Overview

This is a single-arm, open-label, dose-escalating Phase 1 clinical study. It aims to evaluate the safety, tolerability and pharmacokinetic(PK) profiles of the investigational agent, and preliminarily assess its efficacy in subjects with advanced/metastatic renal cell carcinoma, and determine the recommended dose and infusion regimen for Phase 2 trials.

Eligibility

Inclusion Criteria:

1. Age 18 to 70 years (inclusive), regardless of gender;
2. Life expectancy of more than 12 weeks;
3. Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 to 1;
4. Subjects with advanced/metastatic renal cell carcinoma (RCC):
   1. Histologically confirmed clear cell renal cell carcinoma (ccRCC), with an International Metastatic RCC Database Consortium (IMDC) risk stratification of intermediate or high risk as evaluated by the investigator;
   2. Has at least one measurable lesion according to RECIST 1.1;
   3. Tumor tissue samples must test positive for CD70 expression via immunohistochemistry (IHC);
   4. Must have received at least one prior line of systemic therapy (must include at least: (1) immuno-oncology (IO) combination therapy: concomitant targeting of PD-1 and CTLA-4, or (2) an immune checkpoint inhibitor (PD-1/PD-L1 inhibitor) combined with a VEGF/VEGFR-targeted agent);
5. Venous access required for apheresis can be established; hemoglobin ≥ 90 g/L, absolute neutrophil count (ANC) ≥ 1.5×10\^9/L, and platelet count ≥ 100× 10\^9/L, and the leukepheresis can be carried according to the judgement of investigators;
6. Hepatic, renal, cardiac, and pulmonary functions must meet the following criteria:
   1. Creatinine clearance (CrCl) ≥ 50 mL/min (calculated by the Cockcroft-Gault formula);
   2. Left ventricular ejection fraction (LVEF) \> 50%;
   3. Baseline peripheral oxygen saturation \> 95%;
   4. Total bilirubin ≤2 × upper limit of normal (ULN);
   5. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN;
7. Voluntary participation in the clinical study: Must understand and be informed about this study, voluntarily sign the Informed Consent Form (ICF), and be willing to complete all study procedures.

Exclusion Criteria:

1. Prior treatment with anti-CD70 targeted therapies;
2. Brain metastasis from renal cell carcinoma;
3. Concomitant with other uncontrolled malignancies, except for adequately treated cervical carcinoma in situ, basal cell or squamous cell skin cancer, localized prostate cancer after radical surgery, ductal carcinoma in situ after radical surgery, or thyroid cancer after radical surgery;
4. Any uncontrolled active infection, including but not limited to active tuberculosis; presence or suspicion of an uncontrolled infection, or an infection requiring systemic intravenous therapy within 14 days prior to enrollment (including fungal, bacterial, viral, or other infections);
5. Subjects who are hepatitis B surface antigen (HBsAg) positive or hepatitis B core antibody (HBcAb) positive, with peripheral blood HBV DNA titers above the lower limit of detection (LLOD) of the study site; those who are hepatitis C virus (HCV) antibody positive with peripheral blood HCV RNA positive; those who are human immunodeficiency virus (HIV) antibody positive; or those who test positive for syphilis;
6. Any unstable systemic disease, including but not limited to: unstable angina, cerebrovascular accident or transient ischemic attack within 6 months prior to screening, myocardial infarction within 6 months prior to screening, congestive heart failure (New York Heart Association \[NYHA\] classification ≥ III ), poorly controlled diabetes mellitus (glycated hemoglobin HbA1c \> 8% at screening), poorly controlled severe arrhythmia, and hepatic, renal, or metabolic diseases by medication;
7. Pregnant or lactating woman, and female subject who plans to have a pregnancy within 1 year after cell transfusion, or male subject whose partner plans to have a pregnancy within 1 year after cell transfusion (except for subjects of childbearing potential who are willing to use highly effective and reliable methods of contraception uninterruptedly for 1 year after the study treatment);
8. Prior treatment with CAR-T therapy or other genetically modified cell therapies prior to screening;
9. History of implantation of a cardiac pacemaker or deep brain stimulator;
10. Vaccination with live attenuated vaccines within 4 weeks prior to leukapheresis;
11. History of autoimmune diseases (such as Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus) within the past 2 years that resulted in end-organ damage, or required systemic immunosuppressive therapy or other systemic disease-controlling medications;
12. History of central nervous system (CNS) diseases, such as seizures, paralysis, aphasia, stroke, severe brain injury, dementia, Parkinson's disease, or psychiatric disorders; or known active CNS involvement or history thereof;
13. Subjects who are receiving systemic steroid therapy prior to screening, and who are judged by the investigator to require long-term use of systemic steroids during the study treatment period (excluding inhaled or topical steroids);
14. Presence of medical conditions that interfere with the ability to sign the written Informed Consent Form (ICF) or comply with study procedures; or those who are unwilling or unable to comply with study requirements;
15. History of severe immediate hypersensitivity reactions to any of the medications to be used in this study;
16. Any other conditions that, in the opinion of the investigator, make the subject unsuitable for participation in this study.