Effective virus-specific T-cell therapy for high-risk SARS-CoV-2 infections in hematopoietic stem cell transplant recipients: initial case studies and literature review

Abstract

The COVID-19 pandemic has exacerbated mortality rates among immunocompromised patients, accentuating the need for novel, targeted therapies. Transplant recipients, with their inherent immune vulnerabilities, represent a subgroup at significantly heightened risk. Current conventional therapies often demonstrate limited effectiveness in these patients, calling for innovative treatment approaches. In immunocompromised transplant recipients, several viral infections have been successfully treated by adoptive transfer of virus-specific T-cells (VST). This paper details the successful application of SARS-CoV-2-specific memory T-cell therapy, produced by an interferon-γ cytokine capture system (CliniMACS® Prodigy device), in three stem cell transplant recipients diagnosed with COVID-19 (case 1: alpha variant, cases 2 and 3: delta variants). These patients exhibited persistent SARS-CoV-2 PCR positivity accompanied by bilateral pulmonary infiltrates and demonstrated only partial response to standard treatments. Remarkably, all three patients recovered and achieved viral clearance within 3 to 9 weeks post-VST treatment. Laboratory follow-up investigations identified an increase in SARS-CoV-2-specific T-cells in two of the cases. A robust anti-SARS-CoV-2 S (S1/S2) IgG serological response was also recorded, albeit with varying titers. The induction of memory T-cells within the CD4 + compartment was confirmed, and previously elevated interleukin-6 (IL-6) and IL-8 levels normalized post-VST therapy. The treatment was well tolerated with no observed adverse effects. While the need for specialized equipment and costs associated with VST therapy present potential challenges, the limited treatment options currently available for COVID-19 within the allogeneic stem cell transplant population, combined with the risk posed by emerging SARS-CoV-2 mutations, underscore the potential of VST therapy in future clinical practice. This therapeutic approach may be particularly beneficial for elderly patients with multiple comorbidities and weakened immune systems.

Keywords: Adoptive T-cell therapy; COVID-19; CliniMACS® Prodigy; Hematopoietic stem cell transplantation; Immunocompromised; SARS-CoV-2; Virus-specific T-cells.

Fig. 1

Changes in main lymphoid subpopulations by flow cytometry in 3 patients before and after COVID-19 VST treatment. A CD3 + T-cells. B CD4 + T-cells. C CD8 + T-cells. D B-cells. E CD3 + /TCRαβ + T-cells and CD3 + /TCRγδ + T-cells in case 1. F T-regulatory cells. G CD4 + /CD45RA + naive T-cells. H CD4 + /CD45RO + naive T-cells. I CD8 + /CD45RA + naive T-cells. J CD8 + /CD45RO + naive T-cells. Abbreviations: VST, virus specific T-cell; TCR, T-cell receptor

Fig. 1

Changes in main lymphoid subpopulations by flow cytometry in 3 patients before and after COVID-19 VST treatment. A CD3 + T-cells. B CD4 + T-cells. C CD8 + T-cells. D B-cells. E CD3 + /TCRαβ + T-cells and CD3 + /TCRγδ + T-cells in case 1. F T-regulatory cells. G CD4 + /CD45RA + naive T-cells. H CD4 + /CD45RO + naive T-cells. I CD8 + /CD45RA + naive T-cells. J CD8 + /CD45RO + naive T-cells. Abbreviations: VST, virus specific T-cell; TCR, T-cell receptor

Fig. 1

Changes in main lymphoid subpopulations by flow cytometry in 3 patients before and after COVID-19 VST treatment. A CD3 + T-cells. B CD4 + T-cells. C CD8 + T-cells. D B-cells. E CD3 + /TCRαβ + T-cells and CD3 + /TCRγδ + T-cells in case 1. F T-regulatory cells. G CD4 + /CD45RA + naive T-cells. H CD4 + /CD45RO + naive T-cells. I CD8 + /CD45RA + naive T-cells. J CD8 + /CD45RO + naive T-cells. Abbreviations: VST, virus specific T-cell; TCR, T-cell receptor

