A phase I/II dose-escalation multi-center study to evaluate the safety of infusion of natural killer cells or memory T cells as adoptive therapy in coronavirus pneumonia and/or lymphopenia: RELEASE study protocol

I García-García, P Guerra-García, C Ferreras, A M Borobia, A J Carcas, J Queiruga-Parada, J L Vicario, I Mirones, C Solano, C Eguizabal, B Soria, A Pérez-Martínez, I García-García, P Guerra-García, C Ferreras, A M Borobia, A J Carcas, J Queiruga-Parada, J L Vicario, I Mirones, C Solano, C Eguizabal, B Soria, A Pérez-Martínez

Abstract

Background: Moderate/severe cases of COVID-19 present a dysregulated immune system with T cell lymphopenia and a hyper-inflammatory state. This is a study protocol of an open-label, multi-center, double-arm, randomized, dose-finding phase I/II clinical trial to evaluate the safety, tolerability, alloreactivity, and efficacy of the administration of allogeneic memory T cells and natural killer (NK) cells in COVID-19 patients with lymphopenia and/or pneumonia. The aim of the study is to determine the safety and the efficacy of the recommended phase 2 dose (RP2D) of this treatment for patients with moderate/severe COVID-19.

Methods: In the phase I trial, 18 patients with COVID-19-related pneumonia and/or lymphopenia with no oxygen requirement or with an oxygen need of ≤ 2.5 liters per minute (lpm) in nasal cannula will be assigned to two arms, based on the biology of the donor and the patient. Treatment of arm A consists of the administration of escalating doses of memory T cells, plus standard of care (SoC). Treatment of arm B consists of the administration of escalating doses of NK cells, plus SoC. In the phase II trial, a total of 182 patients with COVID-19-related pneumonia and/or lymphopenia requiring or not oxygen supplementation but without mechanical ventilation will be allocated to arm A or B, considering HLA typing. Within each arm, they will be randomized in a 1:1 ratio. In arm A, patients will receive SoC or RP2D for memory T cells plus the SoC. In arm B, patients will receive SoC or RP2D for NK cells plus the SoC.

Discussion: We hypothesized that SARS-CoV-2-specific memory T-lymphocytes obtained from convalescent donors recovered from COVID-19 can be used as a passive cell immunotherapy to treat pneumonia and lymphopenia in moderate/severe patients. The lymphopenia induced by COVID-19 constitutes a therapeutic window that may facilitate donor engraftment and viral protection until recovery.

Trial registration: ClinicalTrials.gov NCT04578210 . First Posted : October 8, 2020.

Keywords: Allogeneic; COVID-19; Lymphopenia; Memory T cells; NK cells; Pneumonia; Protocol; Safety.

Conflict of interest statement

CF, BS, and AP-M filed a patent on this topic. BS received fees from Laminar Pharma, Abbvie, Celgene, Gilead, Sanofi, and Novo-Nordisk not related to this work.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Trial flow chart of the two consecutive phases of the study

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