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The purpose of this study is to see the safety and efficient of neoantigen reactive T cells (NRTs) combined with programmed cell death-1(PD-1) inhibitor(SHR-1210)in the treatment of Chinese patients with advanced refractory solid tumors.
The tumor-specific "none-self" immunogenic neoantigens encoded by either viral genes or somatic mutation genes, possess the potential to induce specific anti-cancer immunity, including cellular and humoral immune responses. Today, numerous clinical trials demonstrate that although these "none-self" antigens initiate the antigen-specific immunoglobulin G antibodies and cluster of differentiation 4(CD4)+/cluster of differentiation 8(CD8)+T-cells response, not all of them show a clinical benefit in the response rate, progression-free survival or overall survival.Immune tolerance induced by PD-1 or programmed cell death-ligand1( PD-L1)maybe play a vital role for these negative outcomes.Personalized cell therapy plus checkpoint inhibitors maybe own a breakthrough in the treatment of those malignant diseases without standard options.Our center has successfully established a new method for preparing personalized neoantigen reactive T cells(NRTS) for adoptive cell therapy(ACT). Today, we will carry out a single center single arm clinical prospective study of NRTs combined with PD-1 inhibitor(SHR-1210) for the treatment of Chinese patients with advanced refractory solid tumors. Participants are assigned to receive 4 circles of cell therapy,and prior to each cycle's immunocytes treatment,preconditional chemotherapy and SHR-1210 will be carried out, and IL-2 continuous intravenous infusion(CIV) will also be given for 5 consecutive days after each time's cell infusion. The safety and clinical response rate(RR) are evaluated. Biomarkers and immunological markers are also monitored.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Neoantigen Reactive T Cells + SHR-1210 | Experimental | Peripheral blood lymphocytes will be collected and neoantigen reactive T cells(NRTs) will be generated in the laboratory;Both Fludarabine 30mg/m2/D and Cyclophosphamide 300mg/m2/D will be i.v. for 3 days before cell infusion; NRTs 0.5~1 x 10^10, will be i.v.Q3 weeks for total 4 doses;programmed cell death-1(PD1) inhibitor SHR-1210,200mg,will be i.v. Q3 weeks for total 4 doses,2 day2 prior to each NRTs infusion;Interleukin-2 (IL-2) will be continuous intravenous infused since the first day of the cell infusion for 5 consecutive days, 4000,000 international unit per day.All Patients will receive a total of 4 cycles of treatment. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Neoantigen Reactive T Cells(NRTs) | Biological | Neoantigen Reactive T Cells in an expected volume of 100 milliliter(mL) will be given by intravenous injection over 2-10 minutes through either a peripheral or a central line. |
| Measure | Description | Time Frame |
|---|---|---|
| Number of participants with Adverse Events | using Common Terminology Criteria for Adverse Events (CTCAE v4.0) in patients | up to 6 months |
| Measure | Description | Time Frame |
|---|---|---|
| Response Rate | Response Rate(RR) will be evaluated according Response Evaluation Criteria in Solid Tumors | At 3, 6 and 12 months |
| Progression free survival (PFS) | the duration of progression free survival is measured from the time of treatment to the first date that recurrent or progressive disease or for any reason of death is objectively documented. |
| Measure | Description | Time Frame |
|---|---|---|
| Overall Survival (OS) | the duration is measured from the time of treatment to the time of death | At 6,12 and 18 months |
| Interferon-gama change of PBMC cells in the peripheral blood stimulated by tumor antigens |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Baorui Liu, M.D & Ph.D | Contact | +86-25-83304616 | 61331 | baoruiliu@nju.edu.cn |
| Zhengyun Zou, M.D & Ph.D | Contact | +86-25-83304616 | 61331 | zouzhengyun@medmail.com.cn |
