Optimized Peptide Vaccines Eliciting Extensive CD8 T-Cell Responses with Therapeutic Antitumor Effects
- 30 November 2009
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 69 (23), 9012-9019
- https://doi.org/10.1158/0008-5472.can-09-2019
Abstract
A major challenge for developing effective therapeutic vaccines against cancer is overcoming immunologic tolerance to tumor-associated antigens that are expressed on both malignant cells and normal tissues. Herein, we describe a novel vaccination approach, TriVax, that uses synthetic peptides representing CD8 T-cell epitopes, Toll-like receptor agonists that function as potent immunologic adjuvants and costimulatory anti-CD40 antibodies to generate large numbers of high-avidity antigen-reactive T cells capable of recognizing and killing tumor cells. Our results show that TriVax induced huge numbers of long-lasting antigen-specific CD8 T cells that displayed significant antitumor effects in vivo. The administration of a TriVax formulation containing a CD8 T-cell epitope derived from a melanosomal antigen (Trp2180-188) elicited antigen-specific CD8 T cells that induced systemic autoimmunity (vitiligo). More important, TriVax immunization was effective in eliciting potent protective antitumor immunity as well as remarkable therapeutic effects against established B16 melanoma. This therapeutic effect was mediated by CD8 T cells via perforin-mediated lysis and required the participation of type-I IFN but not IFNγ. These results suggest that similar strategies would be applicable for the design of effective vaccination for conducting clinical studies in cancer patients. [Cancer Res 2009;69(23):9012–9]Other Versions
This publication has 36 references indexed in Scilit:
- Homeostasis of Naive and Memory T CellsImmunity, 2008
- Adoptive cell transfer: a clinical path to effective cancer immunotherapyNature Reviews Cancer, 2008
- Optimized DNA vaccines to specifically induce therapeutic CD8 T cell responses against autochthonous breast tumorsCancer Immunology, Immunotherapy, 2008
- Overlapping human leukocyte antigen class I/II binding peptide vaccine for the treatment of patients with stage IV melanomaCancer, 2007
- Adoptive T cell therapy for cancer in the clinicJCI Insight, 2007
- Essential role of mda-5 in type I IFN responses to polyriboinosinic:polyribocytidylic acid and encephalomyocarditis picornavirusProceedings of the National Academy of Sciences of the United States of America, 2006
- Innate immune recognition of viral infectionNature Immunology, 2006
- Combined TLR and CD40 Triggering Induces Potent CD8+ T Cell Expansion with Variable Dependence on Type I IFNThe Journal of Experimental Medicine, 2004
- CD3‐mediated apoptosis of human medullary thymocytes and activated peripheral T cells: Respective roles of interleukin‐1, interleukin‐2, interferon‐γ and accessory cellsEuropean Journal of Immunology, 1993
- Multiple Defects of Immune Cell Function in Mice with Disrupted Interferon-γ GenesScience, 1993