HPV16 L1E7 chimeric virus-like particles induce specific HLA-restricted T cells in humans afterin vitro vaccination

Kaufmann, Andreas M.; Nieland, John D.; Schinz, Manuela; Nonn, Marion; Gabelsberger, Josef; Meissner, Harald; Mller, R. T.; Jochmus, Ingrid; Gissmann, Lutz; Schneider, Achim; Drst, M.

doi:10.1002/1097-0215(200102)9999:9999<::aid-ijc1181>3.0.co;2-q

Cited by 62 publications

(37 citation statements)

References 26 publications

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“…Due to efforts by many investigators [2,4,6,7,11,14,18,22,32], numerous CD8 T-cell epitopes of HPV 16 E6 and E7 proteins have been described, and CD8 epitopes relevant to the vast majority of the population are known. On the other hand, only a handful of HPV-specific CD4 T-cell epitopes have been described [i.e., E7 50-62 (33 amino acids long) restricted by DR15, E7 43-77 (35 amino acids long) restricted by DR3, and E7 35-50 (16 amino acids long) restricted by DQ2 described by van der Burg et al [30]; and E7 61-80 (20 amino acids long) restricted by DR9 described by Okubo et al [19].…”

Section: Discussionmentioning

confidence: 99%

A novel CD4 T-cell epitope described from one of the cervical cancer patients vaccinated with HPV 16 or 18 E7-pulsed dendritic cells

Wang

Santin

Bellone

et al. 2008

Cancer Immunol Immunother

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Previously, safety and immunogenicity of human papillomavirus type 16 (HPV16) or 18 E7-pulsed dendritic cells (DC) vaccinations were demonstrated in a dose-escalation Phase I clinical trial which enrolled ten patients diagnosed with stage IB or IIA cervical cancer (nine HPV 16-positive, one HPV 18-positive). The goal of the study was to define the T-cell epitopes of HPV 16 or 18 E7 protein in these patients in order to develop new strategies for treating HPV-associated malignancies. This was accomplished through establishing T-cell lines by stimulating peripheral blood mononuclear cells with autologous mature DC pulsed with the HPV 16 or 18 E7 protein, examining the T-cell responses using ELISPOT assays, and isolating E7-specific T-cell clones based on IFN-γ secretion. Then, the epitope was characterized in terms of its core sequence and the restriction element. Twelve T-cell lines from eight subjects (seven HPV 16-positive, one HPV 18-positive) were evaluated. Positive Tcell responses were demonstrated in four subjects (all HPV 16-positive). All four were positive for the HPV 16 E7 46-70 (EPDRAHYNIVTFCCKCDSTLRLCVQ) region. T-cell clones specific for the E7 47-70 region were isolated from one of the subjects. Further analyses revealed a novel, naturally processed, CD4 T-cell epitope, E7 58-68 (CCKCDSTLRLC), restricted by the HLA-DR17 molecule.

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Section: Discussionmentioning

confidence: 99%

A novel CD4 T-cell epitope described from one of the cervical cancer patients vaccinated with HPV 16 or 18 E7-pulsed dendritic cells

Wang

Santin

Bellone

et al. 2008

Cancer Immunol Immunother

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“…At least in some cases Ag presentation by DCs is the limiting factor in antitumor immunity (31). Vaccines comprising DCs pulsed with TAA-derived peptides, recombinant tumor proteins, virus-like particles containing TAA, and apoptotic tumor cells have proved effective in generating tumor protection in animal models (3,(32)(33)(34), and in generation of tumor Ag-specific T cell responses in vitro in humans (35)(36). DC immunogens genetically modified to express TAA can improve on the pulsing approach by providing more prolonged Ag stimulation (37,38).…”

Section: Discussionmentioning

confidence: 99%

Provision of 4-1BB Ligand Enhances Effector and Memory CTL Responses Generated by Immunization with Dendritic Cells Expressing a Human Tumor-Associated Antigen

