The Safety and Efficacy of Allogeneic CD70 CAR-T Therapy in Unresectable or Metastatic Clear Cell Renal Cell Carcinoma

A Clinical Study to Evaluate the Safety and Efficacy of Allogeneic CD70 CAR-T Therapy in Patients With Unresectable or Metastatic Clear Cell Renal Cell Carcinoma

CLEAR CAR-T cell injection (ET-970) is an engineered CD70-targeting allogeneic Chimeric Antigen Receptor T-Cell (CAR-T cell). This is a multi-center, single-arm, open-label, early exploratory clinical study. The objective of this study is to evaluate the safety and preliminary efficacy of ET-970 in unresectable or metastatic clear cell renal cell carcinoma.

ET-970-RCC01 is an open-label study in subjects with ccRCC and will be conducted in two stages: dose-escalation (stage A) and dose-expansion (stage B). The 3+3 dose-escalation design will be adopted in stage A. The aim of stage B is to further assess the safety and efficacy of ET-970 under the dose which has been evaluated as safe in stage A. During treatment period, the subjects will receive a single-dose of ET-970. The duration of participation for each subject will be approximately 57 weeks since the signing of informed consent.

Key Inclusion Criteria:

1.Age 18-75 years (inclusive), any gender. 2.Confirmed by histopathology and/or cytology as unresectable or metastatic clear cell renal cell carcinoma; 3.Local progression or metastasis after receiving at least second line therapy [including at least one immune checkpoint inhibitor (ICI) and at least one vascular endothelial growth factor tyrosine kinase inhibitor (VEGF TKI)]; 4.Willing to undergo tumor tissue sample collection or provide previous tumor tissue samples for CD70 expression level testing; 5.Positive CD70 expression by immunohistochemical (IHC) staining of tumor tissue (percentage of positive cells ≥ 10%); 6.At least one measurable lesion according to RECIST v1.1 criteria. 7.Karnofsky Performance Status (KPS) ≥ 70%. 8.Organ function must meet the following criteria:

1. Complete blood count (no G-CSF within 1 week prior to blood count testing. or no pegylated G-CSF within 2 weeks prior to blood count testing): Absolute neutrophil count (ANC) ≥ 1.0×10⁹/L. platelet count (PLT) ≥ 100×10⁹/L. hemoglobin ≥ 80 g/L (excluding bone marrow suppression caused by lymphoma involvement of the bone marrow).
2. Coagulation function: International normalized ratio (INR) ≤ 1.5×ULN, and activated partial thromboplastin time (APTT) ≤ 1.5×ULN.
3. Liver function: Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3×ULN (if with liver metastasis, AST and ALT ≤ 5×ULN). total bilirubin ≤ 1.5×ULN.
4. Renal function: Serum creatinine ≤ 1.5×ULN or creatinine clearance (Cockcroft-Gault formula) ≥ 60 mL/min.
5. Cardiac function: Left ventricular ejection fraction (LVEF) on echocardiography (ECHO) ≥ 50%, no pericardial effusion. no clinically significant abnormalities on 12-lead electrocardiogram (ECG).
6. Pulmonary function: End-blood oxygen saturation ≥ 92% while breathing room air without supplemental oxygen. no clinically significant pleural effusion.

9.Subjects and/or their partners of childbearing potential agree to use effective contraceptive measures throughout the entire treatment period and for 52 weeks after treatment, and during this period they must not donate eggs/sperm for assisted reproduction; Female participants of childbearing potential (women who have undergone sterilization surgery or have been postmenopausal for ≥12 months are not considered to have childbearing potential) must present a negative pregnancy test at screening and agree to use effective contraception throughout the study period.

10.Willing to comply with all study procedures and voluntarily participate in this study and sign the informed consent form (ICF).

Key Exclusion Criteria:

1. Expected survival < 3 months.
2. Prior or concurrent active malignancy, with the exception of cured or recurrence-free for at least 3 years of cervical carcinoma in situ, non-invasive basal cell or squamous cell skin cancer, or locally advanced prostate cancer that has received curative treatment, or ductal carcinoma in situ after radical surgery.
3. Prior use of CD70-targeted therapy.
4. Previous treatment with CAR-T or any other genetically engineered cell therapy.
5. History of central nervous system (CNS) disease or clinically significant CNS dysfunction, such as cerebral ischemia/hemorrhage, dementia, cerebellar disease, epilepsy, aphasia, dementia, etc.
6. History of major organ transplantation (e.g., heart, lung, kidney, liver) or hematopoietic stem cell/bone marrow transplantation.
7. Occurrence of myocardial infarction, cardiac angioplasty or stent implantation, unstable angina, or other clinically significant cardiac diseases within 12 months prior to screening.
8. Presence of CNS metastasis or symptoms of CNS metastasis.
9. Toxicities from prior therapy have not recovered to CTCAE grade ≤ 1, except for adverse events without safety risks (e.g., alopecia).
10. The anti-tumor therapy received is still within 5 half-lives prior to the planned ET-970 infusion.
11. Presence of uncontrolled active bacterial, fungal, or viral infections, or other infections deemed by the investigator as unsuitable for study participation.
12. Positive for human immunodeficiency virus (HIV) antibody, positive for Treponema pallidum antibody, positive for hepatitis B surface antigen (HBsAg) or positive for hepatitis B core antibody (HBcAb) with detectable peripheral blood HBV DNA, positive for hepatitis C virus (HCV) antibody with detectable HCV RNA; except for infections that can be prevented or controlled with medication as judged by the investigator.
13. History of other autoimmune diseases requiring immunosuppressive therapy.
14. Known severe allergy to the study drug or any of its components.
15. Pregnant or breastfeeding women.
16. Use of any live vaccines against infectious disease within 6 weeks before lymphodepletion conditioning.
17. Participation in another interventional clinical study and receipt of an active investigational drug within 3 months prior to signing the ICF, or intention to participate in another clinical trial or receive treatment for autoimmune diseases outside the protocol during the entire study period.
18. Psychiatric disorders with depression or suicidal tendencies.
19. Presence of any other medical condition that may affect the evaluation of the safety and efficacy of the study drug.
20. Other factors due to which the patient is deemed unsuitable for participation by the investigator.