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

Phase 1

Recruiting

• Conditions: Severe COVID-19
• Interventions: Other: standard of care (SOC); Biological: Coronavirus-2-specific T cells

• Registration Number: NCT05447013
• Lead Sponsor: George Papanicolaou Hospital

Brief Summary

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

Detailed Description

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

Study Timeline

• Study Start: 2021-06-02
• Study First Submitted: 2022-06-30
• Study First Submitted QC: 2022-07-06
• Study First Posted: 2022-07-07
• Status Verified: 2022-11
• Last Update Submitted: 2022-11-22
• Last Update Posted: 2022-11-23
• Primary Completion: 2022-12-31
• Study Completion: 2022-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 182

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
For Phase II: Arm B	standard of care (SOC)	Standard of care (SOC)
For Phase II: Arm A	Coronavirus-2-specific T cells	Standard of care (SOC) and Coronavirus-specific T cells (CoV-2-STs)

Primary Outcome Measures

Name	Time	Method
Establishment of a CoV-2-STs bank	Within 2 months before recruitment initiation	• Thirty, multi-dose, GMP-generated and released CoV-2-ST products
Establishment of a CoV-2-STs bank of broad HLA coverage	Within 2 months before recruitment initiation	CoV-2-ST products of a broad HLA repertoire
Pharmacodynamic endpoint-1 (Phase I)	Up to the completion of Ph I	•Determination of optimal dose (maximum tolerated dose)
Pharmacodynamic endpoint-2 (Phase I and II)	Up to the completion of Ph I and II	• In vivo expansion of CoV-2-STs after administration
Pharmacodynamic endpoint-3 (Phase II)	Up to the completion of Ph II	• Persistence of circulating donor CoV-2-STs by microchimerism analysis
Efficacy endpoint-1 (Phase II)	Day 30 and Day 60 (end of follow up)	• 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.
Efficacy endpoint-2 (Phase II)	Day 30 and Day 60 (end of follow up)	• 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
Safety endpoints (Phase I and II)	End-of-follow up (day 60) for all patients in Ph I and Ph 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

Secondary Outcome Measures

Name	Time	Method
Efficacy endpoint-1 (Phase II)	Day 30 for all enrolled patients	-Clinical status by the 8-point WHO Ordinal Scale on day 30
Efficacy endpoint-2 (Phase II)	End-of-follow up (day 60)	* 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)
Efficacy endpoint-3 (Phase II)	Day 20 for all enrolled patients	Percentage of patients with negative PCR by day 20
Safety endpoint (Phase I and II)	End-of-follow up (day 60)	•Graft versus host disease (GvHD), by clinical and laboratory assessments

Trial Locations

Locations (2)

George Papanikolaou Hospital - Gene and Cell Therapy Center- Hematology Dpt- Hematopoietic Stem Cell Transplant Center; 🇬🇷 Thessaloniki, Greece

General Hospital of Thessaloniki Ippokratio- 2nd Propedeutic Department of Internal Medicine; 🇬🇷 Thessaloniki, Greece