title: Conjugation of lymphoma idiotype to CD40 antibody enhances lymphoma vaccine immunogenicity and antitumor effects in mice.
abstract: Personalized immunotherapy of lymphoma based on tumor idiotype (Id) has shown anti-idiotype humoral immune responses in 40%-50% and cellular immune responses in 50%-75% of follicular lymphoma patients, indicating that this therapy can be clinically successful. We have developed a novel vaccine against lymphoma consisting of an anti-CD40 Ab (ADX40) chemically conjugated to the tumor idiotype A20 and tested it in a murine lymphoma model. BALB/c mice were immunized with 2 doses of immunogen alone or in conjunction with additional adjuvants before tumor challenge. ADX40-Id vaccination resulted in significantly retarded tumor growth and reduced mouse morbidity. Moreover, similar mouse survival was obtained with 2 injections of ADX40-Id as with 8 injections using the standard therapy of keyhole limpet hemocyanin Id + GM-CSF. Co-administration of ADX40-Id with 3-O-deacyl-4'-monophosphoryl lipid A further significantly enhanced vaccine efficacy, resulting in an increased overall survival. Anti-Id-specific Abs were detected at elevated levels after ADX40-Id immunization; however, in vivo depletion of CD4 and/or CD8 T cells before challenge showed that CD8 effector T cells were the major mediators of tumor protection. The results of the present study show that the ADX40-Id conjugate vaccine is a potential candidate as a stand-alone vaccine or in combination with currently licensed adjuvants for lymphoma immunotherapy.
authors.affiliation: Department of Infection and Immunity, University of Sheffield Medical School, Beech Hill Road, Sheffield, United Kingdom.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Carlring
authors.forename: Marika J
authors.initials: MJ
authors.lastname: Szabo
authors.forename: Robert
authors.initials: R
authors.lastname: Dickinson
authors.forename: Evy
authors.initials: E
authors.lastname: De Leenheer
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Heath
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology*; D000938:Antigen-Presenting Cells / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D004357:Drug Synergism; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000276:immunology; D007130:Immunoglobulin Idiotypes / Q000008:administration & dosage / Q000276:immunology*; D008223:Lymphoma / Q000401:mortality / Q000517:prevention & control / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D016019:Survival Analysis; D018074:Vaccines, Conjugate / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D019496:Cancer Vaccines; D007130:Immunoglobulin Idiotypes; D018074:Vaccines, Conjugate; D016178:Granulocyte-Macrophage Colony-Stimulating Factor