Study on the Safety and Tolerability of PD-1 Knockout Tumor-infiltrating T Cells (TILs) in the Treatment of Advanced Colorectal Cancer

Inclusion criteria

• Patients with advanced colorectal cancer confirmed by histology or cytology, who were not eligible to standard treatment at this stage.
• Patients volunteered to receive surgery or biopsy to obtain tumor tissue for TILs preparation.
• Aged ≥18 and ≤70 years old.
• At least one tumor lesion that could be evaluated according to RECIST, version 1.1.
• ECOG score was 0 or 1.
• Adequate bone marrow and organ function.
• The expected survival time of the enrolled patients was no less than 6 months.

Exclusion criteria

• Received chemotherapy, radiotherapy, biological therapy, endocrine therapy, immunotherapy, traditional Chinese medicine with anti-tumor indications and other anti-tumor treatments within 2 weeks before sampling, except the following:
• Nitrosourea or mitomycin C within 6 weeks before surgery;
• Oral fluorouracils and small molecule targeted drugs for 1 week before surgery.
• Received other unmarketed investigational drug or treatment within 4 weeks before sampling;
• Had undergone major organ surgery (excluding needle biopsy) within 4 weeks before sampling or had significant lesions Trauma, or the need for elective surgery during the trial;
• Received systemic glucocorticoid (prednisone \>10mg/ day or equivalent dose) or other immunosuppressive therapy within 14 days before sampling; Treatment with topical, ocular, intra-articular, nasal, and inhaled glucocorticoids was excluded. Short-term prophylaxis with glucocorticoids (e.g., to prevent contrast allergy)
• Use of immunomodulatory drugs, including but not limited to thymosin, interleukin-2, interferin, etc., within 14 days before sampling;
• Administration of live attenuated vaccine within 4 weeks before sampling;
• The toxicity of previous antineoplastic therapy has not recovered to CTCAE 5.0 grade ≤1 (except for alopecia and other researchers who judged that there was no safety risk);
• Patients with symptomatic central nervous system or leptomeningeal metastases or other evidence of uncontrolled central nervous system or leptomeningeal metastases as judged by the investigator to be ineligible for enrollment;
• Patients with active infection within 1 week before sampling and currently requiring systemic anti-infective treatment;
• A history of immunodeficiency, including positive HIV antibody test;
• Hepatitis B (HBsAg positive and/or hepatitis C (anti-HCV positive) and/or treponema pallidum antibody positive;
• Patients with current interstitial lung disease;
• Has a history of severe cardiovascular and cerebrovascular diseases, including but not limited to:
• severe cardiac rhythm or conduction abnormalities, such as ventricular arrhythmia requiring clinical intervention, degree II-III atrioventricular block, etc.
• Acute coronary syndrome, congestive heart failure, aortic dissection, stroke, or other grade 3 or higher cardiovascular and cerebrovascular events occurred within 6 months before the first dose of dose.
• New York Heart Association (NYHA) functional class ≥II or left ventricular ejection fraction (LVEF) \<50%, or structural heart disease at high risk as judged by other investigators;
• clinically uncontrolled hypertension.
• Patients with active or previous autoimmune diseases (such as systemic lupus erythematosus, rheumatoid arthritis, vasculitis, etc.), excluding patients with clinically stable autoimmune thyroid diseases and well-controlled type I diabetes;
• Received immunotherapy with grade ≥ 3 irAE;
• Clinically uncontrollable serous cavity effusion, which was judged by the investigator as not suitable for enrollment;
• Known alcohol or drug dependence;
• Persons with mental disorders or poor compliance;
• Pregnant or lactating women;