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

George Papanicolaou Hospital182 enrolled

Overview

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

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

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

182

Conditions

Severe COVID-19

Interventions

Coronavirus-2-specific T cellsBIOLOGICAL

Coronavirus-2-specific T cells ex vivo expanded from selected COVID-19 recovered donors

standard of care (SOC)OTHER

standard of care (SOC)

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Locations (2)

General Hospital of Thessaloniki Ippokratio- 2nd Propedeutic Department of Internal Medicine

Thessaloniki, Greece

RECRUITING

George Papanikolaou Hospital - Gene and Cell Therapy Center- Hematology Dpt- Hematopoietic Stem Cell Transplant Center

Thessaloniki, Greece

RECRUITING

Outcomes

Primary Outcomes

Establishment of a CoV-2-STs bank

• Thirty, multi-dose, GMP-generated and released CoV-2-ST products

Time frame: 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

Time frame: Within 2 months before recruitment initiation

Pharmacodynamic endpoint-1 (Phase I)

•Determination of optimal dose (maximum tolerated dose)

Time frame: Up to the completion of Ph I

Pharmacodynamic endpoint-2 (Phase I and II)

• In vivo expansion of CoV-2-STs after administration

Time frame: Up to the completion of Ph I and II

Pharmacodynamic endpoint-3 (Phase II)

• Persistence of circulating donor CoV-2-STs by microchimerism analysis

Time frame: 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.

Time frame: 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

Time frame: Day 30 and Day 60 (end of follow up)

Safety endpoints (Phase I and II)

Central Contacts

Evangelia Yannaki, MD, PI

CONTACT

+30 2313 307518 eyannaki@u.washington.edu

Michael Doumas, MD