Altered peptide ligand vaccination with Flt3 ligand expanded dendritic cells for tumor immunotherapy

Fong, Lawrence; Hou, Yayi; Rivas, A.; Benike, Claudia; Yuen, Alan R.; Fisher, George A.; Davis, Mark M.; Engleman, Edgar G.

doi:10.1073/pnas.141226398

Cited by 484 publications

(308 citation statements)

References 30 publications

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“…Since host T-cell immunity has been correlated with protection from CEA-positive tumor development both in preclinical and clinical studies, 50,51 being able to measure the induction of CD4 1 and CD8 1 T cells quantitatively in mouse models is important. Prior to this work, only limited information has been published on the identification of CEA epitopes specific for C57Bl/6 and CEA transgenic mice.…”

Section: Discussionmentioning

confidence: 99%

Efficient induction of T‐cell responses to carcinoembryonic antigen by a heterologous prime‐boost regimen using DNA and adenovirus vectors carrying a codon usage optimized cDNA

Mennuni

Calvaruso

Facciabene

et al. 2005

Intl Journal of Cancer

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The immunogenic properties of plasmid DNA and recombinant adenovirus (Ad) encoding the carcinoembryonic antigen (CEA) were examined in mice by measuring both the amplitude and type of immune response, and the immunogenicity of codon usage optimized cDNA encoding CEA (CEAopt) was assessed both in C57Bl/6 and CEA transgenic mice. Vectors were injected into quadriceps muscle either alone or in combination, and plasmid DNA was electroporated to enhance gene expression efficiency and immunogenicity. Injection of plasmid pVIJ/CEA followed by Ad-CEA boost elicited the highest amplitude of both CD4 1 and CD8 1 T-cell response to the target antigen, measured by both IFNc-ELIspot assay and intracellular staining. Vectors carrying cDNA of CEAopt expressed a greater amount of the CEA protein than their wild-type counterparts, and this enhanced expression was associated with greater immunogenicity. Both CD4 1 and CD8 1 T-cell epitopes were mapped in the C-terminal portion of the protein. In CEA transgenic mice, only immunization based on repeated injections of pVIJ/ CEAopt followed by Ad-CEAopt was able to elicit a CEA-specific CD8 1 T-cell response, whereas the wild-type vectors did not break tolerance to this target antigen. MC38-CEA tumor cells injected s.c. in CEA transgenic mice vaccinated with CEAopt vectors exhibited delayed growth kinetics. These studies demonstrate that this type of genetic vaccine is highly immunogenic and can break tolerance to CEA tumor antigen in CEA transgenic mice. ' 2005 Wiley-Liss, Inc.Key words: CEA; DNA electroporation; adenovirus Despite improvements in prevention, early detection and treatment, the possibility of curing many cancer patients remains elusive. Thus, cancer continues to be a largely unmet medical need for which more efficient therapeutic strategies must be developed. 1 Particular attention has been given to active specific immunotherapy of cancer, whereby patients are immunized against antigens presented by tumor cells. In fact, experimental and clinical evidence have demonstrated the critical role played by the cellular and humoral responses in controlling tumor growth and metastasis. 2 Many of these therapies are specifically targeted to tumorassociated antigens among which carcinoembryonic antigen (CEA) is a frequent example due to its ectopic and deregulated expression in a large percentage of adenocarcinomas. 3 Human CEA is the prototypic member of the human CEA family, a group of highly glycosylated homotypic/heterotypic cell surface intracellular adhesion molecules, and part of the immunoglobulin gene superfamily. CEA is widely used as human tumor marker, is expressed mostly in the gastrointestinal tract and is overexpressed in many human cancers, including epithelial tumors originating from the gastrointestinal tract, lung, thyroid, breast, prostate, cervix and ovaries. 4 CEA has been the focus of extensive preclinical and clinical investigation aimed at developing a CEA-specific vaccine with a therapeutic impact on tumor progression. 5 In this context, genetic vacc...

