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 À 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 £ 10 5 cells/kg), the next three received the intermediate dose (5 £ 10 5 cells/kg) and the last three received the highest dose (1 £ 10 6 cells/ kg) of CD45RA À 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 À 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 Innovaci on Grant AVI-GVA COVID-19-68 to BS.

Long-Lasting Immunity Against SARS-CoV-2: Dream or Reality?

“…Thus, it is also of great importance to establish suitable therapies such as adoptive T cell transfer for cases of insufficient cellular immune response to SARS-CoV-2. In a recent phase 1 clinical trial by Pérez-Martínez and colleagues, the transfer of CD45RA-depleted memory T cell for treatment of hospitalized COVID-19 patients was shown to be feasible and safe ( 34 ).…”

T Cell Immunity Evaluation and Immunodominant Epitope T Cell Receptor Identification of Severe Acute Respiratory Syndrome Coronavirus 2 Spike Glycoprotein in COVID-19 Convalescent Patients

“…Adoptive T cell therapies have been proven to be an effective treatment approach against malignant tumors and viral infections ( Leen et al, 2006 ). Studies have shown that there were SARS-CoV-2-specific memory T cells in COVID-19 convalescents ( Ferreras et al, 2021 ; Perez-Martinez et al, 2021 ), and the symptoms were significantly improved in patients with SARS-CoV-2 after being treated with SARS-CoV-2-specific memory T cells ( Perez-Martinez et al, 2021 ). This result indicated that adoptive T cell therapies are an effective treatment for COVID-19.…”

Elucidating T Cell and B Cell Responses to SARS-CoV-2 in Humans: Gaining Insights into Protective Immunity and Immunopathology

“…Reports have begun to emerge that demonstrate the potential utility of adoptive transfer therapy using ex-vivo expanded SARS-CoV-2 specific T cells [ 37 , 40 , 41 , 42 , 72 , 73 ]. One of the earliest publications in this context utilized a good manufacturing practice (GMP)-compliant methodology to, in vitro, stimulate and expand virus-specific T cells from convalescent donors using SARS-CoV-2 peptides for the purpose of adoptive immunotherapy aimed at immunocompromised patients exposed to SARS-CoV-2 [ 40 ].…”

“…One of the earliest publications in this context utilized a good manufacturing practice (GMP)-compliant methodology to, in vitro, stimulate and expand virus-specific T cells from convalescent donors using SARS-CoV-2 peptides for the purpose of adoptive immunotherapy aimed at immunocompromised patients exposed to SARS-CoV-2 [ 40 ]. A subsequent clinical trial demonstrated the safety and feasibility of adoptively transferring purified CD45RA − T cells, which were obtained from SARS-CoV-2 convalescent donors, into partially HLA-matched recipients diagnosed with moderate to severe COVID-19 [ 41 ]. Given that patients with severe COVID-19 are often treated with immune suppressants, ex vivo expanded SARS-CoV-2 specific T cells can be additionally manipulated by CRISPR-Cas9 gene-editing methods to render them resistant to glucocorticoids by inactivating the glucocorticoid receptor gene ( NR3C1 ) [ 42 ].…”