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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
18
Prior to CAR-T cell infusion, subjects will receive lymphodepleting chemotherapy based on fludarabine and cyclophosphamide. Surgical method : 1)The patient is taken to the operating room, and the anesthesia method is intravenous anesthesia or local anesthesia. A digital rectal examination is performed, and the anus is dilated to accommodate three fingers. The genitals and perineum are prepared and covered in a sterile manner. An ultrasound probe is inserted into the rectum; (2) Under ultrasound guidance, CAR-T cells are injected into the prostate or localized lesions via the rectum or perineum; (3) Then, the TRUS probe is removed from the patient's rectum.
The First Affiliated Hospital of Zhejiang University
Hangzhou, Zhejiang, China
DLT
adverse events occurring within 28 days after the first infusion that are related to the study drug (definitely related, probably related, possibly related).
Time frame: 28 days
PSA50 response rate
The proportion of participants with a reduction of ≥50% in PSA from baseline to the lowest post-baseline PSA result, which needs to be confirmed by a second consecutive PSA assessment after at least 3 weeks.
Time frame: 6 months
DoPSA50（duration of PSA50 response）
The time from the date of first documented PSA50 response (subsequently confirmed) to the date of documented PSA progression per PCWG3 criteria or death from any cause in the absence of PSA progression.
Time frame: 6 months
DRRPSA50（durable PSA50 response rates）
The percentage of participants with a confirmed PSA50 response lasting at least 6 months, using the number of participants in the PSA evaluable set as the denominator.
Time frame: 6 months
TTPSAP50（time to PSA50 progression )
The time from the date of the first documented PSA50 response (subsequently confirmed) to the date of documented PSA progression per PCWG3 criteria.
Time frame: 6 months
PSA90 response rate
The proportion of participants with a reduction of ≥90% in PSA from baseline to the lowest post-baseline PSA result, which needs to be confirmed by a second consecutive PSA assessment after at least 3 weeks.
Time frame: 6 Months
DoPSA90（duration of PSA90 response）
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The time from the date of first documented PSA90 response (subsequently confirmed) to the date of documented PSA progression per PCWG3 criteria or death from any cause in the absence of PSA progression.
Time frame: 6 months
DRRPSA90（durable PSA90 response rates)
The percentage of participants with a confirmed PSA90 response lasting at least 6 months, using the number of participants in the PSA evaluable set as the denominator.
Time frame: 6 months
TTPSAP90（time to PSA90 progression)
The time from the date of the first documented PSA90 response (subsequently confirmed) to the date of documented PSA progression per PCWG3 criteria.
Time frame: 6 months
ORR
The proportion of patients achieving complete response (CR) or partial response (PR).
Time frame: 6 MONTHS
DOR（Duration of Response）
The duration from the initial achievement of partial response (PR) or complete response (CR) to the occurrence of disease progression or death.
Time frame: 6MONTHS
DCR（Disease Control Rate）
The proportion of patients achieving complete response (CR), partial response (PR), or stable disease (SD).
Time frame: 6months
TTR（Time to Response）
The time from treatment initiation to the first achievement of partial response (PR) or complete response (CR).
Time frame: 6mohths
OS（Overall Survival）
The time from treatment initiation to death from any cause.
Time frame: 6 months
rPFS（Radiographic Progression-Free Survival）
The time from treatment initiation to radiologically documented disease progression or death.
Time frame: 6 months
mFS
The time from treatment initiation to the development of distant metastasis or death.
Time frame: 6 months
In vivo persistence time of CAR-T cells
The time from the infusion of ACT#001-PSMA CAR-T cells to the point when ACT#001-PSMA CAR-T cells can no longer be detected in the body (with 2 consecutive negative test results), which is detected by methods such as QPCR and flow cytometry.
Time frame: 6 months