CT-011, Anti-PD-1 Antibody, Enhances Ex-Vivo T Cell Responses to Autologous Dendritic/Myeloma Fusion Vaccine Developed for the Treatment of Multiple Myeloma

• Published in: Blood 2009-11, Vol.114 (22), p.781-781
• Main Authors: Rosenblatt, Jacalyn, Glotzbecker, Brett, Mills, Heidi, Keefe, Whitney, Wellenstein, Kerry, Vasir, Baldev, Wu, Zekui, Zarwan, Corrine, Schickler, Michael, Rotem-Yehudar, Rinat, Kufe, Donald, Avigan, David
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V114.22.781.781

Abstract 781 We have developed a promising cancer vaccine in which autologous tumor cells are fused with dendritic cells (DCs) resulting in the presentation of tumor antigens in the context of DC mediated costimulation. In animal models, vaccination with fusion cells results in eradication of established tumor, and in clinical trials, both immunologic and clinical responses have been observed. However, response to vaccination may be muted by inhibitory pathways that blunt activated T cell responses. The PD-1/PDL-1 pathway is an important element contributing to tumor mediated immune suppression. In infectious disease models, upregulation of T cell expression of PD-1 is associated with an exhausted phenotype facilitating the development of chronic viral infection. In contrast, PD-1 blockade results in the restoration of functionally active T cells and clearance of infection. The PD-1/PDL-1 pathway is also being evaluated a as a central mechanism by which tumors escape host immunity. CT-011, is a humanized anti PD-1 antibody that is currently evaluated in Phase II studies for the treatment of hematological malignancies and solid tumors. In this study, we evaluated expression of PD-1 on T cells derived from patients with advanced hematologic malignancies, and PDL-1 expression on primary myeloma cells, ex-vivo generated dendritic cells, and DC/tumor fusion cells. We evaluated the effect of PD-1 blockade with CT-011 on T cell response to DC/tumor fusion cell stimulation in vitro. Tumor cells were obtained from bone marrow aspirates of patients with multiple myeloma. Nonadherent peripheral blood mononuclear cells obtained from patients with multiple myeloma and normal volunteers were cultured in RPMI supplemented with 10U/ml IL-2, and expression of PD-1 on CD4+ T cells was assessed by flow cytometric analysis . DCs were generated from adherent mononuclear cells cultured with rhIL-4, GM-CSF and TNFα and fused with tumor cells by coculture in 50% solution of polyethylene glycol. T cells were stimulated by DC/tumor fusions in the presence or absence of 5ug/ml CT-011. We demonstrate that PD-1 expression is markedly upregulated on T cells in patients with advanced multiple myeloma. As compared to a control population of normal volunteers in which mean levels of PD-1 expression was 6% (n=7), mean expression in patients with multiple myeloma was 20% (n=9). These findings suggest that upregulation of PD-1 expression may play a central role in tumor mediated immune suppr