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Don M Benson,
Courtney E Bakan,
Shuhong Zhang,
Shauna M Collins,
Jing Liang,
Shivani Srivastava,
Craig C Hofmeister,
Yvonne Efebera,
Pascale Andre,
Francois Romagne,
Mathieu Bléry, Cécile Bonnafous,
Jianying Zhang,
David Clever,
Michael A Caligiuri,
Sherif S Farag
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ABSTRACT: Multiple myeloma (MM) patients who receive killer cell Ig-like receptor (KIR) ligand-mismatched, T cell-depleted, allogeneic transplantation may have a reduced risk of relapse compared with patients who receive KIR ligand-matched grafts, suggesting the importance of this signaling axis in the natural killer (NK) cell-versus-MM effect. Expanding on this concept, IPH2101 (1-7F9), an anti-inhibitory KIR mAb, enhances NK-cell function against autologous MM cells by blocking the engagement of inhibitory KIR with cognate ligands, promoting immune complex formation and NK-cell cytotoxicity specifically against MM cell targets but not normal cells. IPH2101 prevents negative regulatory signals by inhibitory KIR, whereas lenalidomide augments NK-cell function and also appears to up-regulate ligands for activating NK-cell receptors on MM cells. Lenalidomide and a murine anti-inhibitory NK-cell receptor Ab mediate in vivo rejection of a lenalidomide-resistant tumor. These mechanistic, preclinical data support the use of a combination of IPH2101 and lenalidomide in a phase 2 trial for MM.
Blood 12/2011; 118(24):6387-91. · 9.90 Impact Factor
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ABSTRACT: Natural killer (NK) cells are lymphocytes of the innate immune system able to recognize and kill tumors lacking self-MHC class I molecules. This "missing-self" recognition is mediated by the lack of engagement of MHC class I-specific inhibitory NK cell receptors that include the killer cell Ig-like receptors (KIR) in humans and Ly49 molecules in mice. A promising immunotherapeutic strategy against MHC class I(+) cancer cells is to block NK cell inhibitory receptors using monoclonal antibodies (mAb). However, interactions between MHC class I molecules and their inhibitory receptors are also required for the acquisition of NK cell functional competence, a process referred as to "education." In addition, inhibitory receptors are involved in self-tolerance on educated NK cells. Here, we developed a preclinical mouse model in which all NK cells are educated by a single transgenic inhibitory receptor, human KIR2DL3, through the engagement with its HLA-Cw3 ligand. This approach revealed that NK cells could be reprogrammed to control the development of mouse syngenic tumors in vivo. Moreover, in vivo anti-KIR mAb treatment induced the killing of HLA(+) target cells without breaking self-tolerance. Finally, the long-term infusion of anti-KIR mAb neither abolished NK cell education nor tumor cell recognition. Therefore, these results strongly support the use of inhibitory receptor blockade in cancer patients.
Proceedings of the National Academy of Sciences 07/2009; 106(31):12879-84. · 9.68 Impact Factor
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ABSTRACT: Interest in gamma9delta2 T cells has increased greatly in the past decade. While several protocols allowed the amplification of a large proportion of these cells in vitro, the purity of the final preparation is usually heterogeneous between different donors. Functional studies of this population are often controversial due to the presence of other populations such as NK cells which share a wide range of characteristics. Here, the gamma9delta2 T cells labelled-fraction is purified and mixed with the irradiated unlabelled fraction followed by a single stimulation with phosphoantigen, in turn followed by a classical step of amplification in the presence of interleukin 2. In this study, we describe a straightforward protocol to amplify pure populations of gamma9delta2 T cells which could be useful in fundamental research or in the development of a new generation of gammadelta cell therapy protocol.
Journal of immunological methods 06/2009; 347(1-2):12-8. · 2.35 Impact Factor
