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

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

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.

Inclusion Criteria:

1. Age 18-70 years, male or female.

2. HLA genotype at locus A is 11:01.

3. Disease diagnosis and status:

   1. 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.

   2. Disease types include but are not limited to:

      NK/T-cell lymphoma (NK/TCL); Peripheral T-cell lymphoma (PTCL); Other types.

   3. Definition of relapse: appearance of new lesions at the primary site or other sites after achieving complete remission (CR).

   4. 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.

4. 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).

5. Measurable disease: At least one measurable lesion according to the 2014 Lymphoma Response Evaluation Criteria:

   1. Nodal lesions: longest diameter >15 mm on contrast-enhanced CT, MRI, or PET-CT;
   2. 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.

6. Adequate organ function, defined as:

   1. Hematologic: absolute neutrophil count ≥1×10⁹/L; hemoglobin ≥70 g/L; platelet count ≥50×10⁹/L;
   2. 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);
   3. Renal: serum creatinine ≤1.5× ULN;
   4. Cardiac: left ventricular ejection fraction (LVEF) ≥50%;
   5. Coagulation: fibrinogen ≥1.0 g/L; activated partial thromboplastin time (APTT) ≤1.5× ULN; prothrombin time (PT) ≤1.5× ULN.

7. Expected survival >3 months.

8. ECOG performance status <3.

9. Contraception requirements:

   1. No pregnancy planned during the treatment period;
   2. 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.

10. 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:

1. History of other malignancies, except for:

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

2. 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.

3. Pregnant or breastfeeding women.

4. Presence of severe medical conditions such as intracranial hypertension, impaired consciousness, respiratory failure, or disseminated intravascular coagulation (DIC).

5. 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%.

6. Known active infections or positive screening results for:

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

7. 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.

8. 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).

9. Presence of graft-versus-host disease (GVHD), defined as grade ≥2 acute GVHD or moderate/severe chronic GVHD, or current use of immunosuppressive therapy.

10. History of severe allergic reactions to drugs or excipients required in this study, or history of allergy to tocilizumab.

11. Any condition that, in the opinion of the investigator, makes the subject unsuitable for study participation.