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    Improving the migration and function of CAR T cells in solid tumors


    Principal investigator : Emmanuel Donnadieu
    Contact : emmanuel.donnadieu@inserm.fr – Tel : +33 1 40 51 65

     

    Objective


    Adoptive transfer of T-cells expressing chimeric antigen receptors (CAR) has shown a remarkable clinical efficacy against advanced B-cell malignancies but not yet against solid tumors. By using advanced imaging techniques, we have made significant progress in the understanding of how T cells are blocked in their antitumor activities and revealed a default in the ability of T cells to contact tumor cells. Our goal is to explore the reasons that limit CAR T cells from massively infiltrating solid tumors.
    The group
    In 2020, this group is composed of:
    -    David Espie (PhD student, CIFRE funding),
    -    Lene Vimeux (Engineer, CNRS)
    -    Luca Simula (Post-doc) will join the group at the end of 2020
    -    Emmanuel Donnadieu (Research Director, CNRS).

     

    Research Interests


    Recent years have seen the emergence of novel cancer immunotherapies such as those relying on genetically engineered T cells. Although CAR T cells can be extremely effective in killing malignant B cells, this strategy has not yet produced favorable clinical responses in targeting solid malignancies. Over the last years, we have improved our understanding of key negative and positive regulations of anti-tumoral immune cells that directly apply to CAR T cells. In particular, we have shown that T lymphocytes may be blocked in their antitumor activities and identified a detrimental impact of extracellular matrix and of macrophages associated with progressing tumors (TAM) (Salmon, J. Clin. Invest. 2012) (http://www.ncbi.nlm.nih.gov/pubmed/22293174), (Peranzoni, PNAS 2018) (http://www.ncbi.nlm.nih.gov/pubmed/29632196). Our overall objective is to take advantage of tools and expertise developed by the laboratory to target these cells and elements, in order to overcome them and generate CAR T cells with an improved efficacy against solid tumors.
     
    (sous-groupe ED Video 2)
    The team has numerous interactions with academic and industrial partners (Miltenyi Biotec, Invectys). We participated in a European project (H2020, CARAT) whose objective was to optimize CAR T cell therapy in solid tumors (http://carat-horizon2020.eu/carat-network/partners-in-depth/inserm).
    Most of our experiments rely on the use of powerful and original approaches: confocal and two-photon microscopy, a preclinical model of tumor slices (link towards tissue slice page).

     

    Main publications and presentations


    Kantari-Mimoun C, Barrin S, Haghiri S, Gervais C, Mittelstat J, Mockel-Tenbrinck N, Kinkhabwala A, Damotte D, Lupo A, Sibony M, Alifano M, Vimeux L, Dondi E, Bercovici N, Trautmann A, Kaiser A and E Donnadieu. CAR T cell entry into tumor islets is a two-step process dependent on IFN and ICAM-1.  BioRxiv, 2020.05.27.119198. (https://www.biorxiv.org/content/10.1101/2020.05.27.119198v1)


    Nicolas-Boluda, A., Vaquero, J., Barrin, S., Kantari-Mimoun, C., Ponzo, M., Renault, G., … Donnadieu, E. (2020). Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment. BioRxiv, 2020.05.19.104430. (https://biorxiv.org/cgi/content/short/2020.05.19.104430v1)


    Bercovici N, Guerin MV, Trautmann A, Donnadieu E. (2019). The Remarkable Plasticity of Macrophages: A Chance to Fight Cancer. Frontiers in immunology  10:1563. (http://www.ncbi.nlm.nih.gov/pubmed/31354719)


    Peranzoni E, Lemoine J, Vimeux L, Feuillet V, Barrin S, Kantari-Mimoun C, Bercovici N, Guerin M, Biton J, Ouakrim H, Regnier F, Lupo A, Alifano M, Damotte D, Donnadieu E (2018) Macrophages impede CD8 T cells from reaching tumor cells and limit the efficacy of anti-PD-1 treatment. Proceedings of the National Academy of Sciences of the United States of America 115 (17):E4041-E4050. (http://www.ncbi.nlm.nih.gov/pubmed/29632196)


    Donnadieu, E (2014). Defects in T cell migration within tumors: a role for extracellular matrix architecture. Annual Meeting 2014 of the American Association of Cancer Research. Webcast of the presentation: http://webcast.aacr.org/console/player/23637/?mediaType=audio&speakerp=-1633495356


    Salmon, H., K. Franciszkiewicz, D. Damotte, M.C. Dieu-Nosjean, P. Validire, A. Trautmann, F. Mami-Chouaib, and E. Donnadieu. Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors. J Clin Invest. 2012; 122:899-910. (http://www.ncbi.nlm.nih.gov/pubmed/22293174)

     

    Financial supports


    These projects are supported by la Ligue Contre le Cancer (Equipe Labellisée Ligue Contre le Cancer), les sites de recherche intégré sur le cancer (SIRIC) – Cancer Research for Personalized Medicine (CARPEM), the European Union’s Horizon 2020 and the biotech company Invectys.

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