】；To evaluate the disease progression-free survival of CAR-T cell preparations in CEA-positive advanced lung cancer【efficacy】；To obtain the cytodynamics data of CAR-T cells in vivo【pharmacokinetics】；To obtain the cytodynamics data of CAR-T cells in vivo【pharmacokinetics】；To obtain the cytodynamics data of CAR-T cells in vivo【pharmacodynamics】

• Targeted CEA CAR-T intravenous infusion group · EXPERIMENTAL
• Targeting CEA CAR-T pleural infusion group · EXPERIMENTAL

Lung cancer is the leading cause of morbidity and mortality in the world, of which 80%-85% are non-small cell lung cancer (NSCLC). Most patients with NSCLC are at the advanced stage of diagnosis and have a poor prognosis. The 5-year survival rate of stage III patients is about 15%, the 5-year survival rate of stage IV patients is less than 5%, and the median survival time is only 7 months. CEACAM5 (CEA), also known as CD66e, is a classic tumor marker that has been used as a marker for many types of tumors for 50 years. It is mainly expressed in lung cancer, esophageal cancer, bile duct cancer, colorectal cancer, gastric cancer and other tumor types. In previous CAR-T-related clinical trials targeting CEA, the research team found that CAR-T cell preparations had a certain killing effect on CEA positive tumor cells. At the same time, CAR-T cell preparations cannot be sustained for a long time in the body, which is also a key factor restricting the anti-tumor effect of CAR-T cells in the body. To solve this problem, the killing ability and survival ability of CAR-T cell preparations on tumor cells in vitro and in vivo were improved by optimizing CAR structure and improving culture mode.