Active treatment of murine tumors with a highly attenuated vaccinia virus expressing the tumor associated antigen 5T4 (TroVax) is CD4+ T cell dependent and antibody mediated.
5T4 is a tumor associated antigen that is expressed on the surface of a wide spectrum of human adenocarcinomas. The highly attenuated virus, modified vaccinia Ankara, has been engineered to express human 5T4 (h5T4). In a pre-clinical murine model, the recombinant virus (TroVax) induces protection against challenge with CT26-h5T4 (a syngeneic tumor line expressing h5T4). Anti-tumor activity is long lived, with protection still evident 6 months after the final vaccination. In a therapeutic setting, injection of mice with TroVax results in a reduction in tumor burden of >90%. Depletion of CD8+ T cells has no effect upon therapy in the active treatment model, whereas depletion of CD4+ T cells completely abrogates anti-tumor activity. In a prophylactic setting, depletion of CD4+ and CD8+ T cells after the induction of a h5T4 immune response has no deleterious effect on protection following challenge with CT26-h5T4. In light of these studies, the role of antibodies in protection against tumor challenge was investigated. 5T4 specific polyclonal serum decreased tumor burden by approximately 70%. Thus, we conclude that CD4+ T cells are essential for the induction of a protective immune response and that antibodies are the likely effector moiety in this xenogeneic murine tumor model.
Harrop
Richard
R
Oxford BioMedica (UK) Ltd, The Medawar Centre, Oxford Science Park, OX4 4GA, Oxford, UK. r.harrop@oxfordbiomedica.co.uk
Ryan
Matthew G
MG
Myers
Kevin A
KA
Redchenko
Irina
I
Kingsman
Susan M
SM
Carroll
Miles W
MW
D000818:Animals; D000906:Antibodies / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D000954:Antigens, Surface / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D002277:Carcinoma / Q000276:immunology / Q000628:therapy*; D003110:Colonic Neoplasms / Q000276:immunology / Q000628:therapy*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D016233:Immunotherapy, Active; D007263:Infusions, Parenteral; D008562:Membrane Glycoproteins; D051379:Mice; D008807:Mice, Inbred BALB C; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D019444:Vaccines, DNA; D014616:Vaccinia virus / Q000235:genetics* / Q000276:immunology
D000906:Antibodies; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D019496:Cancer Vaccines; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; C505427:Tpbg protein, mouse; C504058:TroVax; D019444:Vaccines, DNA