This is a single-arm, single-center, open-label clinical trial designed to evaluate the clinical safety and tolerability of different doses of Prostate-Specific Membrane Antigen (PSMA)-Universal Chimeric Antigen Receptor (UCAR) T-lymphocytes (PSMA-UCAR T) for the treatment of patients with refractory castration-resistant prostate cancer (CRPC).

This is a single-arm, single-center, open-label clinical trial, which aims to evaluate safety and clinical efficacy of different doses of PSMA-UCAR T (BRL-302) in treating patients with refractory CRPC.

Three patients will be firstly enrolled at a dose level (DL) of 5.0 × 10^6cells/kg in the DL1 group. Based on preliminary safety data, efficacy information, and PK/PD parameters obtained at DL1 cohort, the investigator may enroll another three patients in a decreased dose level group of DL-2: 3 × 10^6 cells/kg or DL-1:1 × 10^6 cells/ kg, after thorough discussions between the investigators.

Inclusion Criteria:

1. Fully understood and voluntarily signed informed consent for this study;

2. Male, aged 18-80 years;

3. Expected survival of more than 6 months;

4. Metastatic castration-resistant prostate adenocarcinoma (CRPC) patients:

   Have received CRPC standard treatment (such as novel hormone therapies, chemotherapy and radium-223, etc., one or more of the combination therapy) after the diagnosis of CRPC, and is ineffective or progressive :PSA continued rising for 3 months, or bone scan/whole-body MRI/PET-CT showed local recurrence or new metastatic lesions, demonstrating disease progression;

5. PSMA expression in tumor cells was positive in immunohistochemical staining of prostate/metastatic biopsy tissue before enrollment (within 6 months prior to enrollment);

6. ECOG score < 2 ;

7. Virological examination HAV (hepatitis A virus), HBV (hepatitis B virus), HCV (hepatitis C virus), HIV (human immunodeficiency virus), TP (Treponema pallidum) quantitative detection was negative, (antigen and antibody screening method unknown, confirmed by nucleic acid method);

8. Hematological parameters met the following criteria: a. hemoglobin > 100 g/L; b. platelet count > 100 × 10^9/L; c. neutrophils > 1.5 × 10^9/L.

Exclusion Criteria:

Subjects meeting any of the following exclusion criteria will be excluded:

1. Have received any previous treatment with CAR-T therapy ;
2. Have received any previous treatment that targets PSMA;
3. Tumor pathology suggests a special type of prostate cancer (e.g., neuroendocrine prostate cancer, etc.)
4. Severe mental disorders;
5. Suffered from previous malignancies, except for the following: a. basal cell carcinoma or squamous cell carcinoma after standardized treatment; b. having a primary malignancy, but completely resected, with a complete remission time of ≥ 5 years.
6. Subjects with severe cardiovascular disease; a.New York Heart Association (NYHA) stage III or IV congestive heart failure; b.Myocardial infarction ≤ 6 months prior to enrollment or coronary artery bypass graft (CABG); c.Clinically significant ventricular arrhythmia, or history of unexplained syncope, nonvasovagal or not due to dehydration; d.History of severe non-ischemic cardiomyopathy; e.Decreased left ventricular ejection fraction (LVEF < 55%) as assessed by echocardiogram or multigated acquisition (MUGA) scan, abnormal interventricular septal thickness and atrioventricular size associated with myocardial amyloidosis;
7. Active infectious disease or any major infectious event requiring high grade antibiotics;
8. Organ function in the following abnormalities: a. serum aspartate aminotransferase or alanine aminotransferase > 2.5*Upper Limit of Normal (ULN); CK > ULN; CK-MB > ULN; TnT > 1.5*ULN; b. total bilirubin > 1.5*ULN; c. partial prothrombin time or activated partial thromboplastin time or international normalized ratio > 1.5*ULN in the absence of anticoagulant therapy;
9. Participation in other clinical studies in the past three months or previous treatment with any gene therapy product;
10. Intolerance or hypersensitivity to cyclophosphamide or fludarabine chemotherapy;
11. Unsuitability to participate in this clinical study in the opinion of the investigator.