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no funding or finacial support
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This study will evaluate the safety of PD-1 knockout engineered T cells in treating castration resistant prostate cancer (CRPC). Blood samples will also be collected for research purposes.
This is a dose-escalation study of ex-vivo knocked-out, expanded, and selected PD-1 knockout-T cells from autologous origin. Patients are assigned to 1 of 3 treatment groups to determine the maximal tolerant dose. After the lower number of cycles are considered tolerant, an arm of the next higher number of cycles will be open to next patients. Biomarkers and immunological markers are collected and analyzed as well.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Test group | Peripheral blood lymphocytes will be collected and Programmed cell death protein 1(PDCD1) gene will be knocked out by CRISPR Cas9 in the laboratory (PD-1 Knockout T cells). The lymphocytes will be selected and expanded ex vivo and infused back into patients. Cyclophosphamide at 20mg/kg single dose will be administered 3 days i.v. before cell infusion. A total of 2 x 10^7/kg PD-1 Knockout T cells will be infused in one cycle. Each cycle is divided into three administrations, with 20% infused in the first administration, 30% in the second, and the remaining 50% in the third.Interleukin-2 (IL-2) will be given in the following 5 days, 720000 international unit（IU）/Kg/ day (if tolerant). Patients will receive a total of 2, 3, 4 cycles of treatment. |
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| Comparable group | Peripheral blood lymphocytes will be collected and Programmed cell death protein 1(PDCD1) gene will not be knocked out by CRISPR Cas9 in the laboratory (PD-1 Wild-type T cells). The lymphocytes will be selected and expanded ex vivo and infused back into patients. Cyclophosphamide at 20mg/kg single dose will be administered 3 days i.v. before cell infusion. A total of 2 x 10^7/kg PD-1 wild-type T cells will be infused in one cycle. Each cycle is divided into three administrations, with 20% infused in the first administration, 30% in the second, and the remaining 50% in the third. Interleukin-2 (IL-2) will be given in the following 5 days, 720000 international unit（IU）/Kg/day (if tolerant). |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| PD-1 Knockout T Cells | Biological | PD-1 Knockout T Cells and PD-1 wild-type T Cells will be made by Cell Biotech Co., Ltd. 2x107/kg T cells will be used for test group and comparable group separately. |
| Measure | Description | Time Frame |
|---|---|---|
| Number of participants with Adverse Events and/or Dose Limiting Toxicities as a Measure of Safety and tolerability of dose of PD-1 Knockout T cells using Common Terminology Criteria for Adverse Events (CTCAE v4.0) in patients | Dose Escalation - Approximately 6 months |
| Measure | Description | Time Frame |
|---|---|---|
| Response Rate:Response will be evaluated according to RECIST v1.1 | 90 days | |
| Progression free survival - PFS | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to average 10 months |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Department of Urology Peking University First Hospital | Beijing | Beijing Municipality | 100034 | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 25914862 | Background | Taube JM. Unleashing the immune system: PD-1 and PD-Ls in the pre-treatment tumor microenvironment and correlation with response to PD-1/PD-L1 blockade. Oncoimmunology. 2014 Dec 21;3(11):e963413. doi: 10.4161/21624011.2014.963413. eCollection 2014 Nov. | |
| 25518354 | Background | Yatsuda J, Eto M. [Current status and prospects of immunotherapy for castration-resistant prostate cancer]. Nihon Rinsho. 2014 Dec;72(12):2174-8. Japanese. |
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Plan to open
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| ID | Term |
|---|---|
| D003520 | Cyclophosphamide |
| D007376 | Interleukin-2 |
| ID | Term |
|---|---|
| D010752 | Phosphoramide Mustards |
| D009588 | Nitrogen Mustard Compounds |
| D009150 | Mustard Compounds |
| D006846 | Hydrocarbons, Halogenated |
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| Cyclophosphamide | Drug | Cyclophosphamide at 20mg/kg single dose will be administered 3 days i.v. before cell infusion. Interleukin-2 (IL-2) will be given in the following 5 days, 720000 international unit（IU）/Kg/day (if tolerant). |
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| IL-2 | Drug | Interleukin-2 (IL-2) will be given in the following 5 days after cell infusion, 720000 international unit（IU）/Kg/ day (if tolerant). |
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| Overall Survival - OS | The time from randomization to death from any cause, assessed up to 2 years |
| Peripheral blood circulating tumor DNA | 6 weeks |
| Temporal Interleukin-2 change in the peripheral blood | Baseline and 1 month and 3 months |
| Temporal Interferon-γ change in the peripheral blood | Baseline and 1 month and 3 months |
| Temporal Interleukin-6 change in the peripheral blood | Baseline and 1 month and 3 months |
| 27471580 | Result | Modena A, Ciccarese C, Iacovelli R, Brunelli M, Montironi R, Fiorentino M, Tortora G, Massari F. Immune Checkpoint Inhibitors and Prostate Cancer: A New Frontier? Oncol Rev. 2016 Apr 15;10(1):293. doi: 10.4081/oncol.2016.293. eCollection 2016 Apr 15. |
| 25428917 | Result | Bishop JL, Sio A, Angeles A, Roberts ME, Azad AA, Chi KN, Zoubeidi A. PD-L1 is highly expressed in Enzalutamide resistant prostate cancer. Oncotarget. 2015 Jan 1;6(1):234-42. doi: 10.18632/oncotarget.2703. |
| 27641687 | Derived | Yi L, Li J. CRISPR-Cas9 therapeutics in cancer: promising strategies and present challenges. Biochim Biophys Acta. 2016 Dec;1866(2):197-207. doi: 10.1016/j.bbcan.2016.09.002. Epub 2016 Sep 15. |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D063088 | Phosphoramides |
| D009943 | Organophosphorus Compounds |
| D007378 | Interleukins |
| D016207 | Cytokines |
| D036341 | Intercellular Signaling Peptides and Proteins |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D008222 | Lymphokines |
| D011506 | Proteins |
| D001685 | Biological Factors |