4.6 Article

Autocrine costimulation: Tumor-specific CD28-mediated costimulation of T cells by in situ production of a bifunctional B7-anti-CEA diabody fusion protein

Journal

CANCER GENE THERAPY
Volume 9, Issue 3, Pages 275-281

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/sj.cgt.7700438

Keywords

cancer; tumor-specific costimulation; gene therapy; immunotherapy

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T cells require two distinct signals for optimal activation, an antigen-specific signal, provided by engagement of the T-cell receptor (TCR) and a second costimulatory signal mediated by engagement of CD28 with members of the B7 family. Although infiltrating T cells are present in many malignancies, they appear to be mostly allergic and do not attack the tumor, presumably because of the absence of activation and/or costimulatory signals. Here we describe a novel strategy for the in situ activation of tumor-specific T cells. We genetically modified T cells to secrete a bifunctional fusion protein, comprising the extracellular portion of B7-1 fused to an anticarcinoembryonic antigen (CEA) diabody. In coculture with CEA(+) tumor cells autocrine and paracrine secretion of B7-alphaCEA provided a potent tumor-specific costimulatory signal to T cells in combination with a recombinant alphaCEAxalphaCD3 bispecific diabody. B7-alphaCEA was also found to strongly enhance survival and tumor-specific activation of T cells expressing an anti-CEA TCRzeta-based chimeric immune receptor (CIR) both when expressed in cis by the T cells themselves as we! I as in trans, when added to the culture medium. In the absence of costimulatory signals provided by the tumor, our strategy allows T cells to arm themselves by the production of tumor-specific costimulatory proteins. Sustained in situ production of such molecules, like the B7-diabody fusion protein may create a favorable local environment for the activation and proliferation of tumor-reactive T cells and increase the tumoricidal activity of immunotherapeutic approaches targeting the TCR pathway.

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