Tacrolimus-resistant SARS-CoV-2-specific T cell products to prevent and treat severe COVID-19 in immunosuppressed patients

Peter, Lena; Wendering, Désirée J.; Schlickeiser, Stephan; Hoffmann, Henrike; Noster, Rebecca; Wagner, Dimitrios L.; Zarrinrad, Ghazaleh; Münch, Sandra; Picht, S.; Schulenberg, Sarah; Moradian, Hanieh; Mashreghi, Mir‐Farzin; Klein, Oliver; Gossen, Manfred; Roch, Toralf; Babel, Nina; Reinke, Petra; Volk, Hans‐Dieter; Amini, Leila; Schmueck-Henneresse, Michael

doi:10.1016/j.omtm.2022.02.012

Cited by 13 publications

(11 citation statements)

References 134 publications

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“…4 D) [ 58 ]. Furthermore, tacrolimus-resistant FKBP12 (FK506 Binding Protein 1A, 12 kDa) knockout convalescent allogeneic SARS-CoV-2-specific T cells using CRISP-Cas9 technology is also underway to treat immunosuppressed SOT recipients [ 59 ].…”

Section: Discussionmentioning

confidence: 99%

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

Gopcsa,

Réti,

Andrikovics

et al. 2023

GeroScience

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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.

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Section: Discussionmentioning

confidence: 99%

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

Gopcsa,

Réti,

Andrikovics

et al. 2023

GeroScience

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“…This technology provides means with which to alter gene expression profile with the aim of conferring a competitive survival advantage to Tregs ( Amini et al, 2021 ). For example, prospective recipients of Treg products are commonly managed with immunosuppressive drugs, which can interfere with Treg functions ( San Segundo et al, 2006 ; Presser et al, 2009 ), therefore CRISPR gene editing could be used to engineer Treg products which are resistant to the IS pharmaceuticals such as calcineurin inhibitors ( Amini et al, 2020 ; Peter et al, 2022 ).…”

Section: Manufacturing Of Human Regulatory T Cell Productsmentioning

confidence: 99%

Clinical adoptive regulatory T Cell therapy: State of the art, challenges, and prospective

Amini

Kaeda

Fritsche

et al. 2023

Front. Cell Dev. Biol.

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Rejection of solid organ transplant and graft versus host disease (GvHD) continue to be challenging in post transplantation management. The introduction of calcineurin inhibitors dramatically improved recipients’ short-term prognosis. However, long-term clinical outlook remains poor, moreover, the lifelong dependency on these toxic drugs leads to chronic deterioration of graft function, in particular the renal function, infections and de-novo malignancies. These observations led investigators to identify alternative therapeutic options to promote long-term graft survival, which could be used concomitantly, but preferably, replace pharmacologic immunosuppression as standard of care. Adoptive T cell (ATC) therapy has evolved as one of the most promising approaches in regenerative medicine in the recent years. A range of cell types with disparate immunoregulatory and regenerative properties are actively being investigated as potential therapeutic agents for specific transplant rejection, autoimmunity or injury-related indications. A significant body of data from preclinical models pointed to efficacy of cellular therapies. Significantly, early clinical trial observations have confirmed safety and tolerability, and yielded promising data in support of efficacy of the cellular therapeutics. The first class of these therapeutic agents commonly referred to as advanced therapy medicinal products have been approved and are now available for clinical use. Specifically, clinical trials have supported the utility of CD4+CD25+FOXP3+ regulatory T cells (Tregs) to minimize unwanted or overshooting immune responses and reduce the level of pharmacological immunosuppression in transplant recipients. Tregs are recognized as the principal orchestrators of maintaining peripheral tolerance, thereby blocking excessive immune responses and prevent autoimmunity. Here, we summarize rationale for the adoptive Treg therapy, challenges in manufacturing and clinical experiences with this novel living drug and outline future perspectives of its use in transplantation.

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“…To optimize CoV-2-ST performance in the presence of immunosuppressants which are used for the management of severe COVID-19, genetically modified CoV-2-STs resistant to glucocorticoids 186 or tacrolimus 187 have also been proposed (Table 1 ).…”

Section: Extending the Use Of Psts Beyond The Transplant Settingmentioning

confidence: 99%

“…The add-on treatment with CoV-2-STs was well tolerated and increased the likelihood of recovery by day 30, shortened the time to recovery and lowered by 51% the risk of mortality than SoC-alone, suggesting that the off-the-shelf immunotherapy with CoV-2-STs can serve as a safe and effective treatment in a real-world environment for severe COVID-19. 79 To optimize CoV-2-ST performance in the presence of immunosuppressants which are used for the management of severe COVID-19, genetically modified CoV-2-STs resistant to glucocorticoids 186 or tacrolimus 187 have also been proposed (Table 1).…”

Section: Coronavirus Diseasementioning

confidence: 99%

Pathogen-specific T Cells: Targeting Old Enemies and New Invaders in Transplantation and Beyond

et al. 2023

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Adoptive immunotherapy with virus-specific cytotoxic T cells (VSTs) has evolved over the last three decades as a strategy to rapidly restore virus-specific immunity to prevent or treat viral diseases after solid organ or allogeneic hematopoietic cell-transplantation (allo-HCT). Since the early proof-of-principle studies demonstrating that seropositive donor-derived T cells, specific for the commonest pathogens post transplantation, namely cytomegalovirus or Epstein-Barr virus (EBV) and generated by time-and labor-intensive protocols, could effectively control viral infections, major breakthroughs have then streamlined the manufacturing process of pathogen-specific T cells (pSTs), broadened the breadth of target recognition to even include novel emerging pathogens and enabled off-the-shelf administration or pathogen-naive donor pST production. We herein review the journey of evolution of adoptive immunotherapy with nonengineered, natural pSTs against infections and virus-associated malignancies in the transplant setting and briefly touch upon recent achievements using pSTs outside this context.

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Tacrolimus-resistant SARS-CoV-2-specific T cell products to prevent and treat severe COVID-19 in immunosuppressed patients

Cited by 13 publications

References 134 publications

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

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

Clinical adoptive regulatory T Cell therapy: State of the art, challenges, and prospective

Pathogen-specific T Cells: Targeting Old Enemies and New Invaders in Transplantation and Beyond

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