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Graft vs Host Disease

Hematologic Diseases

Homologous Wasting Disease

Injection T lymphocytes iCASP9 ΔCD19 (2.10e6, 5.10e6 and 10.10e6 Gene Modified Cells (GMC)/kg).

Injection T lymphocytes iCASP9 ΔCD19 (2.10e6, 5.10e6 and 10.10e6 GMC/kg). Patients who develop GVHD after administration of Gene Modified Cells (GMC) will be treated with dimerizer drug (AP1903)

Intravenous injection of the T lymphocytes armed with the iCASP9 suicide gene

T lymphocytes iCASP9 ΔCD19

AP1903 drug will be administrated at a dose of 0.4 mg/kg by intravenous route in the two following cases:

* Acute Grade ≥II or symptomatic Grade I GvHD justifying systemic immunosuppression therapy;
* Grade ≥3 toxicity attributable to GMC.

Dimerizer drug AP1903

Eric DECONINCK, MD, PhD, HDR

Fabrice LAROSA, MD

DECONINCK Eric, MD, PhD, HDR

Christophe FERRAND, PhD, HDR

Marina DESCHAMPS, PhD

This study evaluates the frequency of occurrence, severity, and response to treatment by a chemical agent, notably the dimerizer AP1903 (Bellicum Pharmaceuticals compagny), in the case of acute Graft versus Host Disease (aGvHD) occurring after the administration of T-lymphocytes expressing iCASP9 and concomitantly to a bone marrow graft depleted in B- and T-lymphocytes

Haematopoietic transplantation may result in serious complications, notably graft versus host disease (GvHD).

T-lymphocyte depletion of the bone marrow graft is able to prevent GvHD, while increasing the risk of rejection and reducing the antileukaemic effect of the graft (graft versus leukaemia, GvL). In a previous study, the investigators showed that the ex vivo transfer of the Herpes simplex thymidine kinase suicide gene (HSV-TK) into the graft's T lymphocytes prior to reinjection was not associated with immediate toxicity, while allowing for the prolonged recirculation of genetically modified cells (GMC) and control of induced GvHD by ganciclovir (GCV). In addition, this study revealed the existence of GMC resistant to GCV, an immunodeficiency of transduced cells, as well as an increased risk of Epstein-Barr virus (EBV)-induced lymphoproliferative disease. To overcome these difficulties, investigators improved the methodology of producing GMC by using a new vector (pMSCV-iCASP9-2A-ΔCD19) whose susceptibility gene was of human origin and associated with a human surface marker (non-functional) enabling the cell selection process. Moreover, the demonstration that the induced GvHD in this setting could be controlled by the administration of GCV alone led to significantly increase the number of genetically modified T-lymphocytes administered and omit cyclosporin prophylaxis of GvHD.

This phase I study will include 12 patients and will be conducted according the dose escalation method (2.10e6, 5.10e6 and 10.10e6 GMC / kg respectively for levels I, II \& III). GMC will be prepared in the Cell and Tissue Engineering Laboratory (advanced therapy medicinal products departement) of the french Blood center (EFS) in Besançon, France, and sent to the transplantation department.

T Lymphocytes (LT) Expressing iCASP9 and ΔCD19 in Allogeneic Haematopoietic Transplantation.

Use of Genetically Modified T-lymphocytes Expressing the Inducible Human Caspase 9 Gene (iCASP9) and the Selection Gene ΔCD19 in Allogeneic Haematopoietic Transplantation.

Full Blood count and Blood Cell phenotyping (T \& B Lymphocytes, Natural Killers cells (NK), polynuclear cells...)

Hematopoietic reconstitution will be assessed when % of Blood cells reach normal account values.

Bone marrow smear analysis.

Haematopoietic engraftment will be assessed when proportion of marrow cells reach normal account values.

Chimerism Analysis by quantitative mesurement (mesure of % of Donor \& recipient cells)

Full chimerism will be assessed when chimerim will reach 100% of donor profile.

Monitoring of Infections post-transplantation will be studied by analysis of frequency of infection's events.

(number of infection's events by patients and/or frequency)

Molecular residual disease (MRD) analysis of biological markers of the initial hematological disease either by molecular biology and/or flow cytometry.

GvL effect will be assessed by evaluation of decrease of initial tumoral load.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
T Lymphocytes (LT) Expressing iCASP9 and ΔCD19 in Allogeneic Haematopoietic Transplantation.	NCT02849886	Graft Versus Ho... Hematological M...	T lymphocytes i... Dimerizer drug ...	40 Years - 55 Years	Centre Hospitalier Universitaire de Besancon
T Lymphocytes (LT) Expressing iCASP9 and ΔCD19 in Allogeneic Haematopoietic Transplantation.	NCT02849886	Graft Versus Ho... Hematological M...	T lymphocytes i... Dimerizer drug ...	40 Years - 55 Years	Centre Hospitalier Universitaire de Besancon

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