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Amplification of the lytic potential of effector/memory CD8+ cells by vector-based enhancement of ICAM-1 (CD54) in target cells: implications for intratumoral vaccine therapy.

Abstract：

:We demonstrated that enhanced expression of the costimulatory molecules CD80, CD54 and CD48 (designated rF-TRICOM) on target cells, as delivered via a recombinant fowlpox vector, results in an increased state of stimulation of CD8+ T cells, and consequent increased lysis of target cells. CTL studies in conjunction with antibody-blocking studies demonstrated that the enhanced effector activity of these CD8+ T cells is mediated mainly through CD54. Intracellular staining of CD8+ cells that interact with target cells infected with rF-TRICOM showed that they contain higher amounts of perforin and have a higher level of perforin message. Enhanced expression of costimulatory molecules (specifically CD54) on target cells using rF-TRICOM vectors also leads to the formation of stable conjugates/synapses between targets and T cells. The interaction of T cells with target cells that overexpress costimulatory molecules upon infection with rF-TRICOM leads to enhanced signaling through Lck, ZAP70, and STAT-1 in CD8+ T cells and heightened lytic activity of CD8+ cells through the formation of a greater number of immunological synapses. This, in turn, leads to enhanced signaling in T cells. Finally, studies were conducted in mice in which CEA is a self-antigen in an attempt to understand the potential clinical relevancy of intratumoral vaccine therapy. Mice were transplanted subcutaneously with CEA expressing tumors. Intratumoral (i.t.) vaccination was administered 8 days post tumor transplant. Mice vaccinated i.t. with rF-TRICOM demonstrated significantly reduced tumor growth and 40% of the mice had complete tumor regression. The antitumor effects were further improved by the addition of tumor antigen (CEA) in the vaccination by utilizing rF-CEA/TRICOM, with 80% of the mice experiencing complete tumor regression. These studies thus support the concept of intratumoral vaccination employing vectors expressing costimulatory molecules.

journal_name

Cancer Gene Ther

journal_title

Cancer gene therapy

authors

Slavin-Chiorini DC,Catalfamo M,Kudo-Saito C,Hodge JW,Schlom J,Sabzevari H

doi

10.1038/sj.cgt.7700741

subject

Has Abstract

pub_date

2004-10-01 00:00:00

pages

665-80

issue

eissn

0929-1903

issn

1476-5500

pii

7700741

journal_volume

pub_type

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Amplification of the lytic potential of effector/memory CD8+ cells by vector-based enhancement of ICAM-1 (CD54) in target cells: implications for intratumoral vaccine therapy.