A Prospective Randomized Trial of ECP in Subclinical AMR

Official title

The Use of Extracorporeal Photopheresis as Immunomodulatory Therapy of Subclinical Antibody-mediated Rejection After Lung Transplantation: a Prospective RCT

Overview

The goal of this clinical trial is to evaluate the therapeutic effect of extracorporeal photopheresis in subclinical antibody-mediated rejection after lung transplantation.The main questions it aims to answer are: 1. Does ECP therapy result in a significant reduction in MFI (Mean Fluorescence Intensity) from the baseline MFI in clinically stable patients with persistent (\>6 months) dnDSAs (MFI\>1000)? 2. What is the impact of ECP therapy on the following outcomes in these patients: ACR, clinical AMR, CLAD, infections, drop-out rate, survival, adverse events? Participants will be randomized into two groups. Each group will include 40 patients. The control group will be observed and no active treatment will be administered. The treatment group will receive extracorporeal photopheresis. First, a two-day treatment cycle will be performed once every second week for the first two months. Then, a two-day treatment cycle will be performed once a month for 6 months. Researchers will compare the two groups regarding: MFI value, development of ACR, clinical AMR, CLAD, infections, survival, adverse events, immunophenotyping, miRNA expression profiling, cytokine expression, gene expression signature of PBMCs and proteomic characterization.

Detailed description

Donor-specific antibodies (DSA) and antibody-mediated rejection have gained significant attention recently due to their serious consequences, but there are limited effective treatments for persistent DSAs in patients without graft dysfunction due to their associated severe side effects. Our center demonstrated that extracorporeal photopheresis (ECP) can potentially reduce the mean fluorescence intensity of dnDSAs in recipients with antibody-mediated rejection (AMR), suggesting it as a safe option for treating subclinical AMR with dnDSAs and inducing tolerogenic immunomodulation in this complex population.

The hypothesis underlying the proposed randomized controlled trial is that ECP might have the potential to reduce the burden of de novo donor-specific antibodies after lung transplantation, by modulating host humoral alloresponse and promoting tolerance, without provoking side effects.

Our primary objective is to evaluate the therapeutic effect of ECP in terms of reduction of dnDSAs titer in clinically stable patients with persistent (\>6 months) dnDSAs (MFI\>1000). As secondary objective, we intend to assess the therapeutic effect of ECP on incidence of clinical AMR, ACR, CLAD, survival and occurrence of infectious complications as well as the rate of adverse effects. Our experimental objectives are to provide an in-depth analysis of the immunological effects of ECP.

80 patients with persistent dnDSAs (\> 3 months) with a MFI \> 1000 will be randomized into two groups. Each group will include 40 patients. Patients will be stratified according to the presence of HLA-DQ. The control group will be observed and no active treatment will be administered. This is our standard of care in the studied clinical situation. Treatment group will receive extracorporeal photopheresis. First, a two-day treatment cycle will be performed once every second week for the first two months. Then, a two-day treatment cycle will be performed once a month for 6 months. To elucidate the specific mechanisms of ECP in modulating humoral alloresponse, a series of studies are planned: 1) flow cytometric immunophenotyping, 2) miRNA expression profiling, 3) cytokine expression, 4) gene expression signature of PBMCs, 5) proteomic characterization.

The proposed study aims to address this clinical need by investigating the effects of a safe therapeutic modality such as ECP. This study may have a dual benefit: first, it may reduce the burden of dnDSAs in lung transplant recipients, thereby reducing the incidence of antibody-mediated rejection, and second, it may promote host tolerance to the graft. In addition, we will investigate the immunomodulatory mechanisms of ECP in the context of humoral allogeneic response, which has not been previously investigated.

Interventions

• Procedure Extracorporeal Photopheresis
  Patients randomized into the interventional group will receive ECP. ECP will be started within one week after randomization. Initially a two-day treatment cycle will be performed once every second week for the first two months. Then, a two-day treatment cycle will be performed once a month for 6 months.

