RESUMEN
The interaction between CXCR4 on the surface of tumor cells and CXCL12 in the stroma is believed to contribute to tumor cell survival and protection against drug treatment. Inhibition of stromal survival signals by CXCR4 antagonists has been reported to render tumor cells more sensitive to chemotherapy, but little is known about potential synergy with monoclonal antibodies. In this study, administration of the small molecule CXCR4 antagonists plerixafor and GENZ-644494 was found to enhance the anti-tumor activity of the monoclonal antibodies alemtuzumab and rituximab in disseminated lymphoma models. The observed enhancement in therapeutic efficacy by CXCR4 antagonists appeared to involve several factors, including interference with the tumor-promoting signals delivered by CXCL12, disruption of the tumor/stroma interaction and mobilization of effector neutrophils capable of mediating antibody-dependent cell-mediated cytotoxicity. The involvement of neutrophils was further supported by the observed reversal in therapeutic benefit upon neutrophil depletion.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma/tratamiento farmacológico , Receptores CXCR4/antagonistas & inhibidores , Ensayos Antitumor por Modelo de Xenoinjerto , Alemtuzumab , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/farmacología , Citotoxicidad Celular Dependiente de Anticuerpos/efectos de los fármacos , Bencilaminas , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quimiocina CXCL12/metabolismo , Quimiotaxis/efectos de los fármacos , Ciclamas , Sinergismo Farmacológico , Citometría de Flujo , Compuestos Heterocíclicos/administración & dosificación , Compuestos Heterocíclicos/farmacología , Humanos , Linfoma/metabolismo , Linfoma/patología , Ratones , Ratones SCID , Fosforilación/efectos de los fármacos , Piridinas/administración & dosificación , Piridinas/farmacología , Receptores CXCR4/metabolismo , Rituximab , Transducción de Señal/efectos de los fármacos , Carga Tumoral/efectos de los fármacosRESUMEN
BACKGROUND: Polyclonal antithymocyte globulins (ATGs) are used clinically to prevent and treat acute allograft rejection and are believed to modulate the immune response primarily by depleting T cells. However, nondepleting mechanisms may also be important mediators of graft survival. In the present study, 14 lots of thymoglobulin (rabbit ATG) were analyzed and compared for nondepletive immunomodulatory activities in vitro. METHODS: Coincubation of human peripheral blood mononuclear cells with thymoglobulin induces CD4+CD25(high)Foxp3+ regulatory T cells, which were evaluated for consistent ability to suppress T-cell activation in mixed lymphocyte reactions. The consistency of CD2, CD3, CD11a, and CD45 antigen specificities in thymoglobulin was determined using flow cytometry to measure inhibition of fluorescent monoclonal antibody binding to Jurkat T cells. A transwell chemotaxis assay was established and used to evaluate ATG-mediated inhibition of stromal cell-derived factor (SDF)-1alpha-driven Jurkat T-cell migration. RESULTS: Physiologic levels of thymoglobulin produced nondepletive immunomodulatory activities, which were consistent from batch to batch. All lots of thymoglobulin induced functionally immunosuppressive regulatory T cells and inhibited monoclonal antibody binding to key T-cell surface antigens. In addition, these studies provide the first demonstration that thymoglobulin effectively inhibits CXCR4/SDF-1alpha-driven T-cell chemotaxis. CONCLUSIONS: This novel, systematic in vitro analysis of 14 different manufactured lots of thymoglobulin demonstrates the overall consistency of this product and provides further insights into nondepletive mechanisms by which thymoglobulin may generate durable immunoregulation and allograft survival.