PD-1 Knockout Anti-MUC1 CAR-T Cells in the Treatment of Advanced Breast Cancer

This is a single-center, open-label, dose-escalation exploratory study investigating the safety,tolerability and preliminary efficacy of AJMUC1, PD-1 knockout CAR-T cells targeting aberrantly glycosylated MUC1, in the treatment of patients with advanced MUC1 positive breast cancer. The primary objective of this study is to evaluate the safety, tolerability, biological activity, and preliminary antitumor efficacy of AJMUC1. The study adopts a "3+3" dose escalation design to identify the maximum tolerated dose (MTD)/ maximum administered dose (MAD). Three doses are set: 3×105 CAR T cells/kg, 1×106 CAR T cells/kg and 3×106 CAR T cells/kg, with a total of 15 patients planned by the data cutoff date. Participants may receive one, two, three or more cycles of AJMUC1 infusion dependent on the adverse effects and potential clinical benefits.. This study is initiated by the investigators and approved by the Human Ethics Committee of Sun Yat-sen Memorial Hospital affiliated with Sun Yat-sen University. All patients have signed informed consent.

Inclusion criteria

• Patient age: 18-70 years (including the boundary value);
• Pathologically diagnosed with recurrent/metastatic breast cancer (except for intracranial metastasis), who have received at least one standard treatment regimen in the past, the disease is in a stable or progressive state, and refuses to undergo subsequent chemotherapy;
• Abnormal glycosylated MUC1 expression confirmed by immunohistochemistry in tumor tissue or puncture tissue within 12 months;
• Expected survival period ≥ 4 months;
• ECOG score≤2 points;
• The subjects voluntarily joined the study, signed the informed consent form, had good compliance, and cooperated with the follow-up;
• Able to cooperate with tumor puncture;
• At least one measurable lesion that meets the RECIST v1.1 criteria;
• Female patients of childbearing age must not be breastfeeding, and serum or urine HCG test is negative within 72 hours before study enrollment. All subjects must use medically approved contraception during the study period and within 3 months after the end of the study. measures (eg, IUDs, birth control pills) for contraception;
• Organ function and bone marrow reserve are in good condition and the following requirements must be met: (1) The absolute value of neutrophils is ≥1.5×109/L; (2) Platelet count ≥75×109/L; (3) Hemoglobin ≥9g/dl; (4) Bilirubin value < 1.5 times the upper limit of normal (except for obstruction of the bile duct caused by tumor compression); (5) Creatinine value < 1.5 times the upper limit of normal or creatinine clearance rate ≥ 60ml/min; (6) ALT or AST < 2.5 times the upper limit of normal (with liver involvement < 5 times the upper limit of normal); (7) Stable coagulation function: INR≤1.5, PTT<1.2 times the upper limit of normal (except for tumor-related anticoagulation therapy).

Exclusion criteria

• Have used immunosuppressive drugs or hormones within 1 week prior to enrollment;
• Patients with moderate or more moderate pleural and ascites who need catheter drainage to relieve symptoms;
• Human immunodeficiency virus (HIV) positive;
• Active hepatitis B or C infection;
• Pregnant or lactating women;
• Past or concurrent history of other malignant tumors. Excluded: Patients with basal or squamous cell carcinoma of the skin and carcinoma in situ of the cervix who have been cured at any time prior to the study;
• Those with central transfer;
• Serious, uncontrollable concomitant diseases that may affect protocol compliance or interfere with the interpretation of results, or have any serious medical conditions that may affect the subject's safety (such as uncontrollable heart disease, high blood pressure, active or uncontrollable disease) infection, etc.);
• Active autoimmune diseases (including but not limited to, systemic lupus erythematosus, Sjögren syndrome, rheumatoid arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease, etc.);
• Those with a history of organ transplantation;
• Subjects whose last medication was less than 2 weeks before enrollment, or subjects who participated in other relevant clinical studies at the same time;
• Those who have received gene therapy in the past;
• Vaccination with live vaccine within 4 weeks prior to study;
• History of myocardial infarction and severe arrhythmia within half a year; uncontrolled hypertension, coronary heart disease, stroke, liver cirrhosis, nephritis and other serious complications;
• Those who have a history of psychotropic substance abuse and cannot quit or who have a history of mental disorders;
• Hypersensitivity constitution, allergic to human serum albumin;
• Hemorrhagic and thrombotic tendency: patients with clinically significant bleeding symptoms or clear bleeding tendency within 3 months before the study, such as gastrointestinal bleeding, hemorrhagic gastric ulcer, abnormal coagulation function (PT>16s, APTT>43s) , TT>21s, FIB<2g/L), hereditary or acquired bleeding and thrombosis tendency to (such as hemophilia, coagulation disorder, thrombocytopenia, hypersplenism, etc.), are receiving thrombolytic or anticoagulation therapy, arterial/venous thrombotic events occurred within the previous 6 months, such as cerebrovascular disease (including cerebral hemorrhage, cerebral infarction), deep vein thrombosis and pulmonary embolism;
• Other severe, acute, or chronic medical or psychiatric conditions that may increase the risks associated with participation in the study or may interfere with the interpretation of the study results, in the opinion of the investigator.