An exploratory clinical study evaluating the safety and efficacy of ACT#001 chimeric antigen receptor T-cell (CAR-T cell) local injection in the treatment of castration-resistant prostate cancer.

Chimeric Antigen Receptor (CAR) T cells are genetically engineered T cells that can express the introduced CAR gene, which contains signaling molecules such as antigen recognition fragments, T cell receptor activation molecules, and co-stimulatory signals. Currently, in the field of hematological tumors, CD19-targeted CAR-T cells have been clinically proven to effectively treat B-cell malignancies. The US FDA has approved their use for treating relapsed or refractory CD19-positive B-cell malignancies, with favorable therapeutic effects. However, significant challenges remain before CAR-T therapy can be widely applied to solid tumor treatment. For example, the non-specific targeting of CAR-T cells to normal/non-malignant tissues ("on-target, off-tumor toxicity") can be fatal. In fact, off-tumor toxicity to the lungs, cerebral gray matter, and cardiac muscle has resulted in multiple deaths.

Prostate-specific membrane antigen (PSMA) is a surface antigen highly expressed in prostate cancer. Over 98% of lymph node metastases and almost all bone metastases in patients with castration-resistant prostate cancer (CRPC) highly express PSMA, making it an ideal target for prostate cancer treatment. We have developed a thermally activated and regulated FB-PSMA CAR-T cell targeting the prostate cancer antigen PSMA. In vitro, heating at 43°C can activate CAR expression without impairing cell function. After injection into the tumor site, PSMA-expressing prostate cancer cells can activate FB-PSMA CAR-T cells and, through a feedback mechanism, increase the expression level of CAR molecules, thereby enhancing the tumor-killing effect. Once tumor elimination is completed, CAR molecules will gradually degrade to provide a higher level of safety. In a mouse model of prostate cancer xenografts, FB-PSMA CAR-T cells have demonstrated significant anti-tumor effects and good safety.

Based on the above background, we plan to conduct this clinical trial, aiming to explore a new immunotherapeutic approach that can effectively control prostate cancer while maximizing the preservation of urogenital function and the control of oligometastases, thereby addressing the unmet needs in the current treatment of local prostate cancer. We hope that through this study, we can provide a safer and more effective treatment option for prostate cancer patients, while opening up new possibilities for future cancer treatment. This study is designed to evaluate the safety and efficacy of local injection of ACT#001 chimeric antigen receptor T cells (ACT#001-PSMA CAR-T) in the treatment of castration-resistant prostate cancer.

Inclusion Criteria

1. understanding of this study and voluntarily signs the informed consent form;
2. Aged ≥ 18 years;
3. Expected survival time of at least 3 months;
4. non-metastatic CRPC (nmCRPC) (local recurrence) or metastatic CRPC (mCRPC)；
5. continue GnRH analog therapy；
6. at least one evaluable lesion per RECIST 1.1;
7. Has received at least one type of novel endocrine therapy；
8. PSMA positive expression rate > 10%;
9. Eastern Cooperative Oncology Group (ECOG) 0-1;
10. Well organ function
11. Left Ventricular Ejection Fraction (LVEF) > 50%;
12. Oxygen saturation > 92% without oxygen supplementation;
13. agree to use effective contraceptive measures

Exclusion Criteria

1. Presence of brain metastasis;
2. Organ transplantation or pending organ transplantation;
3. Uncontrolled large-volume serous cavity effusions；
4. A history of autoimmune diseases；
5. A history of receiving other cell therapies or genetically modified cell therapies (e.g., TCR-T therapy, CAR-T therapy);
6. A history of receiving any PSMA-targeted therapy;
7. Requirement for steroid therapy (except for physiological replacement therapy);
8. A history of receiving immunotherapies;
9. A history of clinically significant central nervous system (CNS) diseases (either past or present at screening);

(12) A history of other untreated malignant tumors; (13) Participants with severe cardiovascular diseases; (14) Active infectious diseases; (15) Active hepatitis B or hepatitis C virus infection; (16) Active Epstein-Barr virus (EBV) or cytomegalovirus (CMV) infection (17) Intolerance or allergy to cyclophosphamide or fludarabine chemotherapeutic drugs; (18) No accessible injection sites; (19) Assessment by the investigator that the participant is unsuitable for participation in this clinical study.