PD-1 blockade by CT-011, anti-PD-1 antibody, enhances ex vivo T-cell responses to autologous dendritic cell/myeloma fusion vaccine.

Abstract

We have developed a cancer vaccine in which autologous tumor is fused with dendritic cells (DCs) resulting in the presentation of tumor antigens in the context of DC-mediated costimulation. In clinical trials, immunologic responses have been observed, however responses may be muted by inhibitory pathways. The PD1/PDL1 pathway is an important element contributing to tumor-mediated immune suppression. In this study, we demonstrate that myeloma cells and DC/tumor fusions strongly express PD-L1. Compared with a control population of normal volunteers, increased PD-1 expression was observed on T cells isolated from patients with myeloma. It is interesting to note that after autologous transplantation, T-cell expression of PD-1 returned to levels seen in normal controls. We examined the effect of PD-1 blockade on T-cell response to DC/tumor fusions ex vivo. Presence of CT-011, an anti-PD1 antibody, promoted the vaccine-induced T-cell polarization towards an activated phenotype expressing Th1 compared with Th2 cytokines. A concomitant decrease in regulatory T cells and enhanced killing in a cytotoxicity assay was observed. In summary, we demonstrate that PD-1 expression is increased in T cells of patients with active myeloma, and that CT-011 enhances activated T-cell responses after DC/tumor fusion stimulation.

• Authors: Jacalyn Rosenblatt, Brett Glotzbecker, Heidi Mills, Baldev Vasir, Dimitrios Tzachanis, James D Levine, Robin M Joyce, Kerry Wellenstein, Whitney Keefe, Michael Schickler, Rinat Rotem-Yehudar, Donald Kufe, David Avigan
• Journal: Journal of immunotherapy (Hagerstown, Md. : 1997) (J Immunother) Vol. 34 Issue 5 Pg. 409-18 (Jun 2011) ISSN: 1537-4513 [Electronic] United States
• PMID: 21577144 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antibodies, Anti-Idiotypic
• Antigens, CD
• Apoptosis Regulatory Proteins
• B7-H1 Antigen
• CD274 protein, human
• Cancer Vaccines
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor

Topics

• Antibodies, Anti-Idiotypic (immunology)
• Antigens, CD (genetics, immunology, metabolism)
• Apoptosis Regulatory Proteins (genetics, immunology, metabolism)
• B7-H1 Antigen
• Cancer Vaccines (immunology, pharmacology)
• Cell Fusion
• Cell Proliferation (drug effects)
• Cytotoxicity, Immunologic
• Dendritic Cells (chemistry, immunology, metabolism)
• Flow Cytometry
• Humans
• In Vitro Techniques
• Leukocytes, Mononuclear (chemistry, immunology, metabolism)
• Lymphocyte Activation (immunology)
• Multiple Myeloma (immunology, metabolism, pathology, therapy)
• Programmed Cell Death 1 Receptor
• T-Lymphocytes, Cytotoxic (immunology)
• T-Lymphocytes, Regulatory (immunology)
• Th1-Th2 Balance (drug effects)
• Transplantation, Autologous