Vaccination with Human HER-2/neu(435-443) CTL Peptide Induces Effective Antitumor Immunity against HER-2/neu-Expressing Tumor CellsIn vivo

Gritzapis, Angelos D.; Mahaira, Louisa G.; Perez, Sonia A.; Cacoullos, Nike T.; Papamichail, Michael; Baxevanis, Constantin N.

doi:10.1158/0008-5472.can-05-4018

Cited by 43 publications

(55 citation statements)

References 42 publications

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“…This cell line was grown in vivo as ascites by serial passages in C57BL/6 syngeneic mice. HLA-A2.1 transfectants of SKOV3 (SKOV3.A2), SKBR3 (SKBR3.A2) and ALC (ALC.A2.1), and human HER-2/neu transfectants of ALC (ALC.HER) and ALC.A2.1 (ALC.A2.1.HER) were produced as recently described (24).…”

Section: Cell Linesmentioning

confidence: 99%

“…Mice were immunized according to our protocol described recently (24). This included three s.c. injections every 5 days (i.e., days 0, 5, and 10) at the base of the tail, each one consisting of 100 g HER-2(10 85 ) emulsified in 200 l IFA, and 5 i.p.…”

Section: In Vivo Generation Of Her-2(10 85 )-Specific Ctlmentioning

confidence: 99%

“…This was performed as recently described (24). In brief, HHD mice were immunized with 100 g of either HER-2(10 85 ) or control gp (9 154 ) peptide in IFA plus GM-CSF, as above.…”

Section: Protective Tumor Modelmentioning

confidence: 99%

“…Plasmid DNA vaccination and regimens involving active immunization combined with administration of TLR agonists efficiently prevented and/or delayed the onset of mammary carcinomas (21)(22)(23). In our recent study (24), we have shown that immunization with a xenogeneic HER-2/neu CTL peptide induced enhanced rejection of a transplantable HER-2/neu ϩ tumor expressing the self-CTL epitope. Translation of these modalities in phase I/II trials may provide the basis for improved clinical outcome.…”

mentioning

confidence: 99%

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Identification of a Novel Immunogenic HLA-A0201-Binding Epitope of HER-2/neu* with Potent Antitumor Properties

Gritzapis¹,

Voutsas²,

Lekka³

et al. 2008

The Journal of Immunology

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HER-2/neu oncoprotein is overexpressed in a variety of human tumors and is associated with aggressive disease. Immunogenic HER-2/neu CTL epitopes have been used as vaccines for the treatment of HER-2/neu positive malignancies with limited success. By applying prediction algorithms for MHC class I ligands and proteosomal cleavages, in this study, we describe the identification of HER-2/neu decamer LIAHNQVRQV spanning residues 85–94 (HER-2(1085)). HER-2(1085) proved to bind with high affinity to HLA-A2.1 and was stable for 4 h in an off-kinetics assay. This peptide was immunogenic in HLA-A2.1 transgenic (HHD) mice inducing peptide-specific CTL, which responded to tumor cell lines of various origin coexpressing human HER-2/neu and HLA-A2.1. This demonstrates that HER-2(1085) is naturally processed from endogenous HER-2/neu. Five of sixteen HER-2/neu+ HLA-A2.1+ breast cancer patients analyzed had HER-2(1085)-reactive T cells ranging from 0.35–0.70% of CD8+ T cells. Depletion of T regulatory cells from PBMC enabled the rapid expansion of HLA-A2.1/HER-2(1085)pentamer+/CD8+ cells (PENT+/CD8+), whereas significantly lower numbers of CTL could be generated from unfractionated PBMC. HER-2(1085)-specific human CTL recognized the HER-2/neu+ HLA-A2.1+ tumor cell line SKBR3.A2, as determined by IFN-γ intracellular staining and in the high sensitivity CD107α degranulation assay. Finally, HER-2(1085) significantly prolonged the survival of HHD mice inoculated with the transplantable ALC.A2.1.HER tumor both in prophylactic and therapeutic settings. These data demonstrate that HER-2(1085) is an immunogenic peptide, capable of eliciting CD8-mediated responses in vitro and in vivo, providing the platform for further exploitation of HER-2(1085) as a possible target for anticancer immunotherapy.

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Section: Cell Linesmentioning

confidence: 99%

Section: In Vivo Generation Of Her-2(10 85 )-Specific Ctlmentioning

confidence: 99%

“…This was performed as recently described (24). In brief, HHD mice were immunized with 100 g of either HER-2(10 85 ) or control gp (9 154 ) peptide in IFA plus GM-CSF, as above.…”

Section: Protective Tumor Modelmentioning

confidence: 99%

mentioning

confidence: 99%

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Identification of a Novel Immunogenic HLA-A0201-Binding Epitope of HER-2/neu* with Potent Antitumor Properties

Gritzapis¹,

Voutsas²,

Lekka³

et al. 2008

The Journal of Immunology

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“…Induction of antigen-specific CTL by therapeutic peptide vaccination is a promising approach for cancer immunotherapy [1]. The specific cellular immune response starts from recognition by TCR of an immunogenic epitope presented in the context of the class I MHC molecules.…”

