Evaluation of the Safety and Efficacy of LB-DTK-MV in Patients Diagnosed With Antiviral-Resistant CMV, BKV, or EBV Infection or Associated Diseases Following Anticancer Therapy or Allogeneic Hematopoietic Stem Cell Transplantation.

A Single-Center, Open-Label, Phase 1/2 Clinical Trial to Evaluate the Safety and Efficacy of LB-DTK-MV in Patients Diagnosed With Antiviral-Resistant CMV, BKV, or EBV Infection or Associated Diseases Following Anticancer Therapy or Allogeneic Hematopoietic Stem Cell Transplantation.

The goal of this clinical trial is to evaluate the efficacy and safety of Multi-Virus Specific T cells (LB-DTK-MV) to treat patients diagnosed with antiviral-resistant CMV, BKV, or EBV infection or associated diseases after anticancer therapy or allogeneic hematopoietic stem cell transplantation (allo-HSCT). The main questions it aims to answer are:

• What is the maximum tolerated dose of LB-DTK-MV based on dose-limiting toxicity?
• Does the number of CMV, BKV, or EBV virus viral load decrease within 7 or 14 days after the second infusion of LB-DTK-MV?
• Do treatment emergent adverse events occur after the second infusion?

Participants will:

• Receive a single intravenous infusion of LB-DTK-MV during the baseline visit (low dose: 1x10^7/m^2; high dose: 2x10^7/m^2).
• Receive the second infusion of LB-DTK-MV intravenously at the same dose 14 days after the first infusion.
• Attend weekly follow-up visits at the clinic for 6 months after the first dose.

Inclusion Criteria:

1. Patients aged 19 years or older who have undergone myeloablative or non-myeloablative allogeneic hematopoietic stem cell transplantation using bone marrow, single or double umbilical cord blood, or peripheral blood stem cells (PBSCs). Or patients who have undergone any of the following anticancer treatments:

   • CAR-T: Kymriah, Yescarta
   • Bispecific Antibody: Glofitamab, Mosunetuzumab, Teclistamab, Elranatamab, etc

2. Patients diagnosed with single or multiple, antiviral-resistant CMV, BKV, and/or EBV despite receiving standard treatment.

3. Patients who are able to reduce their steroid dosage to 0.5mg/kg/day of Prednisolone (or an equivalent dose) or less.

4. Patients with a hemoglobin level ≥8.0g/dL.

5. Patients with evidence of neutrophil engraftment, defined as an absolute neutrophil count (ANC) maintained at 0.5x10^3/μL or higher for 3 consecutive days following allogeneic hematopoietic stem cell transplantation.

6. Patients with peripheral oxygen saturation (SpO2) ≥90% on room air.

7. Patients who have at least one MHC class I HLA allele that matches the investigational product.

8. For women of childbearing potential, those who tested negative on a pregnancy test (blood test) performed on the screening visit.

9. Female subjects or male subjects with female partners who agree to use the following contraceptive methods during the duration of this clinical trial and who meet the following criteria:

   • Female participants or male participants with female partners who are postmenopausal (diagnosed with non-therapy-induced amenorrhea for 12 months or more or menopause)

   • Female subjects or the female partners of male subjects who are surgically sterile (i.e., lacking ovaries and/or a uterus)

   • Individuals who have agreed to strict abstinence during the clinical trial period [For female participants, intermittent abstinence (e.g., withdrawal during ovulation, the basal body temperature method, or withdrawal after ovulation) does not constitute agreement to abstinence]

   • If the female subject or the female partner of a male subject is a woman of childbearing potential (WOCBP) who has not undergone sterilization, those who meet the following criteria:

     • Hormonal contraceptives (implant, patch, oral)
     • Intrauterine devices
     • Dual barrier method (simultaneous use of the following two contraceptive methods: male condoms, female condoms, cervical caps, contraceptive diaphragms, contraceptive sponges)

10. Individuals who have voluntarily decided to participate in this clinical trial and have provided written consent to comply with the restrictions.

11. Individuals deemed suitable as trial subjects through screening tests (vital signs, physical examination, medical and surgical history, electrocardiogram, laboratory tests, etc.).

Exclusion Criteria:

1. Individuals who have received treatment with ATG (Antithymocyte Globulin), Campath (Alemtuzumab), or other T-cell immunosuppressive monoclonal antibodies within 28 days prior to the first dose.

2. Individuals who meet any of the following criteria at the time of screening:

   • Uncontrolled hypertension

     • Systolic BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg despite taking antihypertensive medication.

   • Uncontrolled diabetes: Severe diabetes is defined as follows:

     • Severe hyperglycemia with HbA1C ≥ 10.0%
     • Individuals who have been hospitalized for diabetic ketoacidosis within the past 12 weeks.
     • Individuals who have received emergency treatment or been hospitalized within the past 12 weeks for severe hypoglycemia (glucose <54 mg/dL) accompanied by seizures and loss of consciousness.

   • Other viral infections [Ex. Human Immunodeficiency Virus(HIV), Hepatitis B Virus(HBV), Hepatitis C Virus(HCV)]. However, patients who are tested negative for HBsAg and positive for anti-HBcAb are not subject to this exclusion criterion.

   • Tuberculosis

   • Syphilis

   • Moderate or severe liver damage [Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) > 5 times the upper limit of normal (ULN)]

   • Chronic kidney disease [eGFR < 30mL/min/1.73m^2]

   • Patients with other uncontrolled infections. However, the following cases are considered controlled infections and do not meet the exclusion criteria:

     • Bacterial infection. Patients must be undergoing definitive antibiotic treatment for the infection and must have shown no signs of progression of the infection for 72 hours prior to enrollment in this clinical trial.
     • Fungal infection. The patient must be receiving systemic antifungal therapy and must have shown no signs of infection progression for 1 week prior to enrollment in this clinical trial.

3. Patients who have undergone allogeneic hematopoietic stem cell transplantation within 28 days prior to the scheduled first dose, or who have received donor lymphocyte infusion (DLI) within 28 days prior to enrollment in this clinical trial.

4. Patients with active acute graft-versus-host disease (GvHD) of grade 2 or higher.

5. Patients requiring urgent anticancer therapy due to rapid tumor progression.

6. Patients with a history of substance abuse within 24 weeks prior to administration of the investigational drug, or patients suspected of taking drugs of concern based on medical history and physical examination.

7. Patients requiring vasopressors.

8. Patients who have previously shown hypersensitivity to T-cell therapy.

9. Patients with a history of autoimmune disease.

10. Patients with hemophilia who are at risk of severe bleeding during administration, or patients receiving anticoagulants.

11. Patients who have received another virus-specific T cell product within 28 days prior to administration of the investigational drug.

12. Patients with a life expectancy of less than 24 hours at the time of the screening visit.

13. Patients aged under 19.

14. Patients deemed ineligible for participation in this clinical trial by the investigator.