Combination of vaccination and chimeric receptor expressing T cells provides improved active therapy of tumors.
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.
Jiang
Hui-Rong
HR
Cancer Research U.K. Immunology Group, Paterson Institute for Cancer Research, University of Manchester and Christie Hospital National Health Service Trust, Manchester M20 4BX, UK.
Gilham
David E
DE
Mulryan
Kate
K
Kirillova
Natalia
N
Hawkins
Robert E
RE
Stern
Peter L
PL
D000256:Adenoviridae; D019264:Adoptive Transfer; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology; D019496:Cancer Vaccines; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003713:Dendritic Cells / Q000276:immunology; D005434:Flow Cytometry; D005822:Genetic Vectors; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000276:immunology*; D014161:Transduction, Genetic
D019496:Cancer Vaccines; D008562:Membrane Glycoproteins; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; C063709:trophoblastic glycoprotein 5T4, human