Complement inhibition does not impair the clinical antiviral capabilities of virus-specific T-cell therapy

Rubinstein, Jeremy D.; Zhu, Xin‐Guang; Lutzko, Carolyn; Leemhuis, Tom; Cancelas, José A.; Jodele, Sonata; Bollard, Catherine M.; Hanley, Patrick J.; Davies, Stella M.; Grimley, Michael; Nelson, Adam

doi:10.1182/bloodadvances.2020002252

Cited by 5 publications

(4 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Crosstalk between complement pathways and adaptive immunity have been described, and C5a has been shown to impact activity of antigen presenting cells as well as survival, differentiation, and activity of CD4 + T cells [68][69][70][71][72] . Of note, Rubinstein et al did not note an adverse impact of TMA or eculizumab treatment on clinical response to VST therapy in 13 patients, and demonstrated persistent interferon-γ release during complement inhibition 73 . Viral load, patient acuity, and degree of HLA match did not appear to impact chances of responses, though confirmation of an HLA restriction shared between the VST donor and recipient trended toward improved responses.…”

Section: Discussionmentioning

confidence: 99%

Antiviral cellular therapy for enhancing T-cell reconstitution before or after hematopoietic stem cell transplantation (ACES): a two-arm, open label phase II interventional trial of pediatric patients with risk factor assessment

Keller,

Hanley,

Chi

et al. 2024

Nat Commun

Self Cite

View full text Add to dashboard Cite

Viral infections remain a major risk in immunocompromised pediatric patients, and virus-specific T cell (VST) therapy has been successful for treatment of refractory viral infections in prior studies. We performed a phase II multicenter study (NCT03475212) for the treatment of pediatric patients with inborn errors of immunity and/or post allogeneic hematopoietic stem cell transplant with refractory viral infections using partially-HLA matched VSTs targeting cytomegalovirus, Epstein-Barr virus, or adenovirus. Primary endpoints were feasibility, safety, and clinical responses (>1 log reduction in viremia at 28 days). Secondary endpoints were reconstitution of antiviral immunity and persistence of the infused VSTs. Suitable VST products were identified for 75 of 77 clinical queries. Clinical responses were achieved in 29 of 47 (62%) of patients post-HSCT including 73% of patients evaluable at 1-month post-infusion, meeting the primary efficacy endpoint (>52%). Secondary graft rejection occurred in one child following VST infusion as described in a companion article. Corticosteroids, graft-versus-host disease, transplant-associated thrombotic microangiopathy, and eculizumab treatment correlated with poor response, while uptrending absolute lymphocyte and CD8 T cell counts correlated with good response. This study highlights key clinical factors that impact response to VSTs and demonstrates the feasibility and efficacy of this therapy in pediatric HSCT.

show abstract

Section: Discussionmentioning

confidence: 99%

Antiviral cellular therapy for enhancing T-cell reconstitution before or after hematopoietic stem cell transplantation (ACES): a two-arm, open label phase II interventional trial of pediatric patients with risk factor assessment

Keller,

Hanley,

Chi

et al. 2024

Nat Commun

Self Cite

View full text Add to dashboard Cite

show abstract

“…9 No large study has described the effect of eculizumab on T-cell function during engraftment. However, a prior study by Rubinstein et al 26 showed that eculizumab therapy did not impair viral specific T-cell function in patients who underwent HCT. Furthermore, multiple studies have shown no adverse effect of pre-HCT eculizumab therapy on engraftment in patients with paroxysmal nocturnal hemoglobinuria.…”

