Adoptive T Lymphocyte Administration for Chronic Norovirus Treatment in Immunocompromised Hosts (ATLANTIC)

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.

Study Overview

• Status: Recruiting
• Conditions: Viral Infection; Hematopoietic Stem Cell Transplantation (HSCT); Primary Immunodeficiency Disorders (PID)
• Intervention / Treatment: Biological: Norovirus -specific T-cell (NST) therapy

Detailed Description

This is an open label, phase I study of norovirus-specific T-cell immunotherapy for treatment of participants with primary immunodeficiency disorders (PID) and chronic norovirus. This study is designed to assess the safety of norovirus-specific T-cell (NST) infusion in this population. 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 undergo HSCT but do not have available donor derived NSTs
   • Participants who have donors from whom NSTs cannot be generated due to norovirus seronegativity Participants will be monitored for infusion-related reactions and GVHD for 1 year following first infusion. During this time, participants will be accessed with regard to the length and quantity of norovirus shedding in stool, and gastrointestinal and constitutional symptoms will be scored by clinicians and participants. Correlative studies of T-cell immune reconstitution against norovirus, norovirus genomic sequences, and composition of the fecal microbiome will also be accessed.

The primary purpose of this phase I study is to assess the safety of administering donor-derived or partially HLA-matched NSTs in immunocompromised participants with chronic norovirus infections. Related and unrelated donors of participants who have chronic norovirus infection after HSCT will be enrolled for screening and production of NSTs from peripheral blood. Following product manufacturing, participants who have undergone HSCT (Arm A) will receive donor-derived NSTs. For participants with PID who have not undergone HSCT (Arm B), high-resolution HLA typing of the participant will be utilized for an inquiry of the NST bank to determine if a partially HLA-matched NST product exists that has antiviral activity mediated through one or more shared HLA alleles. Participants who have undergone HSCT but either do not have available donors for NST generation, or who have donors from whom NSTs cannot be generated due to norovirus seronegativity will also be eligible for inquiry for treatment with partially HLA-matched NSTs if available under study Arm B.

This will be a dose escalation study with two arms. Participants who have undergone HSCT will be enrolled on Arm A and receive NSTs derived from their HSCT donor. Participants with a diagnosis of PID who have not undergone HSCT, or participants who have undergone HSCT but do not have available donor-derived NSTs will be enrolled on Arm B and receive partially-HLA matched NSTs. Investigators will test three doses: 1 x 10^7 /m^2, 2 x 10^7 /m^2, and 4 x 10^7 /m^2. Investigators will have a 45-day safety monitoring period for immediate toxicities following infusion.

• Study Type: Interventional
• Enrollment (Estimated): 48
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Michael Keller, MD; Phone Number: 202-476-5843; Email: mkeller@childrensnational.org
• Study Contact Backup: Name: Fahmida Hoq, MBBS, MS; Phone Number: 202-476-3634; Email: fhoq@childrensnational.org

Study Locations

• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Recruiting
      • Children's National Hospital
      • Contact: Michael Keller, MD; Phone Number: 202-476-5843; Email: mkeller@childrensnational.org
      • Contact: Fahmida Hoq, MBBS, MS; Phone Number: 202-476-3634; Email: fhoq@childrensnational.org
      • Principal Investigator: Michael Keller, MD
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health (NIH)
      • Contact: Alison Han, MD; Phone Number: 301-480-5722; Email: alison.han@nih.gov
      • Principal Investigator: Alison Han, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 months to 80 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Participant Inclusion Criteria for NST Infusion:

1. Participants must meet one of the following criteria:

   1. Recipient of prior myeloablative or non-myeloablative allogeneic hematopoieic stem cell transplant using either bone marrow or peripheral blood stem cells or single or double cord blood, OR
   2. Primary immunodeficiency disorder (as defined by clinical and laboratory evaluations) and have not undergone HSCT.

2. 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.

3. 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.

4. For participants who have undergone HSCT, participants must have stable donor chimerism at the time of 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.

