T CELL THERAPY OPPOSING NOVEL COVID-19 INFECTION IN IMMUNOCOMPROMISED PATIENTS

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 pediatric (≥12 years of age and \<18 years) HSCT recipients (Arm B), and defined dose escalations in each study arm. The study agent will be assessed for safety (stopping rules defined) and antiviral activity.

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.

This will be a dose escalation study with separate study arms for adult (Arm A) and pediatric (Arm B) 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 and participants who are ≥12 years of age and \<18 years of age will be enrolled on Arm B. 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. 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.

Eligibility Criteria:
Inclusion Criteria:

Participant Inclusion Criteria for CST Infusion:

We will enroll participants who are ≥28 days and \<4 months post allogeneic HSCT and are at risk of developing SARS-CoV-2 infection.

1. For receipt 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 receipt of CSTs derived from an HSCT donor under Arm B:

   a. Patients aged ≥12 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 steroids for treatment of GVHD or for other reasons, 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. ≥12 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. Cystatin C with estimated GFR \>60mL/min/1.73m2 (calculated via the CKD-EPI 2012 equation).
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 age.
17. Male and female participants of childbearing age 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 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 age must have a negative pregnancy test and not be lactating.

Exclusion Criteria:

Participants Exclusion Criteria for CST Infusion:

1. Participants receiving biological or immunosuppressive monoclonal antibodies targeting T cells within 28 days prior to CST 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 CST 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 CST infusion.
3. Participants who have received ruxolitinib or other JAK inhibitors within 7 days prior to CST infusion.
4. Participants with uncontrolled or progressing infections or active infections causing fever (temperature ≥38.1°C). Uncontrolled infections are defined as bacterial, fungal, or viral infections (including HIV and Hep B and C) with either clinical signs of worsening despite standard therapy that may be attributed to the uncontrolled infection. Progressing infection is defined as hemodynamic instability, worsening physical signs, or radiographic findings attributable to infection.

   1. For bacterial infections, participants must be receiving definitive therapy and have no signs of progressing infection within 7 days prior to CST infusion.
   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 CST infusion.
5. Participants with unexplained fever (temperature ≥38.1°C) within 7 days prior to CST infusion.
6. Participants with evidence of active SARS-CoV-2 infection based on SARS-CoV-2 RT-PCR positivity.
7. Participants with fever (temperature ≥38.1°C) in the past 7 days.
8. Participants with hypotension (systolic blood pressure \<90 mmHg or mean arterial blood pressure \<55 mmHg in participants \<14 years of age or \<60 mmHg in participants ≥14 years of age).
9. Participants with pulse pressure \>40 mmHg.
10. Participants with respiratory rate \>20 breaths per minute.
11. Participants with heart rate ≥120 beats per minute.
12. Participants with uncontrolled hypertension as defined by systolic blood pressure \>99th percentile for age (children \<18 years), and systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥80 mmHg (participants ≥18 years).
13. Participants with metabolic instability.
14. Pediatric participants with modified Ross heart failure Class II disease and adult participants with NYHA Class II disease.
15. Participants with advanced pulmonary disease as defined by requirement for supplemental oxygen or positive pressure ventilation due to pulmonary disease. (This includes participants with active interstitial lung disease (ILD)/pneumonitis, advanced pulmonary disease, a history of ILD/pneumonitis requiring treatment with systemic steroids or a baseline oxygen requirement).
16. Participants with neurological or psychiatric disorders that would, in the opinion of the investigators, place them at increased risk of harm, impact the investigator's abilities to screen for adverse events in the subject, or impair the subject's ability to provide informed consent.
17. Participants receiving checkpoint inhibitors within the previous 3 months prior to CST infusion, including nivolumimab, pembroluzimab, or other related medications.
18. Participants with proven or suspected MIS (in both adults and children) based on the CDC definition and investigator judgement.
19. Participants who are breastfeeding.
20. Participants who have received live vaccines within 30 days, or any SARS-CoV-2 vaccine in the past 28 days prior to enrollment.
21. Participants with any other unrelated medical conditions that would impact the participant's safety in the opinions of the investigators.
22. Participants anticipated to need a blood transfusion within 48 hours of CST infusion.
23. Participants unwilling to utilize effective contraception during the study period (if applicable)

Donor Exclusion Criteria:

1. Donation of cells would pose a physical or psychological risk to the donor.
2. Prior or current complicated course of COVID-19, including but not limited to MIS, CRS, or thromboembolic complications based on investigator judgement.