SARS-CoV-2 Infection
Conditions
Brief summary
This is an open label, phase I dose-escalation study to evaluate the safety of coronavirus-specific T cell (CST) therapy for prevention of SARS-CoV-2 infection in immunocompromised patients following hematopoietic stem cell transplantation (HSCT). Participants will receive donor-derived CSTs for prevention of SARS-CoV-2 infection after HSCT (≥28 days and \<4 months after HSCT). In this dose escalation trial, three doses (1x107/m2, 2x107/m2, and 4x107/m2) will be tested for safety, with study arms for adult (≥18 years of age and \<80 years) HSCT recipients (Arm A) and two arms for pediatric (≥12 years of age and \<18 years; ≥2 years and \<12 years) HSCT recipients (Arm B and Arm C, respectively), and defined dose escalations in each study arm. The study agent will be assessed for safety (stopping rules defined) and antiviral activity.
Detailed description
The primary purpose of this phase I study is to assess the safety of administering donor-derived CSTs in immunocompromised participants for prevention of SARS-CoV-2 infection. Related and unrelated donors of participants who are at risk of SARS-CoV-2 infection will be enrolled for screening and production of CSTs from peripheral blood. Following product manufacturing, participants who have undergone HSCT will receive donor-derived CSTs for prevention of SARS-CoV-2 infection. It is a dose escalation study with separate study arms for adult (Arm A) and pediatric (Arms B and C) recipients of HSCT who are at risk of SARS-CoV-2 infection. Participants who have undergone HSCT and test negative for SARS-CoV-2 infection will be enrolled and receive one dose of CST product derived from their HSCT donor for prophylaxis. Participants aged ≥18 years and \<80 years will be enrolled on Arm A, participants who are ≥12 years of age and \<18 years of age will be enrolled on Arm B, and participants who are ≥2 years of age and \<12 years of age will be enrolled on Arm C. Investigators will test three doses: 1x107 /m2, 2x107 /m2, and 4x107 /m2. At least 3 adult participants (Arm A) will be enrolled at each dose level before pediatric participants (Arm B) are enrolled. At each dose level, treatment of the first two adult participants enrolled at that dose level will be staggered at least 28 days apart and each will be followed for the 45-day safety monitoring period to assess safety and efficacy of CST product. Once the third adult participant on any given dose level has completed their 45-day safety monitoring period and the safety and efficacy data is reviewed and approved by the FDA, then adult participants can be escalated to the next dose level and pediatric participants can start enrollment at the dose level completed by the adult participants. If participants show evidence of safety and at least 2 of 3 have evidence of antiviral immune reconstitution against SARS-CoV-2, investigators will enroll pediatric participants at that dose level following FDA approval. Additionally, infusion of pediatric participants enrolled at each dose level will be staggered at least 28 days apart, and all enrolled participants will be followed for 45 days for safety monitoring after CST infusion. After receiving the CST infusion, participants will be closely monitored to evaluate their health status and the effects of treatment. Follow-up visits will occur frequently and will continue for up to 1 year after the CST infusion. During these visits, study doctors will perform clinical assessments, including medical history and physical examinations. Blood tests will be conducted, such as complete blood count (CBC) and comprehensive metabolic panel (CMP), and research blood samples will also be collected for analysis. These assessments will help monitor safety, toxicity, and treatment effects.
Interventions
BIOLOGICALCoronavirus-specific T cell (CST)
Participants will receive donor-derived CSTs for prevention of SARS-CoV-2 infection after HSCT (≥28 days and \<4 months after hematopoietic stem cell transplantation (HSCT).