5. Karnofsky/Lansky score > 50
6. 3 months to 80 years of age at enrollment
7. ANC ≥ 500/ul
8. Hemoglobin ≥ 7.0g/dl (level can be achieved with transfusion)
9. Platelets ≥ 20 K/ul (level can be achieved with transfusion)
10. Bilirubin < 2x upper limit normal
11. AST < 3x upper limit normal
12. Serum creatinine < 2x upper limit normal
13. Pulse oximetry of ≥ 90% on room air
14. Negative pregnancy test in female participant of childbearing age.
15. Written informed consent and/or signed assent line from participant, parent or guardian.

Donor Inclusion Criteria:

1. Donors who have fulfilled eligibility as per FDA regulations outlined in 21 CFR 1271 subpart C. This includes that donors have been deemed in good health by donor physician based on physical examination and laboratory testing. If a donor has been chosen for the transplant based on urgent medical need that same donor will also be used for NST generation provided that there are no new reasons for ineligibility since the stem cell collection.
2. Be between 2 to 35 years of age (females) or 2 to 40 years of age (males)
3. Donor or guardian of pediatric donor capable of providing informed consent

4. Donor must have completed infectious Disease (ID) testing up to 7 days before or after the collection of blood from the donor (related or unrelated) for TAA-T manufacturing. The following tests will be performed:

   • AbO/Rh
   • HBsAg
   • HB Core antibody
   • HIV1/2 NAT
   • Syphilis (T. Pallidum IgG)
   • HTLV I/II
   • CMV total
   • HBV/HCV NAT
   • West Nile Virus NAT.
   • Cruz (Chagas) antibody
   • Hepatitis C
5. Female donors of childbearing age must have a negative pregnancy test and not be lactating.

Exclusion Criteria:

Participants Exclusion Criteria for NST Infusion:

1. Participants receiving biological or immunosuppressive monoclonal antibodies targeting T-cells within 28 days prior to NST infusion, including ATG, Alemtuzumab, Basiliximab, Tociluzimab, 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).

2. 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.
3. Participants with SCID who undergone alpha/BetaTCR depleted HSCT within the past 100 days.
4. Participants who have received ruxolitinib or other JAK inhibitors within 7 days prior to NST infusion.

5. 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.

   1. 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.
   2. 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.

6. 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 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 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.

7. Participants with active and uncontrolled relapse of malignancy (if applicable).

   1. 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.
   2. 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.
8. Participants with symptomatic gastrointestinal conditions aside from norovirus, including active inflammatory bowel disease or graft versus host disease (grade II-IV).
9. Participants receiving checkpoint inhibitors within the previous 3 months prior to NST infusion, including nivolumimab, pembroluzimab, or other related medications.
10. Participants receiving oral immunoglobulin, nitazoxanide, or other experimental therapies for norovirus infection within 28 days prior to NST infusion.

Donor Exclusion Criteria:

1. Donation of cells would pose a physical or psychological risk to the donor

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Norovirus -specific T-cell (NST) therapy for chronic norovirus infection; 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: Arm A: Participants who receive donor-derived NST therapy after HSCT; Arm B: Participants who receive partially HLA matched NSTs. The following participants apply:Participants with PID who have not undergone HSCTParticipants who undergo HSCT but do not have available donor derived NSTsParticipants who have donors from whom NSTs cannot be generated due to norovirus seronegativity

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Antiviral activity	Antiviral activity will determined by measurements in viral loads by RT-PCR from stool samples in comparison to the mean baseline viral load.	Stool viral loads will be evaluated for 12 months following the final NST infusion.

Collaborators and Investigators

• Sponsor: Children's National Research Institute
• Investigators: Principal Investigator: Michael Keller, MD, CNH

Study record dates

Study Major Dates

• Study Start (Actual): March 17, 2022
• Primary Completion (Estimated): August 30, 2025
• Study Completion (Estimated): October 30, 2026

Study Registration Dates

• First Submitted: December 28, 2020
• First Submitted That Met QC Criteria: December 28, 2020
• First Posted (Actual): December 31, 2020

Study Record Updates

• Last Update Posted (Estimated): February 29, 2024
• Last Update Submitted That Met QC Criteria: February 28, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Immune System Diseases; Genetic Diseases, Inborn; Virus Diseases; Immunologic Deficiency Syndromes; Primary Immunodeficiency Diseases
• Other Study ID Numbers: Pro00014658

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Data will be made available via publication. All raw data, methodologies and statistical analyses will also be made available upon publication.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No