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This study will test whether anti-EBV autologous TCR-T cell injection is safe and effective for patients with relapsed or refractory EBV-positive lymphoma who have HLA-A11:01. Researchers will look at safety, tolerability, and the maximum tolerated dose or recommended dose for future studies.
The study will also measure how the infused TCR-T cells expand and persist in the body, changes in EBV DNA levels and T-cell subgroups in the blood, and whether the treatment shows early signs of clinical benefit. Researchers will also explore whether the treatment causes an immune response against the infused cells.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| EBV-TCR-T | Experimental |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| EBV TCR-T | Drug | After signing the informed consent form and completing screening according to the inclusion/exclusion criteria, eligible subjects will be sequentially assigned to the following dose cohorts of TCR-T cells (single administration): 1×10⁶ TCR-T cells/kg, 2.5×10⁶ TCR-T cells/kg, 5×10⁶ TCR-T cells/kg, and 10×10⁶ TCR-T cells/kg. The first dose cohort (1×10⁶ TCR-T cells/kg) will use a rapid titration approach. If no significant safety issues occur within 28 days after infusion-defined as ≥Grade 3 non-hematologic toxicity, Grade 4 hematologic toxicity lasting more than 28 days (excluding disease- or chemotherapy-related causes), ≥Grade 2 neurotoxicity, or ≥Grade 3 cytokine release syndrome (CRS)-the next dose cohort will be initiated. If a dose-limiting toxicity (DLT) occurs, evaluation will be performed after 6 subjects have been treated. The subsequent three dose cohorts will follow a "3+3" dose-escalation design, with 3-6 subjects per cohort receiving a single infusion. For subjects in th |
| Measure | Description | Time Frame |
|---|---|---|
| Dose-Limiting Toxicity (DLT) | To evaluate the incidence of dose-limiting toxicities (DLTs) of anti-EBV TCR-T cell injection in subjects with relapsed/refractory EBV-positive HLA-A11:01 lymphoma. | treatment cycle (Day 1 to Day 28) |
| Maximum Tolerated Dose (MTD) | Determination of the maximum tolerated dose of anti-EBV TCR-T cell injection. | From Day 1 of treatment until the end of the dose-escalation phase |
| Recommended Phase 2 Dose (RP2D) | Determination of the recommended dose for the expansion study based on safety, tolerability, and MTD. | At the completion of the dose-escalation phase |
| Measure | Description | Time Frame |
|---|---|---|
| Expansion and persistence of EBV TCR-T cells | To evaluate the in vivo expansion and persistence of anti-EBV TCR-T cells after infusion | From Day 1 of infusion up to 24 months |
| EBV DNA copies in peripheral blood |
| Measure | Description | Time Frame |
|---|---|---|
| Pharmacokinetic (PK) parameters | Maximum concentration (Cmax), time to maximum concentration (Tmax), and area under the curve (AUC0-28d) of anti-EBV TCR-T cells in peripheral blood. | From Day 1 to Day 28 after infusion |
| Pharmacodynamic (PD) parameters |
Inclusion Criteria:
Age 18-70 years, male or female.
HLA genotype at locus A is 11:01.
Disease diagnosis and status:
Histologically or cytologically confirmed EBV-positive lymphoma (tumor tissue must be EBER-positive as confirmed by in situ hybridization [ISH] or fluorescence in situ hybridization [FISH]), with peripheral blood EBV viral load >10³ copies/mL by quantitative real-time PCR.
Disease types include but are not limited to:
NK/T-cell lymphoma (NK/TCL); Peripheral T-cell lymphoma (PTCL); Other types.
Definition of relapse: appearance of new lesions at the primary site or other sites after achieving complete remission (CR).
Definition of refractory disease (meeting any of the following):
No partial remission (PR) after ≥4 cycles of standard therapy; No complete remission (CR) after ≥6 cycles of therapy; Failure to achieve CR after autologous hematopoietic stem cell transplantation; If best response is progressive disease (PD) or treatment is discontinued due to PD, no minimum cycle requirement applies.
Prior treatment requirements:
a) For relapsed/refractory PTCL or NK/TCL, patients must have received at least one prior line of systemic therapy. For relapsed/refractory NK/TCL, patients must have received an asparaginase-containing regimen (patients with stage I/II nasal NK/TCL according to the CA staging system must have also received radiotherapy).
Measurable disease: At least one measurable lesion according to the 2014 Lymphoma Response Evaluation Criteria:
Adequate organ function, defined as:
Expected survival >3 months.
ECOG performance status <3.
Contraception requirements:
Willingness to participate in the study, ability to sign informed consent, comply with the study protocol, and availability of peripheral venous access for lymphocyte collection.
Exclusion Criteria:
Subjects meeting any of the following conditions will not be eligible for enrollment:
History of other malignancies, except for:
Recent anti-tumor therapy: less than 4 weeks since last anti-cancer therapy (radiotherapy, chemotherapy, targeted therapy, immunotherapy, or local therapy), or less than 2 weeks since palliative radiotherapy.
Pregnant or breastfeeding women.
Presence of severe medical conditions such as intracranial hypertension, impaired consciousness, respiratory failure, or disseminated intravascular coagulation (DIC).
Severe organ dysfunction, including:
NYHA class IV cardiac function; Child-Pugh class C liver function; Creatinine clearance <60 mL/min (by Cockcroft-Gault formula); Baseline oxygen saturation <92%.
Known active infections or positive screening results for:
Active central nervous system (CNS) disease (e.g., tumor metastasis, infection, demyelinating disease), including untreated lesions, progressive disease on imaging or symptoms requiring urgent intervention, or requiring high-dose immunosuppressive therapy for control.
Receiving systemic corticosteroid therapy prior to screening and judged by the investigator to require long-term systemic corticosteroid treatment during the study (excluding inhaled or topical use); or receiving systemic corticosteroid treatment within 72 hours before cell infusion (excluding inhaled or topical use).
Presence of graft-versus-host disease (GVHD), defined as grade ≥2 acute GVHD or moderate/severe chronic GVHD, or current use of immunosuppressive therapy.
History of severe allergic reactions to drugs or excipients required in this study, or history of allergy to tocilizumab.
Any condition that, in the opinion of the investigator, makes the subject unsuitable for study participation.
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Xianmin Song, Doctor | Contact | +86 18918029692 | shongxm@139.com |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Shanghai General Hospital | Recruiting | Shanghai | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33242451 | Result | Chou CC, Tsao CF, Liao CK, You HL, Wang MC, Huang WT. Analysis of latent T-cell epitopes in Epstein-Barr virus isolated from extranodal nasal-type natural killer/T-cell lymphoma in Taiwanese population. Exp Mol Pathol. 2021 Feb;118:104577. doi: 10.1016/j.yexmp.2020.104577. Epub 2020 Nov 23. | |
| 37781191 | Result | Barros MHM, Alves PDS. Contribution of the Epstein-Barr virus to the oncogenesis of mature T-cell lymphoproliferative neoplasms. Front Oncol. 2023 Sep 14;13:1240359. doi: 10.3389/fonc.2023.1240359. eCollection 2023. |
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Using a rapid titration combined with a "3+3" design
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|
To evaluate the EBV DNA copy number in peripheral blood after infusion of anti-EBV TCR-T cells.
| From Day 1 of infusion up to 24 months |
| Changes in T-cell subsets in peripheral blood | To evaluate the changes in peripheral blood T-cell subsets after infusion of anti-EBV TCR-T cells. | From Day 1 of infusion up to 24 months |
| Objective Response Rate (ORR) | Proportion of subjects achieving complete response (CR) or partial response (PR) following treatment with anti-EBV TCR-T cells. | At 3 months and 6 months after infusion |
| Duration of Response (DOR) | Duration of response in subjects with relapsed/refractory EBV-positive lymphoma treated with anti-EBV TCR-T cells. | From the first documented response (CR or PR) until disease progression/relapse or death, up to 24 months |
| Progression-Free Survival (PFS) | Progression-free survival following anti-EBV TCR-T cell treatment. | From infusion until documented disease progression or death, up to 24 months |
| Overall Survival (OS) | Overall survival following anti-EBV TCR-T cell treatment. | From infusion until death from any cause, up to 24 months |
plasma cytokine levels at multiple time points after infusion.
| From Day 1 of infusion up to 24 months |
| 24142051 | Result | Hinrichs CS, Restifo NP. Reassessing target antigens for adoptive T-cell therapy. Nat Biotechnol. 2013 Nov;31(11):999-1008. doi: 10.1038/nbt.2725. Epub 2013 Oct 20. |
| 19880495 | Result | Heslop HE, Slobod KS, Pule MA, Hale GA, Rousseau A, Smith CA, Bollard CM, Liu H, Wu MF, Rochester RJ, Amrolia PJ, Hurwitz JL, Brenner MK, Rooney CM. Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients. Blood. 2010 Feb 4;115(5):925-35. doi: 10.1182/blood-2009-08-239186. Epub 2009 Oct 30. |
| 26353084 | Result | Okamoto A, Yanada M, Miura H, Inaguma Y, Tokuda M, Morishima S, Kanie T, Yamamoto Y, Mizuta S, Akatsuka Y, Yoshikawa T, Mizoguchi Y, Nakamura S, Okamoto M, Emi N. Prognostic significance of Epstein-Barr virus DNA detection in pretreatment serum in diffuse large B-cell lymphoma. Cancer Sci. 2015 Nov;106(11):1576-81. doi: 10.1111/cas.12812. Epub 2015 Oct 7. |
| 29920566 | Result | Gao X, Li J, Wang Y, Liu S, Yue B. Clinical characteristics and prognostic significance of EBER positivity in diffuse large B-cell lymphoma: A meta-analysis. PLoS One. 2018 Jun 19;13(6):e0199398. doi: 10.1371/journal.pone.0199398. eCollection 2018. |
| 26202875 | Result | Lu TX, Liang JH, Miao Y, Fan L, Wang L, Qu XY, Cao L, Gong QX, Wang Z, Zhang ZH, Xu W, Li JY. Epstein-Barr virus positive diffuse large B-cell lymphoma predict poor outcome, regardless of the age. Sci Rep. 2015 Jul 23;5:12168. doi: 10.1038/srep12168. |
| 26222726 | Result | Song CG, Huang JJ, Li YJ, Xia Y, Wang Y, Bi XW, Jiang WQ, Huang HQ, Lin TY, Li ZM. Epstein-Barr Virus-Positive Diffuse Large B-Cell Lymphoma in the Elderly: A Matched Case-Control Analysis. PLoS One. 2015 Jul 29;10(7):e0133973. doi: 10.1371/journal.pone.0133973. eCollection 2015. |
| 23649469 | Result | Ok CY, Papathomas TG, Medeiros LJ, Young KH. EBV-positive diffuse large B-cell lymphoma of the elderly. Blood. 2013 Jul 18;122(3):328-40. doi: 10.1182/blood-2013-03-489708. Epub 2013 May 6. |
| 26424652 | Result | Healy JA, Dave SS. The Role of EBV in the Pathogenesis of Diffuse Large B Cell Lymphoma. Curr Top Microbiol Immunol. 2015;390(Pt 1):315-37. doi: 10.1007/978-3-319-22822-8_13. |
| 27269947 | Result | Lesokhin AM, Ansell SM, Armand P, Scott EC, Halwani A, Gutierrez M, Millenson MM, Cohen AD, Schuster SJ, Lebovic D, Dhodapkar M, Avigan D, Chapuy B, Ligon AH, Freeman GJ, Rodig SJ, Cattry D, Zhu L, Grosso JF, Bradley Garelik MB, Shipp MA, Borrello I, Timmerman J. Nivolumab in Patients With Relapsed or Refractory Hematologic Malignancy: Preliminary Results of a Phase Ib Study. J Clin Oncol. 2016 Aug 10;34(23):2698-704. doi: 10.1200/JCO.2015.65.9789. Epub 2016 Jun 6. |
| 28911074 | Result | Lim SH, Hong JY, Lim ST, Hong H, Arnoud J, Zhao W, Yoon DH, Tang T, Cho J, Park S, Ko YH, Kim SJ, Suh C, Lin T, Kim WS. Beyond first-line non-anthracycline-based chemotherapy for extranodal NK/T-cell lymphoma: clinical outcome and current perspectives on salvage therapy for patients after first relapse and progression of disease. Ann Oncol. 2017 Sep 1;28(9):2199-2205. doi: 10.1093/annonc/mdx316. |
| 18042692 | Result | Grogg KL, Miller RF, Dogan A. HIV infection and lymphoma. J Clin Pathol. 2007 Dec;60(12):1365-72. doi: 10.1136/jcp.2007.051953. |
| 20671118 | Result | Fox CP, Haigh TA, Taylor GS, Long HM, Lee SP, Shannon-Lowe C, O'Connor S, Bollard CM, Iqbal J, Chan WC, Rickinson AB, Bell AI, Rowe M. A novel latent membrane 2 transcript expressed in Epstein-Barr virus-positive NK- and T-cell lymphoproliferative disease encodes a target for cellular immunotherapy. Blood. 2010 Nov 11;116(19):3695-704. doi: 10.1182/blood-2010-06-292268. Epub 2010 Jul 29. |
| 23023715 | Result | Kuppers R, Engert A, Hansmann ML. Hodgkin lymphoma. J Clin Invest. 2012 Oct;122(10):3439-47. doi: 10.1172/JCI61245. Epub 2012 Oct 1. |
| ID | Term |
|---|---|
| D054391 | Lymphoma, Extranodal NK-T-Cell |
| D016411 | Lymphoma, T-Cell, Peripheral |
| ID | Term |
|---|---|
| D016399 | Lymphoma, T-Cell |
| D008228 | Lymphoma, Non-Hodgkin |
| D008223 | Lymphoma |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D008232 | Lymphoproliferative Disorders |
| D008206 | Lymphatic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D007160 | Immunoproliferative Disorders |
| D007154 | Immune System Diseases |
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