Phase I dose-escalation single centre clinical trial to evaluate the safety of infusion of memory T cells as adoptive therapy in COVID-19 (RELEASE)

Abstract

Background: Effective treatments are still needed to reduce the severity of symptoms, time of hospitalization, and mortality of COVID-19. SARS-CoV-2 specific memory T-lymphocytes obtained from convalescent donors recovered can be used as passive cell immunotherapy.

Methods: Between September and November 2020 a phase 1, dose-escalation, single centre clinical trial was conducted to evaluate the safety and feasibility of the infusion of CD45RA- memory T cells containing SARS-CoV-2 specific T cells as adoptive cell therapy against moderate/severe cases of COVID-19. Nine participants with pneumonia and/or lymphopenia and with at least one human leukocyte antigen (HLA) match with the donor were infused. The first three subjects received the lowest dose (1 × 105 cells/kg), the next three received the intermediate dose (5 × 105 cells/kg) and the last three received the highest dose (1 × 106 cells/kg) of CD45RA- memory T cells. Clinicaltrials.gov registration: NCT04578210.

Findings: All participants' clinical status measured by National Early Warning Score (NEWS) and 7-category point ordinal scales showed improvement six days after infusion. No serious adverse events were reported. Inflammatory parameters were stabilised post-infusion and the participants showed lymphocyte recovery two weeks after the procedure. Donor microchimerism was observed at least for three weeks after infusion in all patients.

Interpretation: This study provides preliminary evidence supporting the idea that treatment of COVID-19 patients with moderate/severe symptoms using convalescent CD45RA- memory T cells is feasible and safe.

Funding: Clinical Trial supported by Spanish Clinical Research Network PT17/0017/0013. Co-funded by European Regional Development Fund/European Social Fund. CRIS CANCER Foundation Grant to AP-M and Agencia Valenciana de Innovación Grant AVI-GVA COVID-19-68 to BS.

Conflict of interest statement

AP-M filed patent EP20382850 on Memory T cells as adoptive cell therapy for viral diseases. CF filed patent EP20382850 on Memory T cells as adoptive cell therapy for viral diseases. BS received salary from University Miguel Hernandez, a grant from Agencia Valenciana de Innovacion, support from Al-Andalus Biopharma and medical writing from Comunidad de Madrid, since the initial planning of the work. He received grant AVI-GVA CO19–068 and consulting fees from Gilead-Weber. BS is on the board at Institut de Bioengineria de Catalunya and Laminar Pharmaceuticals. BS filed patent EP20382850 on Memory T cells as adoptive cell therapy for viral diseases. BS reports an unpaid role with FAID. BS reports the receipt of equipment, materials, drugs, medical writing, gifts or other services from Al-Andalus BioPharmaSL. CS received fees from MSD, Pfizer and Gilead not related to this topic, and reports payments made by Gilead, MSD, Janssen and Therakos to suppliers for support for attending meetings and/or travel. IG reports a “Rio Hortega” Grant (Plan Estatal de I + D + I 2013–2016. Plan Estatal de Investigación Científica y Técnica y de Innovación (2017–2020). Co-funded by European Regional Development Fund/European Social Fund "A way to make Europe"/"Investing in your future"). All other authors have nothing to declare.

© 2021 The Author(s).

Figures

Fig. 1

CONSORT flow diagram.

Fig. 2

A) RELEASE Study protocol (NCT04578210). Only the first arm of the memory lymphocytes described here. B) Expression of CD45RA+and CD45RA– T on a healthy control and a convalescent donor.

Fig. 3

A) Interaction of virus infected cell with CD4+ T cell by HLA-I complex. B) Patients’ characteristics and doses cohort. C) Time-course, clinical outcomes and patients’ co-morbidities. HD: Hospital Discharge,:No fever,: No extra oxygen needs,: Negative PCR, IC: Ischemic cardiopathy, AH: Arterial hypertension, OB: Obesity, DM: Diabetes mellitus, MS: multiple sclerosis.

Fig. 4

Recovery from lymphopenia after CD45RA− lymphocyte infusion. Lymphocyte recovery (x109/L) one and two weeks after CD45RA− memory T cell infusion. #: Patient number.