Clinical Study of CD70-targeted CAR-T Therapy for Advanced/Advanced Renal Cancer

This is a phase I clinical study to evaluate the safety and tolerability of CAR-T in patients with advanced/metastatic renal cell carcinoma, and to obtain the maximum tolerated dose of CAR-T and phase II Recommended dose.

This is a single-center, single-arm, open-label study. Intravenous infusion group have 4 dose groups, adopting a dose-escalating 3+3 design, and plan to recruit about 12 subjects with CD70-positive advanced/metastatic renal cell carcinoma in Dose discovery phase and 12 subjects in dose expansion phase.

Eligibility Criteria:
Inclusion Criteria:

1. Age ≥18 years old, male or female;
2. Diagnosed with advanced/metastatic renal cell carcinoma (staging according to 2017AJCC) by histopathology or cytology (paraffin section or fresh biopsy tumor tissue specimens), and the tumor is positive for CD70 expression (positive for tumor CD70 confirmed by histology or pathology) (IHC 3+));
3. At least after TKI, anti-vascular drug treatment is ineffective, there is no available standard treatment plan or standard treatment fails or cannot tolerate (disease progression or intolerance such as surgery, chemotherapy, radiotherapy, targeted therapy, etc.) no effective treatment;
4. Measurable and evaluable lesions specified by RECIST version 1.1: Measurable disease is defined as at least one lesion that can be accurately measured on at least one level (long diameter needs to be recorded); ), each lesion must be \>10mm when measured by Magnetic Resonance Imaging (MRI), The lymph node must be \>15mm in the short axis;
5. ECOG 0-2 points (Appendix 2);
6. The expected survival time is more than 12 weeks;
7. No serious mental disorder;
8. The functions of important organs are basically normal:

   1. Hematopoietic function: neutrophils 1.0×109/L, platelets 75×109/L, hemoglobin 80g/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 ≤2.0×ULN (for patients with liver tumor infiltration, it can be relaxed to ≤3.0×ULN);
   5. Total bilirubin ≤2.0×ULN (Gilbert syndrome or combined liver tumor infiltration can be relaxed to ≤3.0×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. Subjects 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. Those who have received CAR-T therapy or other gene-modified cell therapy before screening;
2. Received anti-CD70 drug treatment before screening;
3. Active/symptomatic central nervous system metastases or meningeal metastases at the time of screening; subjects with brain metastases who have been treated must be confirmed to have no imaging evidence of progression ≥ 4 weeks after the end of treatment before they can be enrolled;
4. Received any of the following treatments before screening:

   1. Participated in other interventional clinical studies before screening, including: the last use of unmarketed new drugs is less than 3 months from the time of cell reinfusion, or the last use of marketed drugs is less than 5 months from the time of cell reinfusion half-life;
   2. Received anti-tumor therapy such as chemotherapy and targeted therapy within 2 weeks or at least 5 half-lives (whichever is shorter) before apheresis;
   3. Received systemic corticosteroid therapy at doses greater than 10 mg/day prednisone (or equivalent doses of other corticosteroids) within 2 weeks prior to apheresis (inhalation or topical is allowed in the absence of active autoimmune disease Use steroids and adrenal corticosteroid replacement at doses greater than 10 mg/day of prednisone);
   4. Received live attenuated vaccine within 4 weeks before screening;
5. Active infection or uncontrollable infection requiring systemic treatment within 1 week before screening;
6. Patients with other malignancies other than renal cancer within 3 years before screening, except for the following cases: malignant tumors that have received radical treatment, and no known active disease within ≥3 years before enrollment; or Treated non-melanoma skin cancer with no evidence of disease;
7. 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 a history of unexplained syncope (except those caused by vasovagal or dehydration);
   4. History of severe nonischemic cardiomyopathy.
8. Known to have active or uncontrolled autoimmune diseases, such as Crohns disease, rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, etc.;
9. Hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) positive and peripheral blood hepatitis B virus (HBV) DNA titer detection is greater than the normal range; hepatitis C virus (HCV) antibody positive and peripheral blood type C Hepatitis virus (HCV) RNA titer detection greater than normal range Human immunodeficiency virus (HIV) antibody positive; syphilis positive test; cytomegalovirus (CMV) DNA test positive;
10. The subject has experienced venous thromboembolic events (for example: pulmonary embolism) and still needs anticoagulation therapy, or meets the following conditions: a. Bleeding with grades 3 to 4 for more than 30 days; b. There are veins Sequelae caused by embolism (such as persistent dyspnea and hypoxia); (Note: subjects who have venous embolism but do not meet the above conditions can participate in the trial);
11. Poorly controlled hypertension, defined as systolic blood pressure ≥150 mmHg and/or diastolic blood pressure ≥90 mmHg (The measurement of blood pressure is based on the average of 3 readings at least 2 minutes apart. Patients with blood pressure ≥150/90mmHg at the initial screening can receive antihypertensive treatment, and if they are well controlled after treatment, and blood pressure \<150/90mmHg can be performed. filter);
12. Women who are pregnant or breastfeeding, and male or female subjects who plan to have children within 1 year after receiving CAR-T cell reinfusion;
13. Other investigators deem it unsuitable to participate in the study.