Linkage of foreign carrier protein to a self-tumor antigen enhances the immunogenicity of a pulsed dendritic cell vaccine.
The unique Ag-presenting capabilities of dendritic cells (DCs) make them attractive vehicles for the delivery of therapeutic cancer vaccines. While tumor Ag-pulsed DC vaccination has shown promising results in a variety of murine tumor models and early clinical trials, the optimal form of tumor Ag for use in DC pulsing has not been determined. We have studied DC vaccination using alternative forms of a soluble protein tumor Ag, the tumor-specific Ig idiotype (Id) expressed by a murine B cell lymphoma. Vaccination of mice with Id-pulsed DCs was able to induce anti-Id Abs only when the Id was modified to constitute a hapten-carrier system. DCs pulsed with Id proteins modified to include foreign constant regions, foreign constant regions plus GM-CSF, or linkage to keyhole limpet hemocyanin (KLH) carrier protein were increasingly potent in their ability to elicit anti-Id Abs. Vaccination with Id-KLH-pulsed DCs induced tumor-protective immunity superior to that obtained with Id-KLH plus a chemical adjuvant, and protection was not dependent upon effector T cells. Rather, protection was associated with the induction of high titers of anti-Id Abs of the IgG2a subclass, characteristic of a Th1 response. These findings have implications for the design of therapeutic Ag-pulsed DC vaccines for cancer immunotherapy in humans.
Timmerman
J M
JM
Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Levy
R
R
D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000378:metabolism; D019264:Adoptive Transfer; D000818:Animals; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D002352:Carrier Proteins / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D006433:Hemocyanins / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007130:Immunoglobulin Idiotypes / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D007132:Immunoglobulin Isotypes / Q000008:administration & dosage / Q000096:biosynthesis; D008223:Lymphoma / Q000276:immunology / Q000517:prevention & control; D051379:Mice; D008809:Mice, Inbred C3H; D009368:Neoplasm Transplantation; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000276:immunology; D011994:Recombinant Proteins; D018417:Th1 Cells / Q000276:immunology; D014407:Tumor Cells, Cultured; D018074:Vaccines, Conjugate / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism
D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D002352:Carrier Proteins; D007130:Immunoglobulin Idiotypes; D007132:Immunoglobulin Isotypes; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D018074:Vaccines, Conjugate; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin