Generation of SARS-CoV-2-specific T Lymphocytes From Recovered Donors and Administration to High-risk COVID-19 Patients

Study Overview
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Brief Summary
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Open-label phase I (single-center)/ phase II (multicenter) with randomization 2:1

Detailed Description
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Phase I (single-center): The investigators will administer CoV-2-STs in a dose escalation regimen of 2 dose levels (DL1: 1,5x10^7 CoV-2-STs in total; DL2: 2x10^7 CoV-2-STs/m^2). 3 patients will be treated at each dose level (traditional 3+3 design) following by a 12-day wait period to assess safety of the infusions prior to escalating the next dose level (maximum 12 patients). The maximum tolerated dose will be determined Phase II (multicenter): Randomization 2:1, 60 patients will receive the standard of care (SOC) plus CoV-2-STs (ARM A) at the optimum dose which will be determined in phase I and 30 patients will receive only SOC (Arm Β) Phase II (multicenter, extension): Randomization 2:1, 53 patients will be enrolled in Arm A to receive SOC and up to two doses of COV-2-STs and 27 patients will receive only SOC. Randomization: Patients who meet the eligibility criteria after signing the informed consent form they will randomly be assigned at 2:1 ratio to each of the 2 treatment groups. Patients assigned to arm A will be HLA-typed for HLA-A, B and DRB1 within 24h, and a suitable for them T cell product will be selected from the cell bank. If a suitable product is found, they will continue to arm A, otherwise, they will be assigned to arm B. Objectives: i) To determine the feasibility of establishing a bank with GMP-compliant generated SARS-CoV-2 specific T-cells (CoV-2-STs), well-characterized in terms of specificity, phenotype and expression of human leucocyte antigens (HLA), which will be produced by 30 COVID-19 recovered donors with broad HLA diversity in order to be suitable for administration to at least 90 COVID-19 patients ii) To determine the safety of CoV-2-ST administration as cellular immunotherapy in COVID-19 patients, who meet specific inclusion criteria iii) To determine the efficacy of CoV-2-ST administration as cellular immunotherapy in COVID-19 patients, who meet specific inclusion criteria

Official Title
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Generation of SARS-CoV-2-specific T Lymphocytes From Recovered Donors and Administration to High-risk COVID-19 Patients

Conditions
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Severe COVID-19

Intervention / Treatment
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* Biological: Coronavirus-2-specific T cells
* Other: standard of care (SOC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Hospitalized patients, SARS-CoV-2 PCR positive, within 8 days from the onset of the symptoms (immunosuppressed patients are excluded from the time limit when they become chronic carriers of the virus), who have: Pneumonia or/and SatO2 ≤94% on room air or/and respiratory rate ≥24breaths/min AND lymphopenia CD3+≤650/μl or/and ALC≤1000/microl AND Increased values of D-dimers (≥2Χ) or/and ferritin (>1000ng/ml) or/and CRP (≥3Χ) or/and LDH (≥2Χ) Exclusion Criteria: Age ≤18 and ≥80 years old Onset of symptoms >8 days (immunosuppressed patients are excluded from the time limit when they become chronic carriers of the virus) Corticosteroid administration at a dose of >0.75mg/kg (methylprednisolone equivalent) Multiple organ failure ARDS (acute respiratory distress syndrome) Mechanical ventilation Patients who received ATG, or Campath, or other T-cell-suppressing monoclonal antibody within 28 days prior to admission Patients with concomitant confirmed infection from another pathogen or with very high procalcitonin (PCT) that may indicate additional infection Enrollment in another clinical trial Pregnancy Inability to sign informed consent form Judged ineligible by at the treating physician (treating physician's discretion) Bilirubin ≥2x of upper normal limit AST ≥ 2x of upper normal limit Creatinine ≥ 2x of upper normal limit or with dialysis/hemodialysis needs Karnofsky score ≤50

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: For Phase II: Arm A<br>Standard of care (SOC) and Coronavirus-specific T cells (CoV-2-STs) | Biological: Coronavirus-2-specific T cells<br>* Coronavirus-2-specific T cells ex vivo expanded from selected COVID-19 recovered donors<br>|
| Active Comparator: For Phase II: Arm B<br>Standard of care (SOC) | Other: standard of care (SOC)<br>* standard of care (SOC)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Establishment of a CoV-2-STs bank | • Thirty, multi-dose, GMP-generated and released CoV-2-ST products | Within 2 months before recruitment initiation | 
| Establishment of a CoV-2-STs bank of broad HLA coverage | CoV-2-ST products of a broad HLA repertoire | Within 2 months before recruitment initiation | 
| Pharmacodynamic endpoint-1 (Phase I) | •Determination of optimal dose (maximum tolerated dose) | Up to the completion of Ph I | 
| Pharmacodynamic endpoint-2 (Phase I and II) | • In vivo expansion of CoV-2-STs after administration | Up to the completion of Ph I and II | 
| Pharmacodynamic endpoint-3 (Phase II) | • Persistence of circulating donor CoV-2-STs by microchimerism analysis | Up to the completion of Ph II | 
| Efficacy endpoint-1 (Phase II) | • Recovery and time to recovery. Recovery is defined as a value of 1 to 3 on the 8-point WHO ordinal scale (OS). Time to recovery is the days passed from Day 0 to the 1st day of a score 1 to 3 on the OS for those who recovered or the days passed from Day 0 to the last follow-up for the rest. | Day 30 and Day 60 (end of follow up) | 
| Efficacy endpoint-2 (Phase II) | • Survival by days 30 and 60. Survival is defined as the time-to-event from Day 0 to the date of death or the last follow-up | Day 30 and Day 60 (end of follow up) | 
| Safety endpoints (Phase I and II) | acute toxicity related to the CoV-2-ST infusion, by clinical and laboratory assessments cytokine release syndrome, by clinical and laboratory assessments number of adverse and/or serious adverse events | End-of-follow up (day 60) for all patients in Ph I and Ph II | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy endpoint-1 (Phase II) | -Clinical status by the 8-point WHO Ordinal Scale on day 30 | Day 30 for all enrolled patients | 
| Efficacy endpoint-2 (Phase II) | time to improvement by 1 & 2 categories from day 0 according to the 8-point Ordinal Scale time to PCR negativity time to lymphopenia recovery hospitalization time ( day 0 to discharge) | End-of-follow up (day 60) | 
| Efficacy endpoint-3 (Phase II) | Percentage of patients with negative PCR by day 20 | Day 20 for all enrolled patients | 
| Safety endpoint (Phase I and II) | •Graft versus host disease (GvHD), by clinical and laboratory assessments | End-of-follow up (day 60) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, Virus-specific T cells, SARS-CoV-2, Coronavirus-specific T cells, 2021-001022-22