| Name | Affiliation | Role |
|---|---|---|
| Baorui Liu, M.D & Ph.D | The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University | Recruiting | Nanjing | Jiangsu | 210008 | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 26901407 | Result | Gros A, Parkhurst MR, Tran E, Pasetto A, Robbins PF, Ilyas S, Prickett TD, Gartner JJ, Crystal JS, Roberts IM, Trebska-McGowan K, Wunderlich JR, Yang JC, Rosenberg SA. Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients. Nat Med. 2016 Apr;22(4):433-8. doi: 10.1038/nm.4051. Epub 2016 Feb 22. | |
| 26515495 |
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| SHR-1210 | Biological | SHR-1210 200mg will be administered as an intravenous infusion over 60 minutes. |
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| Fludarabine | Drug | Fludarabine(FLU) 30mg/m2/d×3d,3 days prior to each NRTs infusion as preconditional chemotherapy. |
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| Cyclophosphamide | Drug | Cyclophosphamide(CTX) 300mg/m2/d×3d,3 days prior to each NRTs infusion as preconditional chemotherapy. |
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| Interleukin-2 | Biological | Interleukin-2(IL-2)will be continuous intravenous infused since the first day of the cell infusion for 5 consecutive days, 4000,000 international unit per day. |
|
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| At 6,9 and 12 months |
T cells in the peripheral blood stimulated by tumor antigens for 24 hr,and then Interferon-gama secretion is measured
| At baseline,40days,2 months,6 months and at the time of disease progress |
| Th1/Th2 change in the peripheral blood | cytokines are measured by flow cytometry(FCM) | At baseline,40days,2 months,6 months and at the time of disease progress |
|
| Desrichard A, Snyder A, Chan TA. Cancer Neoantigens and Applications for Immunotherapy. Clin Cancer Res. 2016 Feb 15;22(4):807-12. doi: 10.1158/1078-0432.CCR-14-3175. Epub 2015 Oct 29. |
| 25838374 | Result | Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science. 2015 Apr 3;348(6230):62-8. doi: 10.1126/science.aaa4967. |
| 28197365 | Result | Su S, Zou Z, Chen F, Ding N, Du J, Shao J, Li L, Fu Y, Hu B, Yang Y, Sha H, Meng F, Wei J, Huang X, Liu B. CRISPR-Cas9-mediated disruption of PD-1 on human T cells for adoptive cellular therapies of EBV positive gastric cancer. Oncoimmunology. 2016 Nov 22;6(1):e1249558. doi: 10.1080/2162402X.2016.1249558. eCollection 2017. |
| 28408606 | Result | Stevanovic S, Pasetto A, Helman SR, Gartner JJ, Prickett TD, Howie B, Robins HS, Robbins PF, Klebanoff CA, Rosenberg SA, Hinrichs CS. Landscape of immunogenic tumor antigens in successful immunotherapy of virally induced epithelial cancer. Science. 2017 Apr 14;356(6334):200-205. doi: 10.1126/science.aak9510. |
| 27959684 | Result | Tran E, Robbins PF, Lu YC, Prickett TD, Gartner JJ, Jia L, Pasetto A, Zheng Z, Ray S, Groh EM, Kriley IR, Rosenberg SA. T-Cell Transfer Therapy Targeting Mutant KRAS in Cancer. N Engl J Med. 2016 Dec 8;375(23):2255-2262. doi: 10.1056/NEJMoa1609279. |
| 27827318 | Result | Parkhurst M, Gros A, Pasetto A, Prickett T, Crystal JS, Robbins P, Rosenberg SA. Isolation of T-Cell Receptors Specifically Reactive with Mutated Tumor-Associated Antigens from Tumor-Infiltrating Lymphocytes Based on CD137 Expression. Clin Cancer Res. 2017 May 15;23(10):2491-2505. doi: 10.1158/1078-0432.CCR-16-2680. Epub 2016 Nov 8. |
| 30835255 | Derived | Chen F, Zou Z, Du J, Su S, Shao J, Meng F, Yang J, Xu Q, Ding N, Yang Y, Liu Q, Wang Q, Sun Z, Zhou S, Du S, Wei J, Liu B. Neoantigen identification strategies enable personalized immunotherapy in refractory solid tumors. J Clin Invest. 2019 Mar 5;129(5):2056-2070. doi: 10.1172/JCI99538. Print 2019 May 1. |
| ID | Term |
|---|---|
| C000631724 | camrelizumab |
| C024352 | fludarabine |
| 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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