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The Journal of Immunology, 2002, 169: 5780-5786.
Copyright © 2002 by The American Association of Immunologists

Rejection of Syngeneic Colon Carcinoma by CTLs Expressing Single-Chain Antibody Receptors Codelivering CD28 Costimulation1

Nicole M. Haynes*, Joseph A. Trapani*, Michele W. L. Teng*, Jacob T. Jackson*, Loretta Cerruti{dagger}, Stephen M. Jane{dagger}, Michael H. Kershaw*, Mark J. Smyth2,* and Phillip K. Darcy2,3,*

* Cancer Immunology Program, Sir Donald and Lady Trescowthick Laboratories, Peter MacCallum Cancer Institute, St. Andrew’s Place, East Melbourne, Victoria, Australia; and {dagger} Rotary Bone Marrow Research Laboratory, Royal Melbourne Hospital, Parkville, Victoria, Australia

A new strategy to improve the therapeutic utility of redirected T cells for cancer involves the development of novel Ag-specific chimeric receptors capable of stimulating optimal and sustained T cell antitumor activity in vivo. Given that T cells require both primary and costimulatory signals for optimal activation and that many tumors do not express critical costimulatory ligands, modified single-chain Ab receptors have been engineered to codeliver CD28 costimulation. In this study, we have compared the antitumor potency of primary T lymphocytes expressing carcinoembryonic Ag (CEA)-reactive chimeric receptors that incorporate either TCR-{zeta} or CD28/TCR-{zeta} signaling. Although both receptor-transduced T cell effector populations demonstrated cytolysis of CEA+ tumors in vitro, T cells expressing the single-chain variable fragment of Ig (scFv)-CD28-{zeta} chimera had a far greater capacity to control the growth of CEA+ xenogeneic and syngeneic colon carcinomas in vivo. The observed enhanced antitumor activity of T cells expressing the scFv-CD28-{zeta} receptor was critically dependent on perforin and the production of IFN-{gamma}. Overall, this study has illustrated the ability of a chimeric scFv receptor capable of harnessing the signaling machinery of both TCR-{zeta} and CD28 to augment T cell immunity against tumors that have lost expression of both MHC/peptide and costimulatory ligands in vivo.




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