Fig. 2

Flow cytometry analysis with Miltenyi peptide pool kit for SARS-CoV-2 virus-specific T-cells at screening and follow-up after VST therapy. Note: pale pink background: weakly positive; pink background: strongly positive. Abbreviations: VST, virus-specific T-cell; IFN-γ, interferon-γ; ND, not done

Fig. 3

SARS-CoV-2 serology at screening and follow-up after COVID-19 VST therapy. A Case 1. B Case 2. C Case 3. Abbreviations: VST, virus-specific T-cell; S1/S2, spike protein; AU/ml, antibody unit/ml; IgG, immunoglobulin G; NP, nucleocapsid; S/CO, ratio over threshold value. Note: no background: negative value; pink background: positive value; red background: highly positive value

Fig. 4

Emerging T-cell-based adoptive immunotherapy strategies to treat COVID-19 infection. Main methods: A direct selection with IFNγ CCS CliniMACS® Prodigy device. B Direct selection with CliniMACS® Plus device. C Ex vivo T-cell expansion. D Ex vivo cell expansion and CRISPR gene-modified T-cells. E T-cell receptor-engineered CD8 + T-cell. F Treg/Th2 hybrid T-cells. Abbreviations: PBMC, peripheral blood mononuclear cell; IFNγ, interferon-γ; HLA, human leukocyte antigen; Th, T helper cell; T-reg, T-regulatory cell; NCT, National Clinical Trial; DPC-OHII, Central Hospital of Southern-Pest, National Institute of Hematology and Infectious Diseases; CCS, cytokine capture system; MoAb, monoclonal antibody; ETT-TUKEB, Research Ethics Committee of the Hungarian National Medical Scientific Council; HSCT, hematopoietic stem cell transplantation; IL, interleukin; SOT, solid organ transplantation; CRISPR, RNA-controlled clustered regularly interspaced short palindromic repeats; Cas-9, caspase-9; NR3C1, nuclear receptor subfamily 3 group C member 1; PD1, programmed cell death protein1; ACE2, angiotensin-converting enzyme 2; FKBP12, FK506 binding protein 1A, 12 kDa; KO, knockout; TReAT, Tacrolimus-resistant antiviral T-cell therapy; ARDS, acute respiratory distress syndrome; TCR, T-cell receptor; NA, not available

Fig. 4

Emerging T-cell-based adoptive immunotherapy strategies to treat COVID-19 infection. Main methods: A direct selection with IFNγ CCS CliniMACS® Prodigy device. B Direct selection with CliniMACS® Plus device. C Ex vivo T-cell expansion. D Ex vivo cell expansion and CRISPR gene-modified T-cells. E T-cell receptor-engineered CD8 + T-cell. F Treg/Th2 hybrid T-cells. Abbreviations: PBMC, peripheral blood mononuclear cell; IFNγ, interferon-γ; HLA, human leukocyte antigen; Th, T helper cell; T-reg, T-regulatory cell; NCT, National Clinical Trial; DPC-OHII, Central Hospital of Southern-Pest, National Institute of Hematology and Infectious Diseases; CCS, cytokine capture system; MoAb, monoclonal antibody; ETT-TUKEB, Research Ethics Committee of the Hungarian National Medical Scientific Council; HSCT, hematopoietic stem cell transplantation; IL, interleukin; SOT, solid organ transplantation; CRISPR, RNA-controlled clustered regularly interspaced short palindromic repeats; Cas-9, caspase-9; NR3C1, nuclear receptor subfamily 3 group C member 1; PD1, programmed cell death protein1; ACE2, angiotensin-converting enzyme 2; FKBP12, FK506 binding protein 1A, 12 kDa; KO, knockout; TReAT, Tacrolimus-resistant antiviral T-cell therapy; ARDS, acute respiratory distress syndrome; TCR, T-cell receptor; NA, not available