Evaluation of Safety and Efficacy of Virus Specific T-Cell Administration in Pediatric Patients With Systemic Viral Infection Following Allogeneic Hematopoietic Stem Cell Transplantation.

Official title

A Prospective Clinical Study to Evaluate the Safety and Efficacy of Virus Specific T-Cell Administration in Pediatric Patients With Systemic Viral Infection Following Allogeneic Hematopoietic Stem Cell Transplantation.

Overview

The goal of this prospective clinical study is to evaluate the safety and efficacy of Multi-Virus Specific T cells (LB-DTK-MV) in pediatric patients with systemic viral infection, including CMV, EBV, and BKV, after 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? * What treatment emergent adverse events occur within 14 days after the second infusion? * Is there a clinically significant reduction in CMV, EBV, and BKV viral loads within 14 days following the second infusion? * Is there a clinically significant improvement in clinical symptoms within 14 days following 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 infusion.

Interventions

• Biological LB-DTK-MV
  LB-DTK-MV is a virus-specific T cell therapy product derived from a designated donor and is stored frozen in a colorless, transparent freeze-dried vial until thawed into liquid before administration. Study participants will receive a single intravenous infusion of the assigned cell dose (low dose: 1x10\^7/m\^2;high dose: 2x10\^7/m\^2) of LB-DTK-MV on Visit 2 and 14 days after the initial infusion.

Primary outcome measures

• Viral Load [Time frame: From enrollment through 24 weeks after treatment initiation]
• Immunogenicity Testing [Time frame: From enrollment through 24 weeks after treatment initiation.]
• Adverse Events [Time frame: From the baseline visit through 24 weeks after treatment initiation.]

Eligibility criteria

Inclusion criteria

• Patients with CMV, EBV, and/or BKV infection that is resistant or refractory to standard-of-care treatment and associated with severe complications following allogeneic hematopoietic stem cell transplantation at the ages of 1-25 years.
• 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.
• Patients who have undergone allogeneic hematopoietic stem cell transplantation at least 21 days prior to the screening visit.
• Patients who show complete donor chimerism (PCR-short tandem repeats ≥ 95%) at the time of first dose administration.
• Patients who are able to reduce their steroid dosage to 0.5mg/kg/day of Prednisolone (or an equivalent dose) or less.
• Individuals who have voluntarily decided to participate in this clinical study and have provided written consent to comply with the restrictions.
• For women of childbearing potential, those who tested negative on a pregnancy test (blood test) performed on the screening visit.
• Individuals deemed suitable as study subjects through screening tests (vital signs, physical examination, medical and surgical history, electrocardiogram, laboratory tests, etc.).

Exclusion criteria

• 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.
• Patients with organ failures and/or uncontrolled bacterial or fungal infections.

• 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 who have undergone allogeneic hematopoietic stem cell transplantation or received donor lymphocyte infusion (DLI) within 28 days prior to the scheduled first dose.
• Patients with active graft-versus-host disease (GvHD) of grade 2 or higher.
• Patients with active malignant tumor or uncontrolled recurrence.
• Patients deemed ineligible for participation in this clinical study by the investigator.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

South Korea · 1 center

• The Catholic University of Korea Seoul St.Mary's Hospital — Seoul

Publications

• Jahangiri, V., et al., Post Transplantation Cyclophosphamide (PTCY) Is Associated with Increased Risk of BK Virus-Associated Hemorrhagic Cystitis (BKHC) in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplant (HSCT).Biology of Blood and Marrow Transplantation, 2019. 25(3): p. S359-S360.
• Melenhorst JJ, Leen AM, Bollard CM, Quigley MF, Price DA, Rooney CM, Brenner MK, Barrett AJ, Heslop HE. Allogeneic virus-specific T cells with HLA alloreactivity do not produce GVHD in human subjects. Blood. 2010 Nov 25;116(22):4700-2. doi: 10.1182/blood-2010-06-289991. Epub 2010 Aug 13. PMID 20709906
• Martits-Chalangari K, Spak CW, Askar M, Killian A, Fisher TL, Atillasoy E, Marshall WL, McNeel D, Miller MD, Mathai SK, Gottlieb RL. ALVR109, an off-the-shelf partially HLA matched SARS-CoV-2-specific T cell therapy, to treat refractory severe COVID-19 pneumonia in a heart transplant patient: Case report. Am J Transplant. 2022 Apr;22(4):1261-1265. doi: 10.1111/ajt.16927. Epub 2021 Dec 27. PMID 34910857
• Neller MA, Ambalathingal GR, Hamad N, Sasadeusz J, Pearson R, Holmes-Liew CL, Singhal D, Tunbridge M, Ng WY, Sharplin K, Moore A, Deambrosis D, Soosay-Raj T, McNaughton P, Whyte M, Fraser C, Grigg A, Kliman D, Bajel A, Cummins K, Dowling M, Yeoh ZH, Harrison SJ, Khot A, Tan S, Roos I, Koo RM, Dohrmann S, Ritchie D, Wainstein B, McCleary K, Nelson A, Gardiner B, Inam S, Badoux X, Ma K, Toro C, Hann PMID 39627190
• Liu J, Chang YJ, Yan CH, Xu LP, Jiang ZF, Zhang XH, Liu KY, Huang XJ. Poor CMV-specific CD8+ T central memory subset recovery at early stage post-HSCT associates with refractory and recurrent CMV reactivation. J Infect. 2016 Sep;73(3):261-70. doi: 10.1016/j.jinf.2016.04.033. Epub 2016 Jun 14. PMID 27311748
• Li CR, Greenberg PD, Gilbert MJ, Goodrich JM, Riddell SR. Recovery of HLA-restricted cytomegalovirus (CMV)-specific T-cell responses after allogeneic bone marrow transplant: correlation with CMV disease and effect of ganciclovir prophylaxis. Blood. 1994 Apr 1;83(7):1971-9. PMID 8142663
• Hakki M, Riddell SR, Storek J, Carter RA, Stevens-Ayers T, Sudour P, White K, Corey L, Boeckh M. Immune reconstitution to cytomegalovirus after allogeneic hematopoietic stem cell transplantation: impact of host factors, drug therapy, and subclinical reactivation. Blood. 2003 Oct 15;102(8):3060-7. doi: 10.1182/blood-2002-11-3472. Epub 2003 Jul 3. PMID 12843000
• Gratama JW, van Esser JW, Lamers CH, Tournay C, Lowenberg B, Bolhuis RL, Cornelissen JJ. Tetramer-based quantification of cytomegalovirus (CMV)-specific CD8+ T lymphocytes in T-cell-depleted stem cell grafts and after transplantation may identify patients at risk for progressive CMV infection. Blood. 2001 Sep 1;98(5):1358-64. doi: 10.1182/blood.v98.5.1358. PMID 11520783

Identifiers

NCT: NCT07685457 · LB-DD-DTK-MV-HS-PD-CR

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