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This study will evaluate the safety of PD-1 knockout EBV-CTL cells in treating EBV (Epstein-Barr virus) positive advanced stage malignancies. Blood samples will also be collected for research purposes.
This is a study of CRISPR-Cas9 mediated PD-1 knockout-T cells from autologous origin. Patients are assigned to receive 4 circles of cell therapy. The safety and clinical response are evaluated. Biomarkers and immunological markers are also monitored.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| PD-1 knockout EBV-CTL | Experimental | Peripheral blood lymphocytes will be collected and Programmed cell death protein 1(PDCD1) gene will be knocked out by CRISP-Cas9 system and EBV-CTL will be generated in the laboratory (PD-1 Knockout EBV-CTL). Fludarabine at 30mg/m2 and Cyclophosphamide at 300mg/m2 single dose will be administered 3 days i.v. before cell infusion. A total of 2 x 10^7/kg PD-1 Knockout CTL 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 daily( iv) since the first day of the cell infusion for 5 consecutive days, 4000,000 international unit（IU）/day . Patients will receive a total of four cycles of treatment. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Fludarabine | Drug | To modify immune micro-environment |
|
| Measure | Description | Time Frame |
|---|---|---|
| Number of participants with Adverse Events using Common Terminology Criteria for Adverse Events (CTCAE v4.0) in patients | 6 months |
| Measure | Description | Time Frame |
|---|---|---|
| Response Rate | 90 days | |
| Progression free survival (PFS) | up to 1 year | |
| Overall Survival (OS) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Baorui Liu, MD | Contact | 0086-25-83106666-61331 | baoruiliu07@163.com | |
| Shu Su, MD | Contact | 0086-25-83106666-61331 | ssnine@126.com |
| Name | Affiliation | Role |
|---|---|---|
| Baorui Liu, MD | The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The Comprehensive Cancer Center of Nanjing Drum Tower Hospital | Recruiting | Nanjing | Jiangsu | 210008 | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 25254613 | Background | Kim SY, Park C, Kim HJ, Park J, Hwang J, Kim JI, Choi MG, Kim S, Kim KM, Kang MS. Deregulation of immune response genes in patients with Epstein-Barr virus-associated gastric cancer and outcomes. Gastroenterology. 2015 Jan;148(1):137-147.e9. doi: 10.1053/j.gastro.2014.09.020. Epub 2014 Sep 22. | |
| 26361042 | Background |
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| Cyclophosphamide | Drug | To modify immune micro-environment |
|
|
| Interleukin-2 | Drug | To sustain the survival of infused T cells |
|
|
| up to 3 years |
| The duration of the normalization of tumor marker | up to 3 years |
| Interferon-γ change of T cells in the peripheral blood stimulated by tumor antigens | Baseline and 1 month, 3 months and 6 months |
| Th1/Th2 change in the peripheral blood | Baseline and 1 month, 3 months and 6 months |
| The Comprehensive Cancer Center of Nanjing Drum Tower Hospital | Recruiting | Nanjing | Jiangsu | 210008 | China |
|
| Quan L, Chen X, Liu A, Zhang Y, Guo X, Yan S, Liu Y. PD-1 Blockade Can Restore Functions of T-Cells in Epstein-Barr Virus-Positive Diffuse Large B-Cell Lymphoma In Vitro. PLoS One. 2015 Sep 11;10(9):e0136476. doi: 10.1371/journal.pone.0136476. eCollection 2015. |
| 20948438 | Background | Louis CU, Straathof K, Bollard CM, Ennamuri S, Gerken C, Lopez TT, Huls MH, Sheehan A, Wu MF, Liu H, Gee A, Brenner MK, Rooney CM, Heslop HE, Gottschalk S. Adoptive transfer of EBV-specific T cells results in sustained clinical responses in patients with locoregional nasopharyngeal carcinoma. J Immunother. 2010 Nov-Dec;33(9):983-90. doi: 10.1097/CJI.0b013e3181f3cbf4. |
| 23935598 | Background | Lloyd A, Vickery ON, Laugel B. Beyond the antigen receptor: editing the genome of T-cells for cancer adoptive cellular therapies. Front Immunol. 2013 Aug 5;4:221. doi: 10.3389/fimmu.2013.00221. eCollection 2013. |
| 26818188 | Background | Su S, Hu B, Shao J, Shen B, Du J, Du Y, Zhou J, Yu L, Zhang L, Chen F, Sha H, Cheng L, Meng F, Zou Z, Huang X, Liu B. CRISPR-Cas9 mediated efficient PD-1 disruption on human primary T cells from cancer patients. Sci Rep. 2016 Jan 28;6:20070. doi: 10.1038/srep20070. |
| 24076990 | Background | Mali P, Esvelt KM, Church GM. Cas9 as a versatile tool for engineering biology. Nat Methods. 2013 Oct;10(10):957-63. doi: 10.1038/nmeth.2649. |
| ID | Term |
|---|---|
| D013274 | Stomach Neoplasms |
| D000077274 | Nasopharyngeal Carcinoma |
| D016399 | Lymphoma, T-Cell |
| D006689 | Hodgkin Disease |
| D016403 | Lymphoma, Large B-Cell, Diffuse |
| ID | Term |
|---|---|
| D005770 | Gastrointestinal Neoplasms |
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D004066 | Digestive System Diseases |
| D005767 | Gastrointestinal Diseases |
| D013272 | Stomach Diseases |
| D002277 | Carcinoma |
| D009375 | Neoplasms, Glandular and Epithelial |
| D009370 | Neoplasms by Histologic Type |
| D009303 | Nasopharyngeal Neoplasms |
| D010610 | Pharyngeal Neoplasms |
| D010039 | Otorhinolaryngologic Neoplasms |
| D006258 | Head and Neck Neoplasms |
| D009302 | Nasopharyngeal Diseases |
| D010608 | Pharyngeal Diseases |
| D009057 | Stomatognathic Diseases |
| D010038 | Otorhinolaryngologic Diseases |
| D008228 | Lymphoma, Non-Hodgkin |
| D008223 | Lymphoma |
| D008232 | Lymphoproliferative Disorders |
| D008206 | Lymphatic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D007160 | Immunoproliferative Disorders |
| D007154 | Immune System Diseases |
| D016393 | Lymphoma, B-Cell |
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| ID | Term |
|---|---|
| C024352 | fludarabine |
| C042382 | fludarabine phosphate |
| D003520 | Cyclophosphamide |
| D007376 | Interleukin-2 |
| ID | Term |
|---|---|
| D010752 | Phosphoramide Mustards |
| D009588 | Nitrogen Mustard Compounds |
| D009150 | Mustard Compounds |
| D006846 | Hydrocarbons, Halogenated |
| 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 |
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