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This study will evaluate the safety of PD-1 knockout engineered T cells in treating metastatic advanced bladder cancer. 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 | Experimental | 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 | Placebo Comparator | 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 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). |
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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 |
|---|---|---|---|
| 27376121 | Background | Bidnur S, Savdie R, Black PC. Inhibiting Immune Checkpoints for the Treatment of Bladder Cancer. Bladder Cancer. 2016 Jan 7;2(1):15-25. doi: 10.3233/BLC-150026. | |
| 27326412 | Background | Kim J. Immune checkpoint blockade therapy for bladder cancer treatment. Investig Clin Urol. 2016 Jun;57 Suppl 1(Suppl 1):S98-S105. doi: 10.4111/icu.2016.57.S1.S98. Epub 2016 May 26. |
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plan to share
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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 | Peripheral circuiting tumor DNA is collected at baseline and 6 weeks after last treatment | 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 |
| 27306417 | Background | Aragon-Ching JB, Trump DL. Systemic therapy in muscle-invasive and metastatic bladder cancer: current trends and future promises. Future Oncol. 2016 Sep;12(17):2049-58. doi: 10.2217/fon-2016-0155. Epub 2016 Jun 16. |
| 27229745 | Background | Festino L, Botti G, Lorigan P, Masucci GV, Hipp JD, Horak CE, Melero I, Ascierto PA. Cancer Treatment with Anti-PD-1/PD-L1 Agents: Is PD-L1 Expression a Biomarker for Patient Selection? Drugs. 2016 Jun;76(9):925-45. doi: 10.1007/s40265-016-0588-x. |
| 27402371 | Background | Zibelman M, Plimack ER. Systemic therapy for bladder cancer finally comes into a new age. Future Oncol. 2016 Oct;12(19):2227-42. doi: 10.2217/fon-2016-0135. Epub 2016 Jul 12. |
| 27460757 | Background | Donin NM, Lenis AT, Holden S, Drakaki A, Pantuck A, Belldegrun A, Chamie K. Immunotherapy for the Treatment of Urothelial Carcinoma. J Urol. 2017 Jan;197(1):14-22. doi: 10.1016/j.juro.2016.02.3005. Epub 2016 Jul 25. |
| 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 |