Dataset Information

Interleukin-13 receptor ?2 DNA prime boost vaccine induces tumor immunity in murine tumor models.

ABSTRACT:

Background

DNA vaccines represent an attractive approach for cancer treatment by inducing active T cell and B cell immune responses to tumor antigens. Previous studies have shown that interleukin-13 receptor ?2 chain (IL-13R?2), a tumor-associated antigen is a promising target for cancer immunotherapy as high levels of IL-13R?2 are expressed on a variety of human tumors. To enhance the effectiveness of DNA vaccine, we used extracellular domain of IL-13R?2 (ECD?2) as a protein-boost against murine tumor models.

Methods

We have developed murine models of tumors naturally expressing IL-13R?2 (MCA304 sarcoma, 4T1 breast carcinoma) and D5 melanoma tumors transfected with human IL-13R?2 in syngeneic mice and examined the antitumor activity of DNA vaccine expressing IL-13R?2 gene with or without ECD?2 protein mixed with CpG and IFA adjuvants as a boost vaccine.

Results

Mice receiving IL-13R?2 DNA vaccine boosted with ECD?2 protein were superior in exhibiting inhibition of tumor growth, compared to mice receiving DNA vaccine alone, in both prophylactic and therapeutic vaccine settings. In addition, prime-boost vaccination significantly prolonged the survival of mice compared to DNA vaccine alone. Furthermore, ECD?2 booster vaccination increased IFN-? production and CTL activity against tumor expressing IL-13R?2. The immunohistochemical analysis showed the infiltration of CD4 and CD8 positive T cells and IFN-?-induced chemokines (CXCL9 and CXCL10) in regressing tumors of immunized mice. Finally, the prime boost strategy was able to reduce immunosuppressive CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) in the spleen and tumor of vaccinated mice.

Conclusion

These results suggest that immunization with IL-13R?2 DNA vaccine followed by ECD?2 boost mixed with CpG and IFA adjuvants inhibits tumor growth in T cell dependent manner. Thus our results show an enhancement of efficacy of IL-13R?2 DNA vaccine with ECD?2 protein boost and offers an exciting approach in the development of new DNA vaccine targeting IL-13R?2 for cancer immunotherapy.

SUBMITTER: Nakashima H

PROVIDER: S-EPMC2993653 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Publications

Interleukin-13 receptor α2 DNA prime boost vaccine induces tumor immunity in murine tumor models.

Nakashima Hideyuki H Fujisawa Toshio T Husain Syed R SR Puri Raj K RK

Journal of translational medicine 20101110

<h4>Background</h4>DNA vaccines represent an attractive approach for cancer treatment by inducing active T cell and B cell immune responses to tumor antigens. Previous studies have shown that interleukin-13 receptor α2 chain (IL-13Rα2), a tumor-associated antigen is a promising target for cancer immunotherapy as high levels of IL-13Rα2 are expressed on a variety of human tumors. To enhance the effectiveness of DNA vaccine, we used extracellular domain of IL-13Rα2 (ECDα2) as a protein-boost again ...[more]

PMID: 21067607

Similar Datasets

Project description:BackgroundGene-based vaccination using prime/boost regimens protects animals and humans against malaria, inducing cell-mediated responses that in animal models target liver stage malaria parasites. We tested a DNA prime/adenovirus boost malaria vaccine in a Phase 1 clinical trial with controlled human malaria infection.Methodology/principal findingsThe vaccine regimen was three monthly doses of two DNA plasmids (DNA) followed four months later by a single boost with two non-replicating human serotype 5 adenovirus vectors (Ad). The constructs encoded genes expressing P. falciparum circumsporozoite protein (CSP) and apical membrane antigen-1 (AMA1). The regimen was safe and well-tolerated, with mostly mild adverse events that occurred at the site of injection. Only one AE (diarrhea), possibly related to immunization, was severe (Grade 3), preventing daily activities. Four weeks after the Ad boost, 15 study subjects were challenged with P. falciparum sporozoites by mosquito bite, and four (27%) were sterilely protected. Antibody responses by ELISA rose after Ad boost but were low (CSP geometric mean titer 210, range 44-817; AMA1 geometric mean micrograms/milliliter 11.9, range 1.5-102) and were not associated with protection. Ex vivo IFN-? ELISpot responses after Ad boost were modest (CSP geometric mean spot forming cells/million peripheral blood mononuclear cells 86, range 13-408; AMA1 348, range 88-1270) and were highest in three protected subjects. ELISpot responses to AMA1 were significantly associated with protection (p?=?0.019). Flow cytometry identified predominant IFN-? mono-secreting CD8+ T cell responses in three protected subjects. No subjects with high pre-existing anti-Ad5 neutralizing antibodies were protected but the association was not statistically significant.SignificanceThe DNA/Ad regimen provided the highest sterile immunity achieved against malaria following immunization with a gene-based subunit vaccine (27%). Protection was associated with cell-mediated immunity to AMA1, with CSP probably contributing. Substituting a low seroprevalence vector for Ad5 and supplementing CSP/AMA1 with additional antigens may improve protection.Trial registrationClinicalTrials.govNCT00870987.