Section: Donor Chimerismmentioning

confidence: 93%

Graft rejection markers in children undergoing hematopoietic cell transplant for bone marrow failure

et al. 2021

Self Cite

View full text Add to dashboard Cite

Graft rejection (GR) is a poorly understood complication of hematopoietic cell transplant (HCT). GR risk factors are well-published, but there are no reliable biomarkers or therapies known. Fever is the most common symptom of GR but no study has evaluated fever kinetics as a diagnostic marker of GR. The objectives of this study were to identify mechanisms, biomarkers and potential therapies for GR after HCT. Chemokine ligand 9 (CXCL9), b-cell activating factor (BAFF) and complement markers (sC5b-9, C3a and C5a) were measured in 7 GR patients and compared to 15 HCT controls. All patients had a diagnosis of aplastic anemia, Fanconi anemia or genetically undefined chromosomal fragility syndrome. All GR patients were febrile during GR, therefore control HCT patients were matched for diagnosis and early fevers after HCT. GR patients had significantly higher CXCL9, BAFF and sC5b-9 at the time of fever and GR compared to control HCT patients at the time of fever. The maximum fever was significantly higher and occurred significantly later in the transplant course in GR patients compared to febrile HCT controls. These data support the use of CXCL9, BAFF, sC5b-9 and fever kinetics as GR markers. Two GR patients underwent a 2nd HCT that was complicated by high fevers. Both patients received interferon and complement blockers during their 2nd HCT and both preserved their graft. These laboratory and clinical findings support larger studies to evaluate the safety and efficacy of interferon, complement and BAFF inhibitors for the prevention and treatment of GR after HCT.

show abstract

“…Virus specific T‐cells (VSTs) are a particularly exciting new era of less toxic anti‐viral therapies, that will hopefully reduce the incidence of viral induced TMAs. We have previously shown that VST efficacy is not impaired by eculizumab, which means the two treatments can be safely used together 80 …”

Section: Additional Considerations For Ta‐tma Therapy and Complement ...mentioning

confidence: 95%

“…C5a or C5aR1 blockade can theoretically inhibit VSTs but this pathway is importantly unaffected by C5 blockers like eculizumab 112–114 . Rubinstein et al also previously showed that VSTs are fully functional with concurrent C5 blockade 80 …”

Section: Additional Considerations For Ta‐tma Therapy and Complement ...mentioning

confidence: 99%

Reeling in complement in transplant‐associated thrombotic microangiopathy: You're going to need a bigger boat

Jodele

Sabulski

2023

American J Hematol

Self Cite

View full text Add to dashboard Cite

Over the last decade there have been numerous advances in both the diagnosis and treatment of transplant-associated thrombotic microangiopathy (TA-TMA). These are largely the result of an improved understanding of complement activation in TA-TMA and the ability to prevent end organ injury and death with timely initiation of complementblocking therapies. In this article, we review our current understanding of the pathophysiology of TA-TMA, particularly as it pertains to complement activation, endothelial injury, and clinical management. We then review novel complement-blocking therapies that are currently under investigation for use in TA-TMA, as well as discuss special considerations for complement-blocking therapy in hematopoietic stem cell transplant recipients. Through these reviews we aim to answer or at least provide an educated discussion on the most commonly posed TA-TMA management questions and dilemmas.

show abstract

Complement inhibition does not impair the clinical antiviral capabilities of virus-specific T-cell therapy

Abstract: Key Points The use of terminal complement blockade is compatible with virus-specific T-cell (VST) expansion and clinical effectiveness. VST and complement-blocking agent concurrent therapy may be safely used in patients with thrombotic microangiopathy and viral infections.

Cited by 5 publications

References 24 publications

Antiviral cellular therapy for enhancing T-cell reconstitution before or after hematopoietic stem cell transplantation (ACES): a two-arm, open label phase II interventional trial of pediatric patients with risk factor assessment

Antiviral cellular therapy for enhancing T-cell reconstitution before or after hematopoietic stem cell transplantation (ACES): a two-arm, open label phase II interventional trial of pediatric patients with risk factor assessment

Graft rejection markers in children undergoing hematopoietic cell transplant for bone marrow failure

Reeling in complement in transplant‐associated thrombotic microangiopathy: You're going to need a bigger boat

Contact Info

Product

Resources

About