Work

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

Year: 2010

Type: article

Abstract: We have developed a cancer vaccine in which autologous myeloma 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 signals such as the PD1/PDL1 pathway which blunt activated T cell responses. In this study, we evaluated expression of PD1 on T cells derived from patients with multiple myeloma (MM), and PDL1 expression on primary myeloma cells and DC/MM fusions. We evaluated the effect of PD-1 blockade on T cell response to DC/MM fusion cell vaccination in vitro. Tumor cells were obtained from bone marrow aspirates of MM patients. Nonadherent peripheral blood mononuclear cells (PBMCs) obtained from patients with MM 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 cytometry. DCs were generated from adherent PBMCs cultured with rhIL-4, GM-CSF and TNFα and fused with MM cells by coculture in 50% solution of PEG. T cells were stimulated by DC/MM fusions in the presence or absence of PD-1 blockade. We demonstrate that PD-1 expression is markedly upregulated on T cells in patients with advanced MM. As compared to a control population in which mean levels of PD-1 expression was 6% (n=7), mean expression in patients with MM was 20% (n=9). Mean expression of PDL-1 was 66% on patient derived MM cells (n=3) and>90% on DC/MM fusions (n=2), which potentially provides an inhibitory signal dampening fusion mediated immunologic response. We examined the effect of PD-1 blockade on T cell response to DC/MM fusions ex vivo. Enhanced fusion mediated stimulation of T cells was noted in the presence of anti-PD-1, resulting in a greater than 5 fold increase in T cell proliferation. Interferon gamma secretion by CD4+T cells in response to stimulation by DC/MM fusions increased from 4% to 11% in the presence of PD1 blockade, while IL-10 secretion decreased from 6.5% to 3.5%. In summary, we demonstrate that PD-1 expression is increased in T cells of MM patients, and PD-1 blockade enhances activated T cell responses following stimulation with a DC/MM fusion vaccine. A clinical trial in which MM patients are treated with DC/MM fusions in conjunction with anti-PD1 is planned.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.bbmt.2009.12.250