Adoptive T Lymphocyte Administration for Chronic Norovirus Treatment in Immunocompromised Hosts

NCT04691622 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: Pro00014658
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 3

Brief Summary

This is a Phase I dose-escalation study to evaluate the safety of norovirus -specific T-cell (NST) therapy for chronic norovirus infection in participants following hematopoietic stem cell transplantation (HSCT) or who are immunocompromised due to PID and have not undergone HSCT, or Solid Organ Transplant (SOT) recipients.

Conditions

Viral Infection; Hematopoietic Stem Cell Transplantation (HSCT); Primary Immunodeficiency Disorders (PID)

Outcome Measures

Primary Outcomes (3)

• Incidence of acute GvHD (grade III-IV)

  Number of patients with acute GvHD grades III-IV

  Within 45 days of first NSTs infusion

• Incidence of infusion related adverse events as per CTCAE common criteria guidelines.

  Number of patients with Grades 3-5 infusion-related adverse events

  Within 45 days of first NSTs infusion

• Incidence of non-hematological adverse events

  Number of patients with Grades 4-5 non-hematological adverse events related to the NST product within 45 days of the first infusion

  Within 45 days of first NSTs infusion

Secondary Outcomes (1)

• Antiviral activity

  Stool viral loads will be evaluated for 12 months following the final NST infusion.

Study Arms (1)

Norovirus -specific T-cell (NST) therapy for chronic norovirus infection

EXPERIMENTAL

This is a Phase I dose-escalation study to evaluate the safety of norovirus -specific T-cell (NST) therapy for chronic norovirus infection in participants following hematopoietic stem cell transplantation (HSCT) or with primary immunodeficiency disorders (PID) who have not undergone HSCT. There are two arms in this study: 1. Arm A: Participants who receive donor-derived NST therapy after HSCT 2. Arm B: Participants who receive partially HLA matched NSTs. The following participants apply: * Participants with PID who have not undergone HSCT. * Participants who have undergone HSCT but do not have available donor derived NSTs, or those for whom NSTs cannot be generated due to norovirus seronegativity. * Participants who have undergone SOT.

Biological: Norovirus -specific T-cell (NST) therapy

Interventions

Norovirus -specific T-cell (NST) therapy BIOLOGICAL

Arm A: Investigators will test three doses: 1 x 107 /m2, 2 x 107 /m2, and 4 x 107 /m2. After infusion, participants will have a 45-day safety monitoring period for immediate toxicities following infusion. Arm B: Investigators will test three doses: 1 x 107 /m2, 2 x 107 /m2, and 4 x 107 /m2. After infusion, participants will have a 45-day safety monitoring period for immediate toxicities following infusion.

Norovirus -specific T-cell (NST) therapy for chronic norovirus infection

Eligibility Criteria

• Age: 3 Months - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must meet one of the following criteria:
• Recipient of prior myeloablative or non-myeloablative allogeneic hematopoietic stem cell transplant using either bone marrow or peripheral blood stem cells or single or double cord blood OR
• Primary immunodeficiency disorder (as defined by clinical and laboratory evaluations)81 and have not undergone HSCT, OR
• Recipients of solid organ transplant.
• Documentation of chronic norovirus infection:
• a. Chronic norovirus infections will be defined as having consecutive positive norovirus stool tests (2 or more) spanning a minimum three-month period with attributable signs and symptoms of norovirus disease.
• Participants receiving steroids for treatment of GVHD or for other reasons, dosage must have been tapered to \<0.5 mg/kg/day of prednisone (or equivalent) a minimum of 7 days prior to infusion.
• a. Treatment with enteral topical steroids such as Budesonide at standard doses may be continued if previously utilized but should not be newly initiated in the 3 months after NST therapy.
• For participants who have undergone HSCT, participants must have stable donor chimerism within the 30 days prior to NST infusion.
• a. Stability will be defined as i. \>95% donor chimerism in CD33 and/or whole blood chimerism. OR ii. \>90% donor chimerism with \<5% change between subsequent tests separated by at least 1 week.
• For recipients of solid organ transplants, participants must have stable graft function on maintenance immunosuppression, without evidence of rejection in the past 2 months prior to infusion, as defined by:
• a. Stability of relevant functional testing in the previous 2 months, defined as: i. Renal transplant: renal function ≥ grade 3 per the National Kidney Foundation K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease (2002) ii. Cardiac transplant: maintenance of LVEF \>40% iii. Lung transplant: lack of baseline oxygen requirement iv. Liver transplant: AST/ALT ≤3x upper limit normal and bilirubin ≤2x upper limit normal b. Donor-derived cell free DNA \<2x upper limits for assay in the previous 2 months, c. Stable donor-specific antibody profile in the previous 2 months. i. No increase in antibody titers between most recent testing in the previous 2 months and prior testing.
• Karnofsky/Lansky score \>50
• months to 80 years of age at enrollment.
• ANC ≥500/ul.