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Section: Discussionmentioning

confidence: 99%

Efficient induction of T‐cell responses to carcinoembryonic antigen by a heterologous prime‐boost regimen using DNA and adenovirus vectors carrying a codon usage optimized cDNA

Mennuni

Calvaruso

Facciabene

et al. 2005

Intl Journal of Cancer

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“…Such Flt-3L-induced DC expansion has also been shown to mobilize distinct populations of DC in vivo, which might participate in eliciting T cell responses of different magnitude or quality. In the majority of the studies, recombinant Flt-3L protein (the extracellular domain of Flt-3L) was used to induce DC expansion (23,24,30,31), and this DC expansion has been shown to enhance or modulate vaccine-induced immune responses against cancer and infectious agents in mice and humans (32)(33)(34)(35)(36)(37)(38)(39)(40)(41).…”

Section: Long-term Maintenance Of Gp120-specific Immune Responses By mentioning

confidence: 99%

Long-Term Maintenance of gp120-Specific Immune Responses by Genetic Vaccination with the HIV-1 Envelope Genes Linked to the Gene Encoding Flt-3 Ligand

Gangadhara

Husain

Nayak

et al. 2003

The Journal of Immunology

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DNA vaccines target dendritic cells (DC) to induce Ag-specific immune responses in animals. Potent HIV-specific immunity could be achieved by efficient priming of the immune system by DNA vaccines. We investigated a novel DNA vaccine approach based on the role of growth factors in DC expansion and differentiation. To this end, we constructed chimeric genes encoding the HIV envelope glycoproteins physically linked to the extracellular domain of Fms-like tyrosine kinase receptor-3 ligand (FLex; a DC growth factor; both mouse (m)FLex and human (h)FLex). These chimeric gene constructs synthesized biologically active, oligomeric FLex:gp120 fusion proteins and induced DC expansion (CD11c+CD11b+) when injected i.v. into mice. This DC expansion is comparable to that achieved by FLex DNA encoding native FLex protein. When delivered intramuscularly as DNA vaccines, hFLex:gp120 induced high frequencies of gp120-specific CD8+ T cells in the presence or absence of FLex DNA-induced DC expansion, but gp120 and mFLex:gp120 elicited only low to moderate levels of Ag-specific CD8+ T cells. In contrast, mFLex:gp120 induced high levels of anti-gp120 Abs under identical conditions of DNA vaccination. However, the Ab levels in mice immunized with DNA vaccines encoding hFLex:gp120 and gp120 proteins were low without DC expansion, but reached high levels comparable to that elicited by mFLex:gp120 only after the second boost in the presence of DC expansion. Importantly, the gp120-specific CD8+ T cells persisted at high frequency for 114 days (16 wk) after a booster injection. These experiments provide insight into the importance of modulating DC function in vivo for effective genetic vaccination in animals.

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“…Vaccine-induced T-cell responses were detected in melanoma patients without reporting any clinical responses in some trials, 51,52 whereas clinical responses including stabilization of disease, partial and even complete tumour regression were reported in other trials. [53][54][55][56][57] Although most immunotherapy studies have been performed in melanoma patients, the discovery of antigens on other tumours and the principles gained from melanoma patients can lead to the expansion of these studies to patients with more common tumours. 58 …”

Section: Human Tumour Antigens Recognized By T Cellsmentioning

confidence: 99%

Immunology and immunotherapy approaches for prostate cancer

Elkord

2007

Prostate Cancer Prostatic Dis

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Several mechanisms that impair the immune response to promote tumour progression are reported. These mechanisms aim to reduce the ability of antigen-presenting cells to present antigen and activate naïve T cells to support an active immune response or to create a suppressive environment that induce non-functional tumour-associated antigen-specific T cells. Prostate cancer (PC) alone accounts for 33% of incident cancer cases and about 9% of all cancer-related deaths among men in the USA during 2006. Whereas androgen deprivation has remained the first line of therapy for advanced PC, other therapies are still required due to progression to an androgen-resistant state and eventually loss of control in patients receiving hormonal therapy. Immunotherapy seems to be a promising approach to enhance tumour-specific T-cell responses in different cancers including prostate. More importantly, clinical trials in advanced PC patients have shown that immunotherapy may generate significant clinical responses. Immunology and immunotherapy aspects of PC with focus on prostate-specific antigen will be presented.

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Altered peptide ligand vaccination with Flt3 ligand expanded dendritic cells for tumor immunotherapy

Cited by 484 publications

References 30 publications

Efficient induction of T‐cell responses to carcinoembryonic antigen by a heterologous prime‐boost regimen using DNA and adenovirus vectors carrying a codon usage optimized cDNA

Efficient induction of T‐cell responses to carcinoembryonic antigen by a heterologous prime‐boost regimen using DNA and adenovirus vectors carrying a codon usage optimized cDNA

Long-Term Maintenance of gp120-Specific Immune Responses by Genetic Vaccination with the HIV-1 Envelope Genes Linked to the Gene Encoding Flt-3 Ligand

Immunology and immunotherapy approaches for prostate cancer

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