Hematopoietic Stem Cell Transplantation (HSCT), Primary Immunodeficiency Disorders (PID), Viral Infection
Conditions
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.
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 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. 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 or recipients of SOT (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, recipients of SOT, 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. We will test three doses: 1x107 /m2, 2x107 /m2, and 4x107 /m2. Investigators will have a 45-day safety monitoring period for immediate toxicities following infusion.
Interventions
BIOLOGICALNorovirus -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.
Sponsors
Children's National Research Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Months to 80 Years
Healthy volunteers
No
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 hematopoietic 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)81 and have not undergone HSCT, OR 3. Recipients of solid organ transplant. 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 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. 5. 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. 6. Karnofsky/Lansky score \>50 7. 3 months to 80 years of age at enrollment. 8. ANC ≥500/ul. 9. Hemoglobin ≥7.0g/dl (level can be achieved with transfusion). 10. Platelets ≥20 K/ul (level can be achieved with transfusion). 11. Bilirubin ≤2x upper limit normal. 12. AST ≤3x upper limit normal. 13. Serum creatinine ≤2x upper limit normal OR estimated GFR ≥30 ml/hr. 14. Pulse oximetry of ≥90% on room air. 15. Negative pregnancy test in female participant of childbearing age. 16. Written informed consent and/or signed assent line from participant, parent or guardian. Donor Inclusion Criteria: 1. Donors who have fulfilled eligibility as per United States Food and Drug Administration (FDA) regulations outlined in 21 Code of Federal Regulations (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. For third-party banking, donors must 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 (related or unrelated) must have completed Infectious Disease (ID) testing up to 7 days before or after the collection of blood for NST manufacturing. The following tests will be performed: * HBsAg * HBc Antibody * HCV Antibody * HIV 1/2 Antibody * HTLV I/II Antibody * T. Cruzi Antibody (Chagas) * CMV Total Antibody * Syphilis (T. Pallidum IgG and IgM) * HBV, HCV, HIV Nucleic Acid testing (NAT) * WNV NAT 5. Female donors of childbearing age must have a negative pregnancy test and not be lactating.
Exclusion criteria
Participants
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of acute GvHD (grade III-IV) | Within 45 days of first NSTs infusion | Number of patients with acute GvHD grades III-IV |
| Incidence of infusion related adverse events as per CTCAE common criteria guidelines. | Within 45 days of first NSTs infusion | Number of patients with Grades 3-5 infusion-related adverse events |
| Incidence of non-hematological adverse events | Within 45 days of first NSTs infusion | Number of patients with Grades 4-5 non-hematological adverse events related to the NST product within 45 days of the first infusion |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Antiviral activity | Stool viral loads will be evaluated for 12 months following the final NST infusion. | Antiviral activity will determined by measurements in viral loads by RT-PCR from stool samples in comparison to the mean baseline viral load. |
Countries
United States
Contacts
CONTACTMichael Keller, MD
CONTACTFahmida Hoq, MBBS, MS
PRINCIPAL_INVESTIGATORMichael Keller, MD
CNH
Outcome results
None listed