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J Immunother. 2010 Feb-Mar;33(2):155-66. doi: 10.1097/CJI.0b013e3181bed253.

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

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Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.


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.

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