About the TRACE Project
Transfer of multivirus-specific T cells following transplantation:
The “TRACE” project is a multi-national project (Belgium, France, Germany, Italy, the Netherlands, UK) and is coordinated by the LMU Munich, Germany. The overall objective of the TRACE project is to bring Adoptive Transfer of virus-specific T cells into clinical routine, thereby facilitating that every single patient in Europe will have the possibility to receive this curative treatment.
This project is funded by the European Commission within Horizon2020 Framework Programme.
Allogeneic stem cell transplantation is a curative treatment for a variety of diseases. However, refractory viral infections, such as Cytomegalovirus (CMV), Adenovirus (AdV) and Epstein-Barr virus (EBV) after stem cell transplantation are life-threatening conditions due to the deficient T-cell response and lack of effective treatment options.
Although cellular immunotherapy is considered a major breakthrough in medicine, none of the cellular treatment approaches has yet become a standard treatment. The reason for this limited translation into daily clinical practice is the lack of controlled, prospective clinical trials investigating efficacy of immunotherapy.
TRACE ("TRansfer of Adenovirus, Cytomegalovirus and Epstein-Barr virus-specific T cells") is the first multi-national clinical phase-III trial to prove efficacy and safety of Adoptive T-cell transfer in immunocompromised individuals. TRACE will provide data, approvals of national authorities and logistics to overcome regulatory and structural hurdles.
The study is a major milestone in the development of medicine and health economics to bring such a unique personalised treatment approach into a clinical efficacy trial. Further, it will bring medicine towards physiological self-protection of the human body instead of toxic, cost-intensive agents and will thereby improve survival and quality of life of the patients.
Adoptive T-cell Transfer against Viral Infections
In healthy individuals, persistent viruses like Cytomegalovirus (CMV), Adenovirus (AdV) and Epstein-Barr virus (EBV) are often asymptomatic or cause mild symptoms. However, stem cell transplantation exposes patients to periods of marked immunosuppression, during which viral infections are an important cause of morbidity and mortality. Developments in basic immunology have led to a greater understanding of the nature of protective immunity in immunocompetent donors and this knowledge is now being used to direct immunotherapeutic protocols: Protective T-cell immunity could be restored by means of a procedure known as Adoptive T-cell Transfer.Therefore functional virus-specific T cells are directly isolated from a seropositive donor: The donor’s white blood cells are isolated from peripheral blood using a procedure called leukapheresis. From these cells, virus-specific T cells are selected via the Cytokine Capture Approach (see T-cell Product). Virus-specific T cells are then directly infused into the patient where they are re-stimulated by the viral infection leading to expansion and induction of viral clearance as well as sustained protection.
Virus-specific T cells becoming a Therapeutic Product
Different strategies have been developed to enrich, isolate or purify virus-specific T cells. For the TRACE study, the Cytokine Capture Technique was chosen due to the advantages of isolation of cytotoxic as well as T-helper cells, isolation of functional T-cell clones and of clones against known as well as unknown viral epitopes. Further this approach is available for patients and donors of all HLA-types.
In the TRACE study multivirus-specific (CMV, AdV and EBV-specific) T cells are isolated from blood of seropositive donors by an instrument called CliniMACS® Prodigy. The CliniMACS® Prodigy allows automated manufacturing of this T-cell product for adoptive T-cell therapy via the Cytokine Capture Technique and performs all steps in a functionally closed system.
Within T-cell product manufacture, the cellular starting material is incubated with specific Cytomegalovirus (CMV), Adenovirus (AdV) and Epstein-Barr virus (EBV) antigens. As a consequence, only the virus-specific T cells are induced to produce cytokines as they do under physiological conditions upon viral infection. These virus-specific, cytokine-secreting cells are labelled and conjugated to magnetic particles for the following enrichment using a magnetic column.