Sélection et modifications fonctionnelles des lymphocytes T pour l’immunothérapie

SELECTION & FUNCTIONAL MODIFICATIONS OF T CELLS FOR IMMUNOTHERAPY

To combine the immune potential of T cells and Ab therapy, we have previously shown that T cells transduction with a fusion receptor that binds the Fc portion of human Ig enable them to mediate Ab-dependent cellular cytotoxicity (ADCC) (B. Clémenceau et al., Blood 2006). This fusion receptors previously described included the FcgammaRIIIa (CD16) receptor coupled to different chains intended to translate the signal. More recently, we questioned whether the transfection of CD16 alone into human T lymphocytes and NK cells could be sufficient for CD16 expression and function, or whether the cotransfection of a transducing chain was mandatory. Our results demonstrated that transfection of CD16 alone into a human NK cell line and primary T cells can be sufficient for CD16 expression and function. In the context of immunotherapy, such a strategy is by nature safer than the use of a chimeric receptor, and is freely available (J. Ollier et al, 2017 ImmunoHorizons).

In a further development we showed that a chimeric human/murine Fc receptor could also be expressed and function in a human NK cell line and human T lymphocytes. We used this system of murine/human chimeric effector allowing to perform xenogeneic ADCC assay to search for ADCC antigens useful against Merkel carcinoma cells. (J. Ollier et al., 2018, Cancer Immunol Imunother). In this work we identified EpCAM as one target of interest. Optimization of this screening system for ADCC targets identification is underway in collaboration with two biotechnology companies: CleanCell and OSE imunotherapeutics. Once finalized, the new chimeric effector cells will be used for ADCC target identification against hematologic malignancies.

Analysis of the longevity and maintenance of the functional characteristics of genetically modified T lymphocyte clones enabled us to demonstrate that it is possible to produce genetically modified human T clone libraries for clinical use (R. Vivien R. et al, Cytotherapy, 2018 in press). In this publication was presented a T cell clone which we intend to use in the clinical protocol entitled: “Induction and control of a GVH/GVL effect using HLA-DP specific T cell clones.» This protocol is currently being evaluated by the ANSM. Two other clinical protocols are in progress, which objective are to correct the host/EBV imbalanced in the context of two autoimmune diseases: the lupus (SLE), and multiple sclerosis (SLE). The lupus project is currently including patients (5/10). The SLE project should be send to the ANSM early 2019.

PUBLICATIONS 2017-2018

Jarry U et al, 2018 J Vis Exp, 139: doi:10.3791/57870
Straetemans T et al, 2018 Front Immunol, 30; 9:1062
Ollier J et al, 2018 Cancer Immuno Immunother, 67:1209-1219
Retière C et al, 2018 Oncotarget, 27:11451-11464
Vivien R et al, 2018  Cytotherapy, 20:436-452
Fleurence J et al, 2017 J Immunol Res, doi: 10.1155/5604891
Ollier J et al, 2017 ImmunoHorizon 1:63-70
Vié H et al, 2017 Transfu Clin Biol. 24:256-262
Rossignol A et al, 2017 Mabs 9:521-535