Primary outcome measures

• Reduction of dnDSA titer from baseline MFI [Time frame: 6 months]

Secondary outcome measures (1)

• Incidence of clinical AMR, ACR, CLAD, survival, infectious complications, adverse effects [Time frame: 6 months]

Eligibility criteria

Inclusion criteria

• Bilateral lung transplantation
• dnDSAs > 3 months with a MFI > 1000
• No signs of allograft dysfunction
• Alemtuzumab induction therapy

Exclusion criteria

• Inclusion in other studies
• Retransplantation
• Multi-organ transplantation
• > 12 months after transplantation

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Austria · 1 center

• Medical University of Vienna — Vienna

Belgium · 1 center

• UZ Leuven — Leuven

Croatia · 1 center

• University Hospital Center Zagreb — Zagreb

Denmark · 1 center

• Copenhagen University Hospital, Rigshospitalet — Copenhagen

France · 1 center

• Hôpital Foch — Suresnes

Italy · 1 center

• Policlinico San Matteo Pavia Fondazione IRCCS — Pavia

Slovenia · 1 center

• University Medical Centre Ljubljana — Ljubljana

Publications

• Chambers DC, Perch M, Zuckermann A, Cherikh WS, Harhay MO, Hayes D Jr, Hsich E, Khush KK, Potena L, Sadavarte A, Lindblad K, Singh TP, Stehlik J; International Society for Heart and Lung Transplantation. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-eighth adult lung transplantation report - 2021; Focus on recipient cha PMID 34446355
• Benazzo A, Auner S, Boehm PM, Morscher A, Schwarz S, Vidmar B, Dzubur F, Schweiger T, Hoda AM, Moser B, Matilla JR, Murakozy G, Lang G, Taghavi S, Klepetko W, Hoetzenecker K, Jaksch P. Outcomes with alemtuzumab induction therapy in lung transplantation: a comprehensive large-scale single-center analysis. Transpl Int. 2021 Dec;34(12):2633-2643. doi: 10.1111/tri.14153. Epub 2021 Nov 16. PMID 34738249
• Iasella CJ, Ensor CR, Marrari M, Mangiola M, Xu Q, Nolley E, Moore CA, Morrell MR, Pilewski JM, Sanchez PG, McDyer JF, Zeevi A. Donor-specific antibody characteristics, including persistence and complement-binding capacity, increase risk for chronic lung allograft dysfunction. J Heart Lung Transplant. 2020 Dec;39(12):1417-1425. doi: 10.1016/j.healun.2020.09.003. Epub 2020 Sep 10. PMID 32981841
• Benazzo A, Worel N, Schwarz S, Just U, Nechay A, Lambers C, Bohmig G, Fischer G, Koren D, Murakozy G, Knobler R, Klepetko W, Hoetzenecker K, Jaksch P. Outcome of Extracorporeal Photopheresis as an Add-On Therapy for Antibody-Mediated Rejection in Lung Transplant Recipients. Transfus Med Hemother. 2020 Jun;47(3):205-213. doi: 10.1159/000508170. Epub 2020 May 5. PMID 32595425
• Gasparro FP, Felli A, Schmitt IM. Psoralen photobiology: the relationship between DNA damage, chromatin structure, transcription, and immunogenic effects. Recent Results Cancer Res. 1997;143:101-27. doi: 10.1007/978-3-642-60393-8_8. No abstract available. PMID 8912415
• Kurts C, Kosaka H, Carbone FR, Miller JF, Heath WR. Class I-restricted cross-presentation of exogenous self-antigens leads to deletion of autoreactive CD8(+) T cells. J Exp Med. 1997 Jul 21;186(2):239-45. doi: 10.1084/jem.186.2.239. PMID 9221753
• Maeda A, Schwarz A, Bullinger A, Morita A, Peritt D, Schwarz T. Experimental extracorporeal photopheresis inhibits the sensitization and effector phases of contact hypersensitivity via two mechanisms: generation of IL-10 and induction of regulatory T cells. J Immunol. 2008 Nov 1;181(9):5956-62. doi: 10.4049/jimmunol.181.9.5956. PMID 18941184
• Maeda A, Schwarz A, Kernebeck K, Gross N, Aragane Y, Peritt D, Schwarz T. Intravenous infusion of syngeneic apoptotic cells by photopheresis induces antigen-specific regulatory T cells. J Immunol. 2005 May 15;174(10):5968-76. doi: 10.4049/jimmunol.174.10.5968. PMID 15879089

Identifiers

NCT: NCT06112951 · 1578/2023

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