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Caractérisation de la mort cellulaire induite par un anticorps trifonctionnel

Abstract : The development of cancer in an immunocompetent individual reflects, in part, a tumor escape from the immunosurveillance. The tumor escape is a complex, multifactorial, in which tumor cells will evade the defense mechanisms of the host by changing their microenvironment. Therefore, restoration or induction of these defense mechanisms is one of the therapeutic strategies against cancer. One of the principles of immunotherapy is based on the injection of antibodies that target tumor cells or effector cells of immunity. The anti-tumor efficacy of these antibodies has been greatly improved by a better understanding of modes of action and modulatory effects of these antibodies.Thus, to optimize the action of immune effectors to tumor cells, a bispecific antibody, trifunctional: catumaxomab, capable of binding to the adhesion molecule of the epithelial cells (EpCAM), expressed by tumor cells and the CD3 antigen of T cells, has been developed mainly in intraperitoneal treatment of refractory malignant ascites.The objective of this study was to determine the immunomodulatory effects of catumaxomab on tumoral cells expressing EpCAM, from two experimental models (allogeneic and autologous), evaluate and characterize cytotoxicity induced by catumaxomab, and analyze the presence of stress signals inducing immunogenic cell death such as membrane exposure of calreticulin by pre-apoptotic tumor cells, release of HMGB1 and of adenosine triphosphate (ATP) in the extracellular medium, inducing a T cell activation.In the presence of EpCAM + cells, catumaxomab induced a major the activation of T cells (expression of CD69, CD107a, HLA-DR and PD1), stimulated an inflammatory response Thelper type 1 (Th1) and the synthesis of interferon-gamma by CD8 T cells. Catumaxomab committed CD16 NK cells and monocytes. More, in models allogeneic catumaxomab, caused cell death associated with ATP release and induced an immunogenic cell death after pre-incubation of oxaliplatin.Therefore, catumaxomab modulates the immune environment in malignant ascites, and convert chronic and immunosuppressive inflammation (Th2) in acute and immunogenic inflammation (Th1). However, in these conditions, catumaxomab alone does not seem to trigger immunogenic cell death.the cytotoxicity of this bispecific antibody could be enhance by different techniques: (1) combining with chemotherapy such as oxaliplatin to promote immunogenic cell death, (2) refining its action on CD3 lymphocytes by changing its spatial configuration (BiTE antibody), (3) increasing its affinity for the FcR of accessory cells (Fc aglycosylated), (4) increasing its cytotoxicity by changing the target directed against the immune molecule (anti-PD-1 ...). Finally, the clinical use could be facilitated by this humanizing murine chimeric antibody to prevent the formation of anti-murine antibodies directed against catumaxomab.A phase II clinical trial aimed to evaluate the efficacy of intraperitoneal catumaxomab after complete cytoreductive surgery of gastric carcinomatosis in patients who received preoperative systemic chemotherapy with oxaliplatin have just started. In this study, we will validate the ability of catumaxomab 1) to induce immunogenic cell stress and death of cancer cells, 2) to change the polarization of effector cells to Th1 inflammatory disease, 3) to promote the expression of costimulatory molecules and TRAIL on NK cells and monocytes, and we will correlate these immune biomarkers to treatment efficacy.
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Submitted on : Friday, October 4, 2013 - 4:49:25 PM
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Diane Goere. Caractérisation de la mort cellulaire induite par un anticorps trifonctionnel. Sciences agricoles. Université Paris Sud - Paris XI, 2013. Français. ⟨NNT : 2013PA11T022⟩. ⟨tel-00870033⟩

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