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Blood, 14 May 2009, Vol. 113, No. 20, pp. 4875-4884.
Prepublished online as a Blood First Edition Paper on March 10, 2009; DOI 10.1182/blood-2008-08-172296.
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IMMUNOBIOLOGY
Bromohydrin pyrophosphate enhances antibody-dependent cell-mediated cytotoxicity induced by therapeutic antibodies
Julie Gertner-Dardenne13,
Cecile Bonnafous4,
Christine Bezombes1,2,
Aude-Hélène Capietto1,2,
Virginie Scaglione4,
Sophie Ingoure4,
Delphine Cendron1,2,
Emilie Gross1,2,
Jean-François Lepage4,
Anne Quillet-Mary1,2,
Loîc Ysebaert1,2,5,
Guy Laurent1,2,5,
Hélène Sicard4, and
Jean-Jacques Fournié1,2
1 Inserm U563, Toulouse;
2 Université Toulouse III Paul-Sabatier, Centre de Physiopathologie de Toulouse Purpan, Toulouse;
3 Institut Paoli Calmette, Laboratoire d'Immunologie des Tumeurs, Marseilles;
4 Innate Pharma SA, Marseilles; and
5 Service d'Hematologie, Centre Hospitalier Universitaire Toulouse, Hôpital Purpan, Toulouse, France
In human blood, 1% to 5% of lymphocytes are   T cells; they mostly express the T-cell receptor (TCR)V9, recognize nonpeptide phosphoantigens (PAgs) produced by microbes and tumor cells, and mediate different modes of lytic activities directed against tumor target cells. Antibody-dependent cell-mediated cytotoxicity (ADCC) mediated by cytolytic lymphoid cells is essential for the clinical activity of anticancer monoclonal antibodies (mAbs), but whether PAgs affect ADCC by T cells is unknown. Here we report that, in association with the CD20+-specific mAb rituximab (RTX), the synthetic PAg bromohydrin pyrophosphate (BrHPP) increased TCRV9+ cell binding to CD20+ lymphoma cells in vitro. This combination activated phospho-ZAP70 and phospho-ERK1/2 signaling in TCRV9+ cells and strongly enhanced their ADCC activity. We obtained similar results with BrHPP in the context of the mAbs alemtuzumab and trastuzumab. Furthermore, BrHPP enhanced RTX-mediated depletion of CD20+ cells in vitro from peripheral blood mononuclear cells of healthy subjects and enhanced ADCC by T cells from patients with chronic lymphocytic leukemia. In cynomolgus macaques, a regimen combining RTX, BrHPP, and IL2 activated TCRV9+ lymphocytes and enhanced B-cell depletion from blood and lymph nodes. Thus, the combination with BrHPP PAg is able to improve the efficacy of cancer immunotherapy by therapeutic mAbs.
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