Wiethe

Dittmar

Doan

et al. 2003

The Journal of Immunology

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Up-regulation of receptor-ligand pairs during interaction of an MHC-presented epitope on dendritic cells (DCs) with cognate TCR may amplify, sustain, and drive diversity in the ensuing T cell immune response. Members of the TNF ligand superfamily and the TNFR superfamily contribute to this costimulatory molecule signaling. In this study, we used replication deficient adenoviruses to introduce a model tumor-associated Ag (the E7 oncoprotein of human papillomavirus 16) and the T cell costimulatory molecule 4-1BBL into murine DCs, and monitored the ability of these recombinant DCs to elicit E7-directed T cell responses following immunization. Splenocytes from mice immunized with DCs expressing E7 alone elicited E7-directed effector and memory CTL responses. Coexpression of 4-1BBL in these E7-expressing DCs increased effector and memory CTL responses when they were used for immunization. 4-1BBL expression up-regulated CD80 and CD86 second signaling molecules in DCs. We also report an additive effect of 4-1BBL and receptor activator of NF-κB/receptor activator of NF-κB ligand coexpression in E7-transduced DC immunogens on E7-directed effector and memory CTL responses and on MHC class II and CD80/86 expression in DCs. Additionally, expression of 4-1BBL in E7-transduced DCs reduced nonspecific T cell activation characteristic of adenovirus vector-associated immunization. The results have generic implications for improved or tumor Ag-expressing DC vaccines by incorporation of exogenous 4-1BBL. There are also specific implications for an improved DC-based vaccine for human papillomavirus 16-associated cervical carcinoma.

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“…Strategies that use DCs to deliver TAAs have shown considerable promise in inducing tumor Ag-directed CD8 ϩ CTL responses and curtailment of tumor growth (1). Thus, DCs pulsed with TAA-derived peptides, recombinant tumor proteins, virus-like particles containing TAA, and apoptotic tumor cells have proved effective in generating tumor protection in animal models (30 -32) and in generation of tumor Ag-specific T cell responses in vitro in humans (33,34). DC immunogens genetically modified to express TAA improve on the approach of pulsing DCs with peptide before infusion, by providing more prolonged antigenic stimulation (35,36).…”

Section: Discussionmentioning

confidence: 99%

Enhanced Effector and Memory CTL Responses Generated by Incorporation of Receptor Activator of NF-κB (RANK)/RANK Ligand Costimulatory Molecules into Dendritic Cell Immunogens Expressing a Human Tumor-Specific Antigen

Wiethe

Dittmar

Doan

et al. 2003

The Journal of Immunology

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The outcome of dendritic cell (DC) presentation of Ag to T cells via the TCR/MHC synapse is determined by second signaling through CD80/86 and, importantly, by ligation of costimulatory ligands and receptors located at the DC and T cell surfaces. Downstream signaling triggered by costimulatory molecule ligation results in reciprocal DC and T cell activation and survival, which predisposes to enhanced T cell-mediated immune responses. In this study, we used adenoviral vectors to express a model tumor Ag (the E7 oncoprotein of human papillomavirus 16) with or without coexpression of receptor activator of NF-κB (RANK)/RANK ligand (RANKL) or CD40/CD40L costimulatory molecules, and used these transgenic DCs to immunize mice for the generation of E7-directed CD8+ T cell responses. We show that coexpression of RANK/RANKL, but not CD40/CD40L, in E7-expressing DCs augmented E7-specific IFN-γ-secreting effector and memory T cells and E7-specific CTLs. These responses were also augmented by coexpression of T cell costimulatory molecules (RANKL and CD40L) or DC costimulatory molecules (RANK and CD40) in the E7-expressing DC immunogens. Augmentation of CTL responses correlated with up-regulation of CD80 and CD86 expression in DCs transduced with costimulatory molecules, suggesting a mechanism for enhanced T cell activation/survival. These results have generic implications for improved tumor Ag-expressing DC vaccines, and specific implications for a DC-based vaccine approach for human papillomavirus 16-associated cervical carcinoma.

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HPV16 L1E7 chimeric virus-like particles induce specific HLA-restricted T cells in humans afterin vitro vaccination

Cited by 62 publications

References 26 publications

A novel CD4 T-cell epitope described from one of the cervical cancer patients vaccinated with HPV 16 or 18 E7-pulsed dendritic cells

A novel CD4 T-cell epitope described from one of the cervical cancer patients vaccinated with HPV 16 or 18 E7-pulsed dendritic cells

Provision of 4-1BB Ligand Enhances Effector and Memory CTL Responses Generated by Immunization with Dendritic Cells Expressing a Human Tumor-Associated Antigen

Enhanced Effector and Memory CTL Responses Generated by Incorporation of Receptor Activator of NF-κB (RANK)/RANK Ligand Costimulatory Molecules into Dendritic Cell Immunogens Expressing a Human Tumor-Specific Antigen

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