Sponsors
Children's National Research Institute
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Participant Inclusion Criteria for CST Infusion: 1. For recipient of CSTs derived from an HSCT donor under Arm A: a. Patients aged ≥18 years and \<80 years who were recipients of prior myeloablative or non-myeloablative allogeneic HSCT using either bone marrow or peripheral blood stem cells or single or double cord blood ≥28 days and \<4 months ago who are at risk of SARS-CoV-2 infection. 2. For recipient of CSTs derived from an HSCT donor under Arms B and C: a. Patients aged ≥2 years and \<18 years who were recipients of prior myeloablative or non-myeloablative allogeneic HSCT using either bone marrow or peripheral blood stem cells or single or double cord blood ≥28 days and \<4 months ago who are at risk of SARS-CoV-2 infection. 3. Have evidence of primary engraftment following HSCT (defined by ANC ≥500/mm3 for three consecutive measurements on different days, respectively) 4. Participants receiving calcineurin inhibitors for treatment of GVHD, or for other reasons, should not have any dosage changes within 7 days prior to infusion\*\* a. For patients receiving steroids, dosage must have been tapered to \<0.5 mg/kg/day of prednisone (or equivalent) at least 7 days prior to infusion. 5. Karnofsky/Lansky score \>70. 6. ≥2 years to \<80 years of age at enrollment. 7. Absolute neutrophil count (ANC) ≥500/ul. 8. Hemoglobin ≥8.0g/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. Aspartate transaminase (AST) ≤2.5x upper limit of normal. 12. Alanine transaminase (ALT) ≤2.5x upper limit of normal. 13. Estimated GFR \>60mL/min/1.73m2 (calculated per institutional standards). 14. Pulse oximetry of ≥92% on room air for at least 7 days prior to infusion. 15. Age appropriate mean arterial pressure without the use of vasopressors. 16. Negative pregnancy test in female participant of childbearing potential. 17. Male and female participants of childbearing potential must use highly effective birth control measures or practice abstinence for a minimum of 6 months after receiving study therapy 18. Written informed consent and/or signed assent line from participant, parent or guardian. Donor Inclusion Criteria: 1. Donors for allogeneic (i.e. HLA matched or mismatched related or unrelated) stem cell transplants who have fulfilled eligibility as per 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 CST generation provided that there are no new reasons for ineligibility since the stem cell collection. 2. Donor or guardian of pediatric donor capable of providing informed consent. 3. 2 to 80 years of age. 4. Female donors of childbearing potential must have a negative pregnancy test.
Exclusion criteria
Participants
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of grade ≥3 infusion-related Adverse Events (AEs) | Within 45 days of CST infusion | Number of patients with grade ≥3 infusion-related AEs at 45 days of following CST infusion. |
| Incidence of acute Graft Vs Host Disease (aGVHD) grade ≥3 | Within 45 days of CST infusion | Number of patients with aGVHD grade ≥3 within 45 days of CST infusion. |
| Incidence of Systemic Inflammatory Response Syndrome (SIRS) or CRS | Within 45 days of CST infusion | Number of patients with systemic Inflammatory Response Syndrome (SIRS) or CRS |
| Incidence of Multi-System Inflammatory Syndrome (MIS) | Within 45 days of CST infusion | Number of patients with MIS |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| COVID-19 antiviral immunity using intracellular flow cytometry | At 45 days following CST infusion | Participant serum and PBMCs will be monitored for COVID-19 virus specific T cell activity at 45 days following CST infusion by phenotypic and functional studies including ELIspot with appropriate viral specific peptide mixtures and available HLA-restricted epitope peptides, intracellular cytokine staining, serum cytokine profiling and/or other assays as they become available for immune profiling purposes |
| COVID-19 antiviral immunity using intracellular ELIspot assays | At 45 days following CST infusion | Participant serum and PBMCs will be monitored for COVID-19 virus specific T cell activity at 45 days following CST infusion by phenotypic and functional studies including ELIspot with appropriate viral specific peptide mixtures and available HLA-restricted epitope peptides, intracellular cytokine staining, serum cytokine profiling and/or other assays as they become available for immune profiling purposes |
| Persistence of infused CSTs | Within 12 months | Persistence of infused T cells will be monitored using deep sequencing to track the TCRB repertoire in the participant peripheral blood |
| Antiviral Activity | Within 12 months | Antiviral activity will be assessed by measurement of SARS-CoV-2 viral load by screening RT-PCR from oral/salivary samples or from respiratory samples for any participant who develops a positive SARS-CoV-2 RT-PCR post CST infusion |
Countries
United States
Contacts
CONTACTSusan Conway, MD
CONTACTFahmida Hoq, MBBS
Outcome results
None listed