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

Overview

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.

Detailed description

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.

Interventions

• Biological CAR-T cell immunotherapy
  This CAR-T cell immunotherapy with a novel specific Chimeric antigen receptor aiming at PSMA.

Primary outcome measures

• Safety Evaluation:Incidence and Severity of Adverse Events [Time frame: First 1 month after CAR-T cells infusion]
• Effectiveness Evaluation [Time frame: 3 months after CAR-T cells infusion]

Secondary outcome measures (2)

• Progression-free Survival (PFS) [Time frame: 24 months after CAR-T cells infusion]
• Overall Survival (OS) [Time frame: 24 months after CAR-T cells infusion]

Eligibility criteria

Inclusion criteria

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

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

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

Exclusion criteria

• Infectious diseases (such as HIV, active hepatitis B or C infection, active tuberculosis, etc.);
• 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);
• The vital signs are abnormal and those who cannot cooperate with the inspectors;
• Those with mental illness or mental illness who can't cooperate with treatment and curative effect evaluation;
• Highly allergic constitution or severe allergic history, especially those who are allergic to IL-2;
• Subjects with systemic infection or local severe infection who need anti-infection treatment;
• Complicated dysfunction of heart, lung, brain, liver, kidney and other important organs;
• Patients with other tumors;
• Doctors think that there are other reasons that can't be included in the treatment.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Affiliated Hospital of Xuzhou Medical University — Xuzhou

Publications

• Mohler JL, Antonarakis ES, Armstrong AJ, D'Amico AV, Davis BJ, Dorff T, Eastham JA, Enke CA, Farrington TA, Higano CS, Horwitz EM, Hurwitz M, Ippolito JE, Kane CJ, Kuettel MR, Lang JM, McKenney J, Netto G, Penson DF, Plimack ER, Pow-Sang JM, Pugh TJ, Richey S, Roach M, Rosenfeld S, Schaeffer E, Shabsigh A, Small EJ, Spratt DE, Srinivas S, Tward J, Shead DA, Freedman-Cass DA. Prostate Cancer, Versi PMID 31085757
• Gansler T, Ganz PA, Grant M, Greene FL, Johnstone P, Mahoney M, Newman LA, Oh WK, Thomas CR Jr, Thun MJ, Vickers AJ, Wender RC, Brawley OW. Sixty years of CA: a cancer journal for clinicians. CA Cancer J Clin. 2010 Nov-Dec;60(6):345-50. doi: 10.3322/caac.20088. PMID 21075954
• Slovin SF. Immunotherapy for castration-resistant prostate cancer: has its time arrived? Expert Opin Biol Ther. 2020 May;20(5):481-487. doi: 10.1080/14712598.2020.1735345. Epub 2020 Mar 5. PMID 32097050
• Esmaeilzadeh A, Tahmasebi S, Athari SS. Chimeric antigen receptor -T cell therapy: Applications and challenges in treatment of allergy and asthma. Biomed Pharmacother. 2020 Mar;123:109685. doi: 10.1016/j.biopha.2019.109685. Epub 2019 Dec 17. PMID 31862474
• Zuccolotto G, Fracasso G, Merlo A, Montagner IM, Rondina M, Bobisse S, Figini M, Cingarlini S, Colombatti M, Zanovello P, Rosato A. PSMA-specific CAR-engineered T cells eradicate disseminated prostate cancer in preclinical models. PLoS One. 2014 Oct 3;9(10):e109427. doi: 10.1371/journal.pone.0109427. eCollection 2014. PMID 25279468
• Minn I, Huss DJ, Ahn HH, Chinn TM, Park A, Jones J, Brummet M, Rowe SP, Sysa-Shah P, Du Y, Levitsky HI, Pomper MG. Imaging CAR T cell therapy with PSMA-targeted positron emission tomography. Sci Adv. 2019 Jul 3;5(7):eaaw5096. doi: 10.1126/sciadv.aaw5096. eCollection 2019 Jul. PMID 31281894
• Santoro SP, Kim S, Motz GT, Alatzoglou D, Li C, Irving M, Powell DJ Jr, Coukos G. T cells bearing a chimeric antigen receptor against prostate-specific membrane antigen mediate vascular disruption and result in tumor regression. Cancer Immunol Res. 2015 Jan;3(1):68-84. doi: 10.1158/2326-6066.CIR-14-0192. Epub 2014 Oct 30. PMID 25358763
• Zhang Q, Li H, Yang J, Li L, Zhang B, Li J, Zheng J. Strategies to improve the clinical performance of chimeric antigen receptor-modified T cells for cancer. Curr Gene Ther. 2013 Feb;13(1):65-70. doi: 10.2174/156652313804806570. PMID 23256743

Identifiers

NCT: NCT05354375 · XYFY2021-KL172-02

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