Tumour-associated antigen (TAA)-specific cytotoxic T cell (CTL) response in vitro and in a mouse model, induced by TAA-plasmids delivered by influenza virosomes

Correale, Pierpaolo; Cusi, Maria Grazia; Sabatino, Marianna; Micheli, Lucia; Pozzessere, Daniele; Nencini, Cristina; Valensin, Pier Egisto; Petrioli, Roberto; Giorgi, Giorgio; Zurbriggen, Rinaldo; Glück, Reinhard; Francini, Guido

doi:10.1016/s0959-8049(01)00241-6

Cited by 32 publications

(15 citation statements)

References 12 publications

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“…Plasmid DNA was purified using the Qiagen Endo Free plasmid kit (Qiagen, Valencia, CA) as described by the manufacturer. The influenza virosomes were prepared as described elsewhere (43,44). The nonencapsulated plasmids were separated by 0.1 gel filtration on a High Load Superdex 200 column (Amersham Pharmacia Biotech, Piscataway, NJ).…”

Section: Generation Of a Pth-rp Plasmid/influenza Virosomesmentioning

confidence: 99%

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High-Affinity HLA-A(*)02.01 Peptides from Parathyroid Hormone-Related Protein Generate In Vitro and In Vivo Antitumor CTL Response Without Autoimmune Side Effects

Francini¹,

Scardino

Kosmatopoulos

et al. 2002

The Journal of Immunology

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Parathyroid hormone-related protein (PTH-rP), a protein produced by prostate carcinoma and other epithelial cancers, is a key agent in the development of bone metastases. We investigated whether the protein follows the self-tolerance paradigm or can be used as a target Ag for anticancer immunotherapy by investigating the immunogenicity of two HLA-A(*)02.01-binding PTH-rP-derived peptides (PTR-2 and -4) with different affinity qualities. PTH-rP peptide-specific CTL lines were generated from the PBMC of two HLA-A(*)02.01+ healthy individuals, stimulated in vitro with PTH-rP peptide-loaded autologous dendritic cells and IL-2. The peptide-specific CTLs were able to kill PTH-rP+HLA-A(*)02.01+ breast and prostate carcinoma cell lines. The two peptides were also able to elicit a strong antitumor PTH-rP-specific CTL response in HLA-A(*)02.01 (HHD) transgenic mice. The vaccinated mice did not show any sign of side effects due to cell-mediated autoimmunity or toxicity. In this study we describe two immunogenic and toxic-free PTH-rP peptides as valid candidates for the design of peptide-based vaccination strategies against prostate cancer and bone metastases from the most common epithelial malignancies.

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Section: Generation Of a Pth-rp Plasmid/influenza Virosomesmentioning

confidence: 99%

“…The construct GC90V used in this study was formerly generated and characterized in our laboratory (44).…”

Section: Ag-specific Ctl In Hhd Transgenic Mice Vaccination With Pthrmentioning

confidence: 99%

High-Affinity HLA-A(*)02.01 Peptides from Parathyroid Hormone-Related Protein Generate In Vitro and In Vivo Antitumor CTL Response Without Autoimmune Side Effects

Francini¹,

Scardino

Kosmatopoulos

et al. 2002

The Journal of Immunology

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“…Previous studies of our group demonstrated that a specific cytotoxic T-cell (CTL) response ex vivo could be elicited from healthy donor PBMC as well as tumour-infiltrating lymphocytes (TILs) derived from prostate carcinoma bone metastases stimulated in vitro with autologous dendritic cells (DC) pulsed with peptide epitopes derived from PTH-rP-expressing HLA-A(*)02.01-binding amino-acid consensus motifs (Correale et al, 2001a;Francini et al, 2002). Although some of them expressed nonconventional HLA-A(*)02.01-binding motifs, these peptides were all able to induce a PTH-rP-specific CTL response in human PBMCs in vitro and in a former HLA-A(*)02.01 transgenic mice model in vivo.…”

mentioning

confidence: 99%

“…Immunopotentiating reconstituted influenza virosomes (IRIV) are influenza virosomes carrying on the surface the two envelope glycoproteins of the influenza virus, one of which is the influenza haemagglutinin (HA) that facilitates the targeting of plasmid DNA to APCs, improving the transfection efficiency and reducing the rate of DNA degradation by extracellular nucleases (Meyer et al, 1995;Dzau et al, 1996). We previously showed the GC90/IRIV capacity to elicit a CTL response in vivo into BALB/c mice and in vitro in human PBMC stimulated with IL-2 and autologous GC90/IRIV-infected DC (Correale et al, 2001a).…”

mentioning

confidence: 99%

In vivo study of the GC90/IRIV vaccine for immune response and autoimmunity into a novel humanised transgenic mouse

