A Study of CA9-Targeted CAR Macrophage Therapy in Advanced Clear Cell Renal Cell Carcinoma

Prior treatment

• 2\. History of or concurrent active malignancy, except for cervical carcinoma in situ that has been cured or remained recurrence-free for at least 3 years, noninvasive basal cell or squamous cell carcinoma of the skin, ductal carcinoma in situ after curative resection, or localized prostate cancer with no evidence of recurrence after definitive treatment.
• 3\. Prior treatment with CA9-targeted cellular therapy, or other CA9-targeted therapy that, in the investigator's judgment, may interfere with the safety or efficacy assessments of this study.
• 4\. Prior treatment with CAR-T, CAR-NK, CAR-M, or other genetically engineered cellular therapy.
• 7\. Myocardial infarction, percutaneous coronary intervention, coronary stent placement, unstable angina, or other clinically significant severe cardiovascular disease within 12 months before screening.
• 8\. Toxicities related to prior anticancer therapy that have not recovered to Grade ≤1 according to CTCAE v5.0, except for alopecia, stable endocrine abnormalities, or other toxicities considered by the investigator not to pose a safety risk.
• 9\. Prior anticancer therapy for which the protocol-specified washout period has not been completed, or for which fewer than 5 half-lives of the respective treatment have elapsed before study treatment.
• 15\. Participation in another interventional clinical study with receipt of investigational treatment within 3 months before signing informed consent, or planned participation in another clinical study during the study period.
• 21\. Inability, as determined by the investigator, to tolerate filgrastim mobilization, PBMC collection, cell manufacturing, or subsequent cellular therapy procedures.

Other illness

• 5\. History of clinically significant central nervous system disease or dysfunction, including but not limited to stroke, intracranial hemorrhage, epilepsy, dementia, cerebellar disease, or aphasia; or active central nervous system metastases with associated symptoms.
• 6\. History of solid organ transplantation (e.g., heart, lung, liver, or kidney) or hematopoietic stem cell/bone marrow transplantation.
• 10\. Uncontrolled active bacterial, viral, fungal, or other pathogenic infection, or other infectious disease considered by the investigator to preclude participation in the study.
• 11\. Positive human immunodeficiency virus (HIV) antibody; untreated syphilis with positive Treponema pallidum antibody; hepatitis B surface antigen (HBsAg) positivity with detectable HBV DNA; or detectable hepatitis C virus (HCV) RNA. Participants whose infection can be adequately controlled with prophylactic or therapeutic medication, as determined by the investigator, may be eligible.
• 12\. Known active autoimmune disease requiring systemic treatment, or a history of severe autoimmune disease considered by the investigator to confer a high risk associated with study treatment.
• 13\. History of severe hypersensitivity to filgrastim, the cellular product, any medication used during the study, or any of their components.
• 16\. Depression, suicidal ideation, psychiatric disorder, or other psychological or psychiatric condition that may adversely affect study compliance or safety.
• 17\. Uncontrolled systemic inflammatory disease, a history of hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS), or a condition considered by the investigator to confer a high risk of cytokine storm.
• 19\. End-stage renal disease, dialysis dependence, or severe renal impairment considered by the investigator to preclude safe intratumoral injection.
• 20\. Unsuitability for ultrasound-guided intratumoral injection based on imaging assessment, including but not limited to inability to establish a safe puncture route, proximity of the target lesion to major blood vessels or vital organs, high bleeding risk, or a lesion location that cannot be safely accessed.
• 23\. Any other condition that, in the investigator's judgment, makes the participant unsuitable for participation in the study.

Lab values

• 18\. Clinically significant coagulation abnormality, bleeding tendency, or inability to discontinue anticoagulant or antiplatelet therapy, including but not limited to INR \>1.5, APTT \>1.5 × the upper limit of normal (ULN), or platelet count \<75 × 10⁹/L.
• 22\. Any disease, laboratory abnormality, or social circumstance that may interfere with safety or efficacy assessments or the participant's ability to complete the study.

Other

• 1\. Life expectancy of less than 3 months.
• 14\. Pregnant or breastfeeding women; participants of childbearing potential and their partners who are unwilling to use effective contraception during the study.

• 1\. Male or female participants aged 18 to 75 years.
• 2\. Histologically confirmed clear cell renal cell carcinoma (ccRCC).
• 3\. Unresectable locally advanced or metastatic renal cell carcinoma.
• 4\. Participants with advanced disease who require later-line systemic treatment following progression on prior standard anticancer therapy, as determined by the investigator.
• 5\. At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.
• 6\. At least one tumor lesion suitable for ultrasound-guided intratumoral injection, including a primary renal tumor, residual renal lesion, or locoregionally recurrent lesion in the renal region.
• 7\. Evidence of CA9 expression in the lesion intended for injection or a representative tumor lesion, as determined according to protocol-defined criteria.
• 8\. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
• 9\. Life expectancy of at least 12 weeks.
• 10\. Adequate bone marrow function, defined as an absolute neutrophil count (ANC) ≥1.5 × 10⁹/L, platelet count (PLT) ≥100 × 10⁹/L, and hemoglobin (Hb) ≥90 g/L, and meeting the requirements for peripheral blood mononuclear cell (PBMC) collection.
• 11\. Adequate hepatic function, defined as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × the upper limit of normal (ULN), or ≤5 × ULN in the presence of liver metastases, and total bilirubin ≤1.5 × ULN.
• 12\. Adequate renal function, defined as estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m² or serum creatinine ≤1.5 × ULN.
• 13\. Adequate coagulation function for tumor puncture and intratumoral injection, defined as international normalized ratio (INR) ≤1.5 and activated partial thromboplastin time (APTT) ≤1.5 × ULN.
• 14\. Considered by the investigator to be able to tolerate filgrastim mobilization, PBMC collection, and subsequent cellular therapy procedures.
• 15\. Screening for hepatitis B, hepatitis C, human immunodeficiency virus (HIV), and syphilis meeting protocol-defined requirements.
• 16\. Considered by the investigator to be able to tolerate ultrasound-guided tumor puncture and intratumoral injection.
• 17\. Voluntary participation in the study and provision of written informed consent before initiation of any study-related procedures.