You may not qualify if:

• Participants receiving biological or immunosuppressive monoclonal antibodies targeting T cells within 28 days prior to NST infusion, including ATG, Alemtuzumab, Basiliximab, Tocilizumab, Brentuximab, or other medications under this category as determined by the investigators.
• a) If alemtuzumab has been received within 6 weeks prior to NST infusion, plasma levels should be obtained to ensure drug clearance (≤0.16 pg/ml).
• Participants who have received donor lymphocyte infusion (DLI), chimeric antigen receptor T cell infusion, or other experimental cellular therapies within 28 days prior to NST infusion.
• Participants with SCID who have undergone α/β TCR depleted HSCT within the past 100 days post-transplant.
• Participants who have received ruxolitinib or other JAK inhibitors within 7 days prior to NST infusion.
• Participants with uncontrolled or progressing infections other than norovirus. Uncontrolled infections are defined as bacterial, fungal, or non-targeted viral infections with either clinical signs of worsening despite standard therapy, or chronic gastrointestinal symptoms that may be attributed to the uncontrolled infection. Progressing infection is defined as hemodynamic instability, worsening physical signs, or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection.
• For bacterial infections, participants must be receiving definitive therapy and have no signs of progressing infection within 7 days prior to NST infusion and or no chronic gastrointestinal symptoms associated with this bacterial infection.
• For fungal infections, participants must be receiving definitive systemic anti-fungal therapy and have no signs of progressing infection within 7 days prior to NST infusion.
• Participants must not have other active gastrointestinal infections to which symptoms may be attributable, including parasitic infections (cryptosporidium, giardiasis), viral infections aside from norovirus (CMV colitis, rotavirus, adenovirus), or bacterial infections with C. difficile, Yersinia, Campylobacter, Salmonella, Shigella, or enteroinvasive or enterotoxigenic E. coli.
• a) Testing for unrelated gastrointestinal (GI) infections must be performed within 14 days prior to NST infusion, and must include: i. Crytosporidium/Giardia testing via antigen or PCR testing. ii. Stool viral testing for rotavirus and adenovirus via antigen or PCR testing.
• iii. Stool bacterial culture or PCR testing. iv. C. difficile toxin PCR. b) Determination of active infection versus chronic carriage/shedding will be made by the investigators and clinical providers and will depend on the presence of clinical symptoms corresponding with the timing of positive test results, presence of a clinical response to targeted therapy, and by histological or other testing if clinically indicated.
• Participants with active and uncontrolled relapse of malignancy (if applicable).
• Failure of primary engraftment is defined as failure to achieve platelet and/or neutrophil engraftment (ANC \<500/ul and/or platelets \<20 K/ul) following HSCT.
• Secondary graft failure is defined as \<5% donor chimerism (CD3+ or CD34+) or permanent loss of neutrophil and/or platelet engraftment (ANC \<500/ul and/or platelets \<20 K/ul) at any time after primary engraftment.
• Participants with symptomatic gastrointestinal conditions aside from norovirus, including active inflammatory bowel disease or graft versus host disease (grades 2 to 4).

Sponsors & Collaborators

• Children's National Research Institute: lead

Study Sites (3)

Children's National Hospital

Washington D.C., District of Columbia, 20010, United States

RECRUITING

Johns Hopkins University

Baltimore, Maryland, 21287, United States

RECRUITING

National Institutes of Health (NIH)

Bethesda, Maryland, 20892, United States

RECRUITING

MeSH Terms

Conditions

Virus Diseases; Primary Immunodeficiency Diseases

Interventions

Therapeutics

Condition Hierarchy (Ancestors)

Infections; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Immunologic Deficiency Syndromes; Immune System Diseases

Study Officials

• Michael Keller, MD

  CNH

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Michael Keller, MD

CONTACT

202-476-5843; MKeller@childrensnational.org

Fahmida Hoq, MBBS, MS

CONTACT

202-476-3634; fhoq@childrensnational.org

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: December 28, 2020
• First Posted: December 31, 2020
• Study Start: March 17, 2022
• Primary Completion (Estimated): August 30, 2028
• Study Completion (Estimated): October 30, 2028
• Last Updated: January 26, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)