Section: Introductionmentioning

confidence: 99%

Rational optimization of tumor epitopes using in silico analysis‐assisted substitution of TCR contact residues

et al. 2009

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Altered peptide ligands with increased affinity of the peptide-MHC complex for the TCR provide an alternative strategy to natural T-cell epitopes for cancer immunotherapy, as they can recruit and stimulate stronger T-cell repertoires. However, it remains unclear how alterations of the TCR contact residues improve the interaction between the peptide-MHC complex and the TCR molecule. In this study, we introduced a molecular simulation strategy to optimize a tumor immunodominant epitope NY-ESO-1 157-165 by the substitution of the potential TCR contact residues. We correlated molecule simulation with T-cell activation capacity assay and detected the effect of modifications of TCR contact residues on T-cell recognition. An agonist peptide W5F with substitution at Trp5 with Phe was identified and it exhibits a stronger ability to induce a cross-reactive CTL response with the WT peptide. Additionally, the W5F-induced CTL could be maintained with the WT peptide and possess higher capacity in lysing native NY-ESO-1-expressing tumor cells. These results provide important insights into the enhanced immunogenicity of epitopes through substitution at the TCR contact sites and revealed a novel molecular simulation approach for rational therapeutic peptide vaccine design.Key words: Cancer immunotherapy . Epitope . Molecular simulation . TCR contact residue IntroductionInduction of antigen-specific CTL by therapeutic peptide vaccination is a promising approach for cancer immunotherapy [1]. The specific cellular immune response starts from recognition by TCR of an immunogenic epitope presented in the context of the class I MHC molecules. Thus, modulation of CTL response by manipulating T-cell epitopes is a particularly attractive approach for cancer immunotherapy, because peptides from cancer cells are usually poorly immunogenic and often induce immune-tolerance [2,3]. Vaccination with altered peptide ligands (APL), which can be generated by appropriate amino acid substitutions at certain T-cell epitopes, has become an attractive strategy to enhance specic T-cell responses to tumors. This strategy can be achieved by two general approaches: (i) by increasing the affinity between the epitope and the MHC through substitution in the MHC anchor residues or (ii) by enhancing the interactions between the TCR and peptide-MHC (pMHC) complex through alteration at the TCR contact residues [4,5].Although APL with altered MHC contact residues can efficiently activate tumor-specific T cells in vitro, vaccination with this kind of APL has generally failed to elicit an effective anti-tumor CTL response 2248that can lead to clinical tumor regression [6,7]. APL with increased pMHC complex affinity for the TCR molecule, which are designed by modifications at the TCR contact sites rather than the MHC anchor residues, have unexpected potency to induce stronger T-cell responses and may even covert cross-reactive T cells from a tolerance state [8][9][10]. According to the structure of the TCR/pMHC complex established by X-ray crystallography, recogni...

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Production of a bioactive recombinant chicken matrix metalloproteinase‐11 peptide in Escherichia coli

Paul

Kumar

Kataria

2017

Biotech and App Biochem

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Matrix metalloproteinase-11 (MMP-11) is known to be highly expressed in metastatic and most invasive forms of tumors. Being selectively expressed in tumor tissues, MMP-11 is a promising target for immunotherapy against tumors. Here, we report the production of a thioredoxin-tagged bioactive recombinant chicken MMP-11 (cMMP-11) peptide excluding the secretory signal and propeptide in Escherichia coli T7 Express lysY using pET32b(+) vector. High-level expression and purification of the bioactive peptide were achieved by induction with 1.0 mM isopropyl-β-d-thiogalactopyranoside for 4 H at 37 °C followed by affinity chromatography under denaturing condition and slow dialysis. The recombinant peptide exhibited both caseinolytic and gelatinase activities without requiring activation by 4-aminophenylmercuric acetate. The antisera raised against the peptide in rabbits showed a strong reaction with the whole recombinant peptide as well as 37 kDa cMMP-11 mature peptide and cross-reactivity with a 43 kDa protein in murine breast tumor of 4T1 origin in Western blot analysis. The 43 kDa protein in the tumor homogenate showed immunoreactivity with a monoclonal antibody against human MMP-11, suggesting it to be murine MMP-11 having cross-reactivity with the antisera raised against cMMP-11 peptide. Altogether, the study characterized the production of a bioactive and immunogenic recombinant cMMP-11 peptide in E. coli.

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Vaccination with Human HER-2/neu(435-443) CTL Peptide Induces Effective Antitumor Immunity against HER-2/neu-Expressing Tumor CellsIn vivo

Cited by 43 publications

References 42 publications

Identification of a Novel Immunogenic HLA-A0201-Binding Epitope of HER-2/neu* with Potent Antitumor Properties

Identification of a Novel Immunogenic HLA-A0201-Binding Epitope of HER-2/neu* with Potent Antitumor Properties

Rational optimization of tumor epitopes using in silico analysis‐assisted substitution of TCR contact residues

Production of a bioactive recombinant chicken matrix metalloproteinase‐11 peptide in Escherichia coli

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Vaccination with Human HER-2/neu(435-443) CTL Peptide Induces Effective Antitumor Immunity against HER-2/neu-Expressing Tumor CellsIn vivo

Cited by 43 publications

References 42 publications

Identification of a Novel Immunogenic HLA-A*0201-Binding Epitope of HER-2/neu with Potent Antitumor Properties

Identification of a Novel Immunogenic HLA-A*0201-Binding Epitope of HER-2/neu with Potent Antitumor Properties

Rational optimization of tumor epitopes using in silico analysis‐assisted substitution of TCR contact residues

Production of a bioactive recombinant chicken matrix metalloproteinase‐11 peptide in Escherichia coli

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Identification