et al. 2003

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Parathyroid hormone-related protein (PTH-rP), a secreted protein produced by prostate carcinoma and other epithelial cancers, is considered a key agent for the development of bone metastases. We investigated the construct GC90/IRIV, composed of immunopotentiating reconstituted influenza virosomes (IRIV) containing PTH-rP gene plasmids (GC90), as a potential tool for human anticancer immunotherapy into humanised mice transgenic for HLA-A(*)02.01, the human-b2 microglobulin, and the human CD8a molecule. Intranasal administration of GC90/IRIV resulted in the induction of a PTH-rP-specific multiepitope cytotoxic T-cell (CTL) response. Cytotoxic T cells derived from vaccinated mice were capable of lysing in vitro syngenic murine PTH-rP transfectants and human HLA-A(*)02.01 þ /PTH-rP þ prostate carcinoma LNCaP cells as well. The immune response capacity and the absence of any sign of toxicity and/or autoimmunity in vivo suggest the GC90/IRIV vaccine as a valid tool for active specific immunotherapy of human cancers and metastases overexpressing PTH-rP. British Journal of Cancer (2003) (Zaccagnini, 1999) and the development of hormone-resistant metastatic bone metastases is one of the major causes of morbidity and mortality related to this malignancy. Parathyroid hormone-related protein (PTH-rP) is an attractive candidate as a target antigen in the protocol of active specific immunotherapy of prostate carcinoma and epithelial malignancy bone metastases. It was originally described as the factor responsible for humoral hypercalcaemia of malignancy (HHM) (Suva et al, 1987;Francini et al, 1993). It is expressed in 90% of prostate and (spindle-cell) lung cell carcinomas and 95% of bone metastases of epithelial cancers, and is produced in small amounts in normal adult tissues (Iguchi et al,

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“…Similar to viral vectors the mildly acidic pH in the lumen of endosomes triggers the fusion of virosomal with endosomal membranes and thus the release of encapsulated material such as DNA, RNA, or proteins into the cytosol of APCs. Therefore, exogenous in virosomes encapsulated antigens may access the MHC class I pathway without the need of de novo protein synthesis [11,12,14,34]. Not all virosomes are likely to fuse with endosomal membranes, and therefore a fraction will become available for the MHC class II pathway.…”

Section: Discussionmentioning

confidence: 99%

Virosomes as new carrier system for cancer vaccines

Schwaninger

Waelti

Zajac

et al. 2004

Cancer Immunol Immunother

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HER-2/neu, a tumor-associated antigen (TAAg), plays a critical role in oncogenesis of various tumor types, and its selective overexpression by malignant tumor cells makes it an ideal target for immunotherapy. A prerequisite for clinical vaccines is the construction of safe and highly immunogenic reagents able to generate efficient immune responses against TAAg. Previous protein vaccines, consisting of the extracellular domain of HER-2/neu (p NeuECD ), were shown to elicit an immune response that did not provide protection from transplantable tumors expressing HER-2/neu. Here we showed that virosomes, which consist of reconstituted viral envelopes without viral genetic material, can act as a carrier and an adjuvant for a truncated protein p NeuECD . Mice vaccinated with p NeuECD either encapsulated in virosomes or bound to the virosomal membrane (Vir-p NeuECD ), generated rNeu-specific humoral and cytotoxic immune responses. In addition, Vir-p NeuECD induced significant tumor rejection and additionally did not lead to delayed tumor formation when compared with free p NeuECD in complete Freund's adjuvant. There was no difference between the virosomal constructs. Taken together these results suggest that virosomes, as clinically approved safe vaccines, can be used to elicit both humoral and cellmediated responses against TAAg and induce tumor rejection. Our model is providing important preclinical data to design human vaccination trials for patients with tumors overexpressing HER-2/neu, either as a primary vaccination or as a boost in combination with other vaccines in a context of an adjuvant treatment plan.

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Tumour-associated antigen (TAA)-specific cytotoxic T cell (CTL) response in vitro and in a mouse model, induced by TAA-plasmids delivered by influenza virosomes

Cited by 32 publications

References 12 publications

High-Affinity HLA-A(*)02.01 Peptides from Parathyroid Hormone-Related Protein Generate In Vitro and In Vivo Antitumor CTL Response Without Autoimmune Side Effects

High-Affinity HLA-A(*)02.01 Peptides from Parathyroid Hormone-Related Protein Generate In Vitro and In Vivo Antitumor CTL Response Without Autoimmune Side Effects

In vivo study of the GC90/IRIV vaccine for immune response and autoimmunity into a novel humanised transgenic mouse

Virosomes as new carrier system for cancer vaccines

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