Objectif Adoptive cell transfer of tumor-reactive lymphocytes has been shown to mediate the regression of large solid tumors in cancer patients. To overcome the need to isolate and expand tumor-reactive lymphocytes that pre-exist in the patient, it is possible to engineer cells to express a tumor-specific T-cell receptor - TCR, thus reprogramming their specificity. This pioneering therapeutic approach has been demonstrated to cause cancer regression in terminal melanoma patients that were refractory to previous treatments. However, little is known about TCR affinity requirements for mounting an optimal immune response in this context. While high affinity TCR may confer to the host lymphocyte excellent cytotoxic ability, several studies have shown that a too-high affinity may actually be detrimental to T-cell function. We therefore hypothesize that T-cell receptor affinity can influence the cytotoxic activity of lymphocytes in TCR-transfer treatment and that it is possible to define an optimal range or threshold of TCR affinity for mounting an efficient anti-tumor response. To test this, we propose to use the ovalbumine specific OT1 TCR model and to construct a CDR3-modified TCR library that will be retrovirally transduced into a reporter cell line. By combining the efficacy of a high-throughput screening method and the direct selection of mutant TCR ex-vivo, we are planning to isolate several TCRs with different affinities. These molecules will be transduced and expressed in primary lymphocytes to assess their biological function in-vitro. Using the B16-OVA melanoma model, we will adoptively transfer lymphocyte populations expressing mutant TCRs with different affinities and compare their activity in order to study the influence of TCR affinity on anti-tumor cytotoxic response. Thus, we expect to answer both fundamental and translational questions related to the ability of the immune system to recognize and eliminate tumor cells in the context of TCR-transfer treatment. Champ scientifique medical and health sciencesclinical medicineoncologyskin cancermelanomamedical and health sciencesbasic medicineimmunology Mots‑clés Cancer Immunotherapy DNA therapy Immunology T-cell receptor T-lymphocytes Programme(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Thème(s) PEOPLE-2007-4-3.IRG - Marie Curie Action: "International Reintegration Grants" Appel à propositions FP7-PEOPLE-2007-4-3-IRG Voir d’autres projets de cet appel Régime de financement MC-IRG - International Re-integration Grants (IRG) Coordinateur BAR ILAN UNIVERSITY Contribution de l’UE € 100 000,00 Adresse BAR ILAN UNIVERSITY CAMPUS 52900 Ramat Gan Israël Voir sur la carte Type d’activité Higher or Secondary Education Establishments Contact administratif Estelle Waise (Ms.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée
