CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

1. Age ≥18 years old;
2. Advanced/metastatic gynecological tumor confirmed by histopathology or cytology (paraffin sections or fresh biopsy tumor tissue specimens) (CD70 positive tumor expression (CD70 positive tumor confirmed by histology or pathology (IHC 3+));
3. Failure or intolerance after standard treatment (disease progression or intolerance such as surgery, chemotherapy, radiotherapy, targeted therapy, etc.), and currently no effective treatment;
4. According to the RECIST version 1.1 standard, there is at least one measurable diameter and evaluable target lesion. Measurable lesions are defined as: extranodal lesions with CT scan diameter ≥10mm, lymph node lesions with CT scan diameter ≥15mm, scan layer thickness ≤ 5mm, and have not received local treatment;
5. ECOG 0 \~ 2 points ;
6. Expected survival time is more than 12 weeks;
7. No serious mental disorders;
8. The functions of important organs are basically normal:

   1. Hematopoietic function: neutral granules \>1.0×109/L, platelet \>75×109/L, hemoglobin \>80g/L;
   2. Cardiac function: Echocardiography indicated cardiac ejection fraction ≥50%, and no obvious abnormality was found in electrocardiogram;
   3. Renal function: serum creatinine ≤2.0×ULN;
   4. Liver function: ALT and AST ≤2.0×ULN (patients with liver tumor infiltration can be relaxed to ≤3.0×ULN);
   5. Total bilirubin ≤2.0×ULN (Gilbert syndrome or liver tumor infiltration can be relaxed to ≤3.0×ULN);
   6. Blood oxygen saturation in non-oxygen state\>92%.
9. Have the criteria for simple or intravenous blood collection, and no other contraindications for cell collection;
10. The subject agrees to use a reliable and effective contraceptive method for contraception (excluding safe period contraception) within 1 year from signing the informed consent to receiving the CAR T cell infusion;
11. The subject or his/her guardian agrees to participate in the clinical trial and signs the ICF, indicating that he/she understands the purpose and procedure of the clinical trial and is willing to participate in the study.

Exclusion Criteria:

1. Received anti-CD70 drug therapy before screening;
2. Active/symptomatic central nervous system metastasis or meningeal metastasis at the time of screening; Treated subjects with brain metastases can only be enrolled if no radiographically demonstrated progression is demonstrated ≥4 weeks after the end of treatment.
3. Received any of the following treatments prior to screening:

   1. Participated in other interventional clinical studies before screening, including: the time of last use of unmarketed new drugs less than 3 months from cell transfusion, or the time of last use of marketed drugs less than 5 half-lives from cell transfusion;
   2. Received anti-tumor therapy such as chemotherapy or targeted therapy within 2 weeks of preapheresis or at least 5 half-lives (whichever is shorter); Received systemic radiation within 4 weeks and local radiation within 2 weeks; Or received radioactive drugs (strontium, samarium) within 8 weeks prior to treatment.
   3. Systemic corticosteroid therapy with doses greater than 10mg/ day of prednisone (or equivalent doses of other corticosteroids) within 2 weeks of preapheresis (in the absence of active autoimmune disease, inhaled or topical steroid use and adrenocortical replacement with doses greater than 10mg/ day of prednisone efficacy dose are permitted);
   4. Received live attenuated vaccine within 4 weeks prior to screening;
4. There is an active or uncontrolled infection requiring systemic treatment within 1 week prior to screening;
5. Had malignancies other than the target tumor within 3 years prior to screening, except for malignancies that had received radical treatment and had no known active disease for ≥3 years prior to enrollment; Or adequately treated non-melanoma skin cancer with no evidence of disease;
6. Have any of the following heart conditions:

   1. New York Heart Association (NYHA) Stage III or IV congestive heart failure;
   2. Had myocardial infarction or coronary artery bypass grafting (CABG) within ≤6 months before enrollment;
   3. A history of clinically significant ventricular arrhythmia, or unexplained syncope (other than those caused by vasovagal or dehydration);
   4. History of severe non-ischemic cardiomyopathy.
7. Known to have active or uncontrolled autoimmune diseases, such as Crohns disease, rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, etc.
8. Hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) positive and peripheral blood hepatitis B virus (HBV) DNA titer greater than the normal range; Hepatitis C virus (HCV) antibody positive and peripheral blood hepatitis C virus (HCV) RNA titer greater than the normal range; Positive for human immunodeficiency virus (HIV) antibodies; Syphilis positive; Cytomegalovirus (CMV) DNA test positive;
9. The subject has a history of venous embolism (e.g., pulmonary embolism) and currently requires anticoagulant therapy, or if: a. Bleeding with grade 3 to 4 persists for more than 30 days; b. have sequelae from venous embolism (e.g. persistent dyspnea and hypoxia); (Note: Participants who have venous embolism but do not meet the above criteria can participate in the test);
10. Poorly controlled hypertension, defined as systolic blood pressure ≥150mmHg and/or diastolic blood pressure ≥90mmHg (Blood pressure values are measured based on the average of 3 readings at least 2 minutes apart, patients with blood pressure ≥150/90 MMHG at initial screening may receive antihypertensive treatment, if well controlled after treatment, And blood pressure \< 150/90mmHg can be screened);
11. Women who are pregnant or breastfeeding, and male or female subjects who plan to have a family within 1 year after receiving CAR T cell transfusion;
12. Conditions deemed unsuitable for participation in the study by other researchers.

主要终点：Incidence of Adverse events after CD70 CAR-T cells infusion [Safety and Tolerability] · Therapy-related adverse events were recorded and assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, Version 5.0) · 28 days；Obtain the maximum tolerated dose of CD70 CAR-T cells[Safety and Tolerability] · Dose-limiting toxicity after cell infusion · 28 days
次要终点：Disease control rate of CAR-T cell preparations in CD70 positive advanced malignancies [Effectiveness]；Objective response rate (ORR) of CD70 CAR-T treatment in patients with CD70-positive advanced malignancies[Effectiveness]；Duration of Response (DOR) of CD70 CAR-T treatment in patients with CD70-positive advanced malignancies[Effectiveness]；Progress-free survival(PFS) of CD70 CAR-T treatment in patients with CD70-positive advanced malignancies[Effectiveness]；Overall survival(OS)of CD70 CAR-T treatment in patients with CD70-positive advanced malignancies[Effectiveness]；AUCS of CD70 CAR-T cells [Cell dynamics]；CMAX of CD70 CAR-T cells [Cell dynamics]；TMAX of CD70 CAR-T cells[Cell dynamics]

• Intravenous of CD70-targeted CAR-T · EXPERIMENTAL · Infusion of CD70-targeted CAR-T cells by dose of 1-10x10\^6 cells/kg
• intraperitoneal injection of CD70-targeted CAR-T · EXPERIMENTAL · Infusion of CD70-targeted CAR-T cells by dose of 1-10x10\^6 cells/kg

This is a single-center, double-arm, open-label study. this study plans to evaluate the safety and efficacy of CD70-targeting CAR-T cells in the treatment of CD70-positive advanced/metastatic Gynecologic Cancer, and obtain recommended doses and infusion patterns.