Clinical Study of PSMA-targeted CAR-T Cells in the Treatment of Castration-resistant Prostate Cancer

This is an experimental study to evaluate the safety and effectiveness of PSMA-targeted CAR-T cells in the treatment of castration-resistant prostate cancer.

We designed a clinical study and divided the trial into two phases.

Phase 1 (climbing test): 9 patients were randomly divided into 3 groups (n=3). 9 patients were treated with cyclophosphamide at the dose of 60mg/kg/d 8-7 days before CAR-T cell infusion, and fludalabine at the dose of 25mg/m\^2/d 6-2 days before CAR-T cell infusion. On Day 0, CAR T cells were injected into patients in group 1, 2 and 3 at the dose of 1\*10\^8/ person, 1\*10\^9/ person and 1\*10\^10/ person, respectively. The infusion time exceeded 15-30min. On day 0-14, IL-2 (75000IU/kg) was injected subcutaneously once a day. From day 15-28, IL-2 (75000IU/kg) was subcutaneously injected into the patients three times a week. The purpose of this study is to assess subjects' MTD (maximum tolerated dose) against CAR T cells.

Phase 2: After determining the appropriate therapeutic dose for patients with prostate cancer, the remaining 11 patients received the same pre-treatment of chemotherapy. Then, the appropriate therapeutic dose of CAR T cells according to the results of phase 1 was infused on Day 0. On day 0-14,IL-2 (75000IU/kg) was given subcutaneously once a day. On day 15-28, IL-2 (75000IU/kg) was given subcutaneously three times a week.

Subjects will collect peripheral blood every four weeks, detect PSA and other related indicators to evaluate the curative effect, safety and survival rate of CAR-T cell transplantation. After 6 months of close follow-up, the subjects will have a quarterly medical history assessment, physical examination and blood test, bone metastasis assessment by bone ECT, prostate and pelvic cavity assessment by prostate MRI, and general information by PET CT if necessary for two years. After this assessment, the subjects will enter an annual telephone follow-up and questionnaire survey for up to five years to assess the long-term health problems of treatment, such as recurrence of malignant tumors.

Eligibility Criteria:
Inclusion Criteria:

1. Male patients aged from 18 to 75 years old;
2. The patients' ECOG score ≤ 2;
3. Prostate cancer patients in castration resistance stage (with or without distant metastasis):

   1. Previous new endocrine therapy is ineffective;
   2. Past treatment with too much citabine or cabatase is ineffective.
4. Have measurable or evaluable lesions;
5. The patients' main tissues and organs function well:

   1. Liver function: ALT/AST \< 3 times the upper limit of normal value (ULN);
   2. renal function: creatinine \< 220 μ mol/L;
   3. Lung function: indoor oxygen saturation ≥ 95%;
   4. Cardiac function: Left ventricular ejection fraction (LVEF)≥40%
6. Patients or their legal guardians voluntarily participate and sign the informed consent form.

Exclusion Criteria:

1. Infectious diseases (such as HIV, active hepatitis B or C infection, active tuberculosis, etc.);
2. Feasibility evaluation screening proves that the transfection of targeted lymphocytes is less than 10% or the amplification under the co-stimulation of CD3/CD28 is insufficient (\< 5 times);
3. The vital signs are abnormal and those who cannot cooperate with the inspectors;
4. Those with mental illness or mental illness who can't cooperate with treatment and curative effect evaluation;
5. Highly allergic constitution or severe allergic history, especially those who are allergic to IL-2;
6. Subjects with systemic infection or local severe infection who need anti-infection treatment;
7. Complicated dysfunction of heart, lung, brain, liver, kidney and other important organs;
8. Patients with other tumors;
9. Doctors think that there are other reasons that can't be included in the treatment.