TRACE is a prospective, multicentre, double blind, placebo controlled randomized phase-III trial. Patients can be included, if viremia is resistant to at least two weeks of antiviral first-line therapy. Only IMPs produced using cells from the original SCT donor are accepted. The IMP consists of donor derived CD4+ and CD8+ T lymphocytes enriched for CMV, EBV, and AdV specificity using the CliniMACS IFNy-Capture System after exposure to overlapping peptide mix. Patients are randomized 2:1 (verum:placebo).
The TRACE project started with creating the basis for manufacturing of the multivirus-specific T-cell product investigated in the clinical trial. Regulatory and logistic hurdles of individualized T-cell products were overcome by harmonization of GMP-procedures and logistics. 7 manufacturing centres have been approved by local as well as competent national authorities. The academic GMP sites can produce for each other across borders, ensuring rapid supply with minimal shipment distances. This model maximizes product freshness and guarantees patient access within and beyond TRACE countries, while building a European infrastructure for decentralized manufacturing of virus-specific T-cell therapies and beyond.
In parallel, the infrastructure for the clinical trial in terms of Sponsor contact office, eCRF, trial committees, data management, security structure and regulatory approach has been set-up. Clinical trial approvals have been obtained from the competent authorities as well as central ethics committees for the participating countries Italy, Germany, the Netherlands, Belgium, France and Spain. Site feasibility assessment has been performed and 33 sites have been selected. The regulatory approach established a comprehensive framework for multinational cell therapy trials, not only setting new ethical standards for randomization, donor use, blinding, patient safety, and data integrity, but also providing a scalable regulatory strategy that can guide all future cell therapy studies. Regulatory and GMP harmonization approach have been made publicly available.
As part of the project, comprehensive immune monitoring before and after adoptive transfer in patients and donors have been established, correlating in vivo T-cell frequencies, gene-expression profiles, functional and phenotypic characteristics with clinical outcomes. Induction of a virus-specific T cell response in vivo could be successfully detected and characterized. The results will guide the design of next-generation, genetically enhanced T-cell therapies with improved efficacy and durability in immunocompromised patients.
The pre-planned interim analysis was performed after 39 evaluable patients (57% of the aimed total). In the interim analysis, 2 primary efficacy endpoints were assessed in 39 evaluable patients across the 2 treatment groups (placebo or verum). The primary endpoints were viral clearance (two consecutive negative PCRs) and progression rates between Day 7 and Week 8 after investigational medical product (IMP) infusion. Significance levels were adjusted for multiple testing. Safety analysis was performed, with GvHD as AE of special interest and no safety concerns have been raised. In light of this last evidence, the independent advisory board (“Scientific Ethics Advisory and Data Safety Monitoring Board”) recommended the study to continue.
