Injection of CD4 and CD8 + T Cells Anti-Cytomegalovirus (CMV) or Anti-adenovirus (CTLantiCMV)
Other: Cell therapy
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Injection of CD4 and CD8 + T Cells Anti-CMV or Anti-adenovirus for the Treatment of Viral Infections Occurring After Allogenic Hematopoietic Stem Cell Transplantation (HSCT)|
- CMV blood viral load by PCR [ Time Frame: at day 21 ] [ Designated as safety issue: No ]
- GvHa evaluation [ Time Frame: at week 1, 2 ,3 ,4 and at month 1, 2, 3, 4, 5, 6 ] [ Designated as safety issue: Yes ]
- Evaluation of clinical signs according to interested organs (lung, liver, bowel,…) [ Time Frame: at week 1, 2 ,3 ,4 and at month 1, 2, 3, 4, 5, 6 ] [ Designated as safety issue: No ]
- Increase of T cells [ Time Frame: at week 1, 2 ,3 ,4, 6, 8, 10, 12 and at month 3, 4, 5, 6 ] [ Designated as safety issue: No ]
|Study Start Date:||September 2010|
|Study Completion Date:||May 2014|
|Primary Completion Date:||January 2014 (Final data collection date for primary outcome measure)|
Experimental: CD4 and CD8 T cell
Injection of specific CD4 and CD8 T cell
Other: Cell therapy
Injection of specific T cell by intravenous way with a posology of 1000 to 5000 CD3 IFN γ+ / kg.
A second injection could be made at day 21
Other Name: Specific CD4 and CD8 T cell
Cytomegalovirus (CMV) and adenoviruses infections are a major source of morbidity and mortality after allogenic haematopoietic stem cell transplantation (HSC). Conventional antiviral therapy have sometimes insufficient efficiency and a significant potential toxicity. Over the last ten years, adoptive immunotherapy has demonstrated its efficiency in treatment of viral infections in this context. Different methods have been used but organizational and technological barriers have prevented a wide use of this therapeutic approach.
This protocol aims to assess the efficiency of treatment by injection of donor CD4 + and CD8 + T cells specifically directed against cytomegalovirus or adenovirus, to patients receiving allogenic transplant with infection of one of these two viruses, and in conventional antiviral treatment failure. Donor memory T cells will be obtained from an aphaeresis of mononuclear cells and will be selected on the basis of their ability to produce interferon-gamma (IFN-g) after stimulation with viral peptides. The speed (48 hours) and the reproducibility of this method let hope a better feasibility for clinical use compared to previously developed technologies. Given epidemiology different after allogenic transplant of HSC of these two viruses, and the relative low expected number of patients with adenovirus infection, statistical analysis will focus exclusively on patients who received T cells for CMV infection. The study of efficiency and tolerance of this adoptive immunotherapy for adenovirus will be considered as a secondary purpose.
This is a multicenter non-comparative phase I/II protocol, which predicts the inclusion of 30 patients with 25 patients infected with CMV, to demonstrate efficiency of 55% with a minimum required efficiency of 30%, an alpha risk of 10% and a strength of 90%. The main purpose of the study is to evaluate the efficiency of this treatment on the level of CMV viral replication 21 days after the first injection. A positive response is defined by a viral load became undetectable or reduced by at least 2 log10. A negative response is defined on the basis of unchanged or increased viral load after injection of T cells; a partial response is defined as a significant decrease (greater than 0.3log10 copies / ml but less than 2 log10) of the viral load, which still remains above the detection threshold. For patients with an isolated organ damage (patient without PCR), a positive response is defined by the healing of the affected organ. In case of negative or partial response 21 days after the first injection, a second injection if available can be programmed in the absence of clinical signs of graft versus host or aggravation of pre-existing GVHa. The secondary purposes are: a) assess the tolerance, in terms of occurrence of acute reaction graft versus host (GVHa) directly due to the injection of T cells ; b) evaluation of indirect biological parameters of efficiency such as injected T cells expansion studied using tetramers specific secretion of IFN-g; c) the study of efficiency and tolerance of this immunotherapy against adenovirus. Inclusion criteria concern children and adults who have received allogenic transplant of HSC, which donor is CMV + and having an active viral infection: 1) in conventional antiviral treatment failure, with a persistent viral load and/or increased after 15 days of treatment or with CMV or ADV disease with organ damage documented without systemic replication (if possible, with a CMV PCR or ADV PCR positive in the organ), or 2) in intolerance or toxicity situation of this treatment which prevents its pursuit. Donor T cells will be injected if the following conditions are observed : 1) donor chimerism > 10%, 2) absence of GvHa ≥ grade II 3) absence of severe organ failure. The antiviral drug therapy may eventually be continued jointly with cellular immunotherapy.
Number of participating centers: grafter centers of Ile-de-France and Hospital Edouard HERRIOT to Lyon, CHU of Nantes, CHU of Poitiers (so 10 centers). The study duration will be 42 months, with an inclusion period of 36 months and a follow-up period of 6 months from the last inclusion. If the study gives expected results, a compared phase III trial will be considered for the treatment of CMV infections and a Phase I/II for the treatment of adenoviral infection.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01325636
|Biotherapy department, Hôpital Necker - Enfants Malades|
|Paris Cedex 15, France, 75743|
|Principal Investigator:||Marina CAVAZZANA, ph||Assistance Publique - Hôpitaux de Paris|