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Combination of Vaccination and Chimeric Receptor Expressing T Cells Provides Improved Active Therapy of Tumors¹

Hui-Rong Jiang^*, David E. Gilham, Kate Mulryan^*, Natalia Kirillova, Robert E. Hawkins and Peter L. Stern^2,*

^* Cancer Research U.K. Immunology Group, Paterson Institute for Cancer Research, and Cancer Research U.K. Medical Oncology Department, University of Manchester and Christie Hospital National Health Service Trust, Manchester, United Kingdom

We have generated murine T cells expressing chimeric immune receptors (CR) against human 5T4 oncofetal Ag (h5T4) and evaluated their tumor therapeutic efficacy alone and in combination with immunization using a replication-defective adenovirus encoding h5T4 (Rad.h5T4) and bone marrow-derived dendritic cells (BMDC). The h5T4-specific engineered T cells demonstrated Ag-specific, non-MHC-restricted cytolysis of h5T4-positive B16 and CT26 tumor cells in vitro by cytotoxicity assay and antitumor activity in vivo using a Winn assay. In the s.c. injected B16h5T4 melanoma model, early local but not systemic i.v. administration of syngeneic h5T4-specific CR T cells significantly increased mice survival. This improvement was further enhanced when combined with immunization with Rad.h5T4, followed by post-CR T cell treatment with BMDC in the active therapy model, possibly through mechanisms of enhancing Ag-specific cellular immune responses. This synergistic effect was lost without delivery of the BMDC. Our findings suggest that combining engineered T cells with specific vaccination strategies can improve the active tumor therapy.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ N.K. was funded by the Kay Kendall Leukemia Fund. H.-R.J., D.E.G., K.M., R.E.H., and P.L.S. are all supported by Cancer Research U.K.

² Address correspondence and reprint requests to Professor Peter L. Stern, Cancer Research U.K. Immunology Group, Paterson Institute for Cancer Research, Christie Hospital National Health Service Trust, Manchester M20 4BX, U.K. E-mail address: pstern{at}picr.man.ac.uk

³ Abbreviations used in this paper: TAA, tumor-associated Ag; BMDC, bone marrow-derived dendritic cell; CR, chimeric immune receptor; DC, dendritic cell; h5T4, human 5T4 oncofetal Ag; LN, lymph node; Rad.GFP, first generation E1/E3 deleted adenovirus expressing GFP; Rad.h5T4, first generation E1/E3-deleted adenovirus expressing human 5T4; scFv, single-chain variable fragment.