Generation of tumor-specific T lymphocytes using dendritic cell/tumor fusions and anti-CD3/CD28.

Abstract

Adoptive immunotherapy with tumor-specific T cells represents a promising treatment strategy for patients with malignancy. However, the efficacy of T-cell therapy has been limited by the ability to expand tumor-reactive cells with an activated phenotype that effectively target malignant cells. We have developed an anticancer vaccine in which patient-derived tumor cells are fused with autologous dendritic cells (DCs), such that a wide array of tumor antigens are presented in the context of DC-mediated costimulation. In this study, we demonstrate that DC/tumor fusions induce T cells that react with tumor and are dramatically expanded by subsequent ligation of the CD3/CD28 costimulatory complex. These T cells exhibit a predominantly activated phenotype as manifested by an increase in the percentage of cells expressing CD69 and interferon gamma. In addition, the T cells upregulate granzyme B expression and are highly effective in lysing autologous tumor targets. Targeting of tumor-specific antigen was demonstrated by the expansion of T cells with specificity for the MUC1 tetramer. Stimulation with anti-CD3/CD28 followed by DC/tumor fusions or either agent alone failed to result in a similar expansion of tumor-reactive T cells. Consistent with these findings, spectratyping analysis demonstrates selective expansion of T-cell clones as manifested by considerable skewing of the Vbeta repertoire following sequential stimulation with DC/tumor fusions and anti-CD3/CD28. Gene expression analysis was notable for the upregulation of inflammatory pathways. These findings indicate that stimulation with DC/tumor fusions provides a unique platform for subsequent expansion with anti-CD3/CD28 in adoptive T-cell therapy of cancer.

• Authors: Jacalyn Rosenblatt, Zekui Wu, Baldev Vasir, Corrine Zarwan, Richard Stone, Heidi Mills, Thea Friedman, Panagiotis A Konstantinopoulos, Dimitrios Spentzos, Musie Ghebremichael, Kristen Stevenson, Donna Neuberg, James D Levine, Robin Joyce, Dimitrios Tzachanis, Vassiliki Boussiotis, Donald Kufe, David Avigan
• Journal: Journal of immunotherapy (Hagerstown, Md. : 1997) (J Immunother) 2010 Feb-Mar Vol. 33 Issue 2 Pg. 155-66 ISSN: 1537-4513 [Electronic] United States
• PMID: 20145548 (Publication Type: Journal Article)

Chemical References

• Antigens, CD
• Antigens, Differentiation
• Cancer Vaccines
• MUC1 protein, human
• Mucin-1
• Interferon-gamma
• Granzymes

Topics

• Antigen Presentation (immunology)
• Antigens, CD (biosynthesis, genetics, immunology)
• Antigens, Differentiation (biosynthesis, genetics, immunology)
• Cancer Vaccines
• Cell Fusion
• Cell Proliferation
• Clone Cells
• Cytotoxicity, Immunologic
• Dendritic Cells (immunology, metabolism, pathology)
• Genes, T-Cell Receptor beta
• Granzymes (biosynthesis, genetics)
• Humans
• Interferon-gamma (metabolism)
• Lymphocyte Activation
• Mucin-1 (immunology, metabolism)
• T-Lymphocytes (immunology, metabolism, pathology)