Safety and Efficacy of Anti-EBV Autologous TCR-T Cell Injection in Relapsed/Refractory EBV-Positive Lymphoma

Официальное название

The Safety and Efficacy of Anti-EBV Autologous TCR-T Cell Injection for Treating Relapsed/Refractory EBV-positive Lymphoma Patients With HLA-A11:01

Обзор

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.

Вмешательства

• Препарат EBV TCR-T
  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-

Первичные конечные точки

• Dose-Limiting Toxicity (DLT) [Срок оценки: treatment cycle (Day 1 to Day 28)]
• Maximum Tolerated Dose (MTD) [Срок оценки: From Day 1 of treatment until the end of the dose-escalation phase]
• Recommended Phase 2 Dose (RP2D) [Срок оценки: At the completion of the dose-escalation phase]

Вторичные конечные точки (7)

• Expansion and persistence of EBV TCR-T cells [Срок оценки: From Day 1 of infusion up to 24 months]
• EBV DNA copies in peripheral blood [Срок оценки: From Day 1 of infusion up to 24 months]
• Changes in T-cell subsets in peripheral blood [Срок оценки: From Day 1 of infusion up to 24 months]
• Objective Response Rate (ORR) [Срок оценки: At 3 months and 6 months after infusion]
• Duration of Response (DOR) [Срок оценки: From the first documented response (CR or PR) until disease progression/relapse or death, up to 24 months]
• Progression-Free Survival (PFS) [Срок оценки: From infusion until documented disease progression or death, up to 24 months]
• Overall Survival (OS) [Срок оценки: From infusion until death from any cause, up to 24 months]

Критерии участия

Критерии включения

• 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:

• Nodal lesions: longest diameter >15 mm on contrast-enhanced CT, MRI, or PET-CT;
• Extranodal lesions: longest diameter >10 mm. For patients with bone-marrow-only involvement who have no measurable lesions on imaging, the presence of ≥5% lymphoma cells in bone marrow biopsy or flow cytometry can be considered an evaluable lesion.
• Adequate organ function, defined as:

• Hematologic: absolute neutrophil count ≥1×10⁹/L; hemoglobin ≥70 g/L; platelet count ≥50×10⁹/L;
• Hepatic: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × the upper limit of normal (ULN), and total bilirubin (TBIL) ≤ 1.5 × ULN (except when liver function abnormalities are attributable to the underlying disease);
• Renal: serum creatinine ≤1.5× ULN;
• Cardiac: left ventricular ejection fraction (LVEF) ≥50%;
• Coagulation: fibrinogen ≥1.0 g/L; activated partial thromboplastin time (APTT) ≤1.5× ULN; prothrombin time (PT) ≤1.5× ULN.
• Expected survival >3 months.
• ECOG performance status <3.
• Contraception requirements:

• No pregnancy planned during the treatment period;
• Women of childbearing potential must have a negative pregnancy test and agree to use effective contraception during the study and for 4 months after the end of treatment.
• 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.

Критерии исключения

Subjects meeting any of the following conditions will not be eligible for enrollment:

• History of other malignancies, except for:

• Basal cell carcinoma of the skin;
• Squamous cell carcinoma of the skin;
• Superficial bladder cancer;
• Carcinoma in situ of the cervix;
• Gastrointestinal mucosal carcinoma in situ;
• Other malignancies considered acceptable by the investigator (must have received curative treatment with no recurrence within the past 5 years).
• 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:

• Hepatitis B virus (HBV): HBsAg positive, or HBcAb positive with HBV-DNA above the detection limit of the study center;
• Hepatitis C virus (HCV): HCV antibody positive and HCV RNA ≥ upper limit of normal (ULN);
• Human immunodeficiency virus (HIV) or Treponema pallidum (syphilis) antibody positive;
• Active tuberculosis (TB) (must be excluded by chest X-ray, sputum test, and clinical symptoms) or history of active TB;
• Severe acute or chronic infections requiring systemic treatment.
• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Shanghai General Hospital — Шанхай

Публикации

• 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. PMID 33242451
• 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. PMID 37781191
• 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. PMID 24142051
• 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. PMID 19880495
• 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. PMID 26353084
• 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. PMID 29920566
• 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. PMID 26202875
• 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. PMID 26222726

Идентификаторы

NCT: NCT07162012 · SHSYXY-EBV-TCR-T-202505

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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