Evaluation of Safety and Efficacy of Autologous LB-DTK-CMV in Patients With Antiviral-Resistant and Refractory Cytomegalovirus Retinitis.

Official title

An Exploratory Clinical Study of Autologous LB-DTK-CMV in Patients With Antiviral-Resistant and Refractory Cytomegalovirus Retinitis.

Overview

The goal of this exploratory clinical study is to evaluate the safety and efficacy of Cytomegalovirus-Specific T cells (LB-DTK-CMV) to treat patients diagnosed with antiviral-resistant and refractory cytomegalovirus retinitis. The main questions it aims to answer are: * What adverse events occur after the infusion of LB-DTK-CMV? * What is the duration of efficacy following treatment? * Is there a clinically significant reduction in CMV viral load in plasma and aqueous humor after the infusion? * Is there a clinically significant improvement in clinical symptoms after the infusion? Participants will: * Receive two infusions of LB-DTK-CMV at 2x10\^7cells/m\^2 at two-week intervals beginning at the baseline visit (Cycle 1). * Take a three-week resting period following completion of Cycle 1. * Receive two infusions of LB-DTK-CMV at 2x10\^7cells/m\^2 at two-week intervals beginning three weeks after the last dose of Cycle 1 (Cycle 2).

Interventions

• Biological LB-DTK-CMV
  LB-DTK-CMV is a CMV-specific T cell therapy product derived from a patient (autologous) and is stored frozen in a colorless, transparent freeze-dried vial until thawed into liquid before administration.

Primary outcome measures

• Viral Load [Time frame: From screening through 24 weeks after treatment initiation]
• Clinical Symptom Assessment [Time frame: From the screening through 24 weeks after treatment initiation.]
• Immunogenicity Testing [Time frame: From the screening through 24 weeks after treatment initiation.]
• Adverse Events [Time frame: From the baseline visit throughout 24 weeks after treatment initiation.]

Eligibility criteria

Inclusion criteria

• Patients aged 19 years or older who have been diagnosed with CMV retinitis and have undergone hematopoietic stem cell transplantation or solid organ transplantation for the treatment of hematologic malignancies, or have received high-dose immunosuppressive therapy for the treatment of autoimmune diseases, and who meet at least one of the following criteria:

• Patients with persistent or progressive CMV retinitis despite systemic antiviral therapy or intravitreal antiviral treatment.
• Patients who have showed persistent CMV viremia despite systemic antiviral therapy or developed new CMV retinitis.
• Patients with CMV UL54 or UL97 mutations associated with antiviral resistance.
• Patients with adverse effects or toxicities limiting the administration of more than one systemic antiviral drug.
• Patients who are pregnant and able to reduce their steroid dosage to 0.5mg/kg/day of Prednisolone (or an equivalent dose) or less.
• For women of childbearing potential, those who tested negative on a pregnancy test (blood test) performed on the screening visit.
• Individuals who have voluntarily decided to participate in this clinical study and have provided written consent to comply with the restrictions.
• 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.
• 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 severe 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

• 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 Alanin aminotransferase (ALT) > 5 times the upper limit of normal (ULN)
• Chronic kidney disease

• eGFR < 30mL/min/1.73m\^2
• 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 study.
• Fungal infection: Patients must be receiving systemic antifungal therapy and must have shown no signs of infection progression for 1 week prior to enrollment in this clinical study.
• Patients who have received donor lymphocyte infusion (DLI) within 28 days prior to the scheduled first dose.
• Patients with active malignant tumor or uncontrolled recurrence.
• Patients with uncontrolled ophthalmic diseases other than CMV retinitis.
• Female subjects who are pregnant, breastfeeding, of childbearing potential, or not using appropriate contraceptive methods.
• Patients with a life expectancy of less than 24 hours at the time of the screening visit.
• Patients who have received an investigational product from another clinical study within 24 weeks prior to administration of the investigational product in this study.
• 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

• Sugar EA, Jabs DA, Ahuja A, Thorne JE, Danis RP, Meinert CL; Studies of the Ocular Complications of AIDS Research Group. Incidence of cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Am J Ophthalmol. 2012 Jun;153(6):1016-24.e5. doi: 10.1016/j.ajo.2011.11.014. Epub 2012 Feb 4. PMID 22310076
• Shamim MM, U.S., Characteristics and Management of Drug-Resistant CMV Retinitis.Ophthalmic Pearls, 2022.
• Royston L, Papanicolaou GA, Neofytos D. Refractory/Resistant Cytomegalovirus Infection in Transplant Recipients: An Update. Viruses. 2024 Jul 5;16(7):1085. doi: 10.3390/v16071085. PMID 39066247
• Jabs DA, Enger C, Dunn JP, Forman M. Cytomegalovirus retinitis and viral resistance: ganciclovir resistance. CMV Retinitis and Viral Resistance Study Group. J Infect Dis. 1998 Mar;177(3):770-3. doi: 10.1086/514249. PMID 9498461
• Simmons HZ, Bazzell AF, Dains JE. Adverse Effects of Virus-Specific T-Cell Therapy: An Integrative Review. J Adv Pract Oncol. 2019 Mar;10(2):120-131. Epub 2019 Mar 1. PMID 31538024
• Cruz CR, Hanley PJ, Liu H, Torrano V, Lin YF, Arce JA, Gottschalk S, Savoldo B, Dotti G, Louis CU, Leen AM, Gee AP, Rooney CM, Brenner MK, Bollard CM, Heslop HE. Adverse events following infusion of T cells for adoptive immunotherapy: a 10-year experience. Cytotherapy. 2010 Oct;12(6):743-9. doi: 10.3109/14653241003709686. PMID 20429793
• Khoury R, Grimley MS, Nelson AS, Leemhuis T, Cancelas JA, Cook E, Wang Y, Heyenbruch D, Bollard CM, Keller MD, Hanley PJ, Lutzko C, Pham G, Davies SM, Rubinstein JD. Third-party virus-specific T cells for the treatment of double-stranded DNA viral reactivation and posttransplant lymphoproliferative disease after solid organ transplant. Am J Transplant. 2024 Sep;24(9):1634-1643. doi: 10.1016/j.ajt. PMID 38643944
• Tzannou I, Papadopoulou A, Naik S, Leung K, Martinez CA, Ramos CA, Carrum G, Sasa G, Lulla P, Watanabe A, Kuvalekar M, Gee AP, Wu MF, Liu H, Grilley BJ, Krance RA, Gottschalk S, Brenner MK, Rooney CM, Heslop HE, Leen AM, Omer B. Off-the-Shelf Virus-Specific T Cells to Treat BK Virus, Human Herpesvirus 6, Cytomegalovirus, Epstein-Barr Virus, and Adenovirus Infections After Allogeneic Hematopoietic PMID 28783452

Identifiers

NCT: NCT07679412 · LB-AT-DTK-CMV-RT-AD-CR

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