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

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

Study Overview

• Status: Recruiting
• Conditions: Severe COVID-19
• Intervention / Treatment: Biological: Coronavirus-2-specific T cells; Other: standard of care (SOC)

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 Type: Interventional
• Enrollment (Anticipated): 182
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Evangelia Yannaki, MD, PI; Phone Number: +30 2313 307518; Email: eyannaki@u.washington.edu
• Study Contact Backup: Name: Michael Doumas, MD; Phone Number: +30 2310 992899; Email: michalisdoumas@yahoo.co.uk

Study Locations

• Greece
  • Thessaloniki, Greece, 54642
    • Recruiting
    • General Hospital of Thessaloniki Ippokratio- 2nd Propedeutic Department of Internal Medicine
    • Contact: Michael Doumas, MD; Phone Number: +30 2310 992899; Email: michalisdoumas@yahoo.co.uk
  • Thessaloniki, Greece, 57010
    • Recruiting
    • George Papanikolaou Hospital - Gene and Cell Therapy Center- Hematology Dpt- Hematopoietic Stem Cell Transplant Center
    • Contact: Evangelia Yannaki, MD, PI; Phone Number: +30 2313 307518; Email: eyannaki@u.washington.edu
    • Contact: ANASTASIA PAPADOPOULOU, CO-PI; Phone Number: +30 2313 307963; Email: apapadopoulou.gpapanikolaou@n3.syzefxis.gov.gr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: George Papanicolaou Hospital
• Collaborators: General Hospital Of Thessaloniki Ippokratio
• Investigators: Principal Investigator: Evangelia Yannaki, MD,PI, George Papanicolaou Hospital

Study record dates

Study Major Dates

• Study Start (Actual): June 2, 2021
• Primary Completion (Anticipated): December 31, 2022
• Study Completion (Anticipated): December 31, 2022

Study Registration Dates

• First Submitted: June 30, 2022
• First Submitted That Met QC Criteria: July 6, 2022
• First Posted (Actual): July 7, 2022

Study Record Updates

• Last Update Posted (Actual): November 23, 2022
• Last Update Submitted That Met QC Criteria: November 22, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: SARS-CoV-2; COVID-19; Virus-specific T cells; Coronavirus-specific T cells; 2021-001022-22
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: CoV-2-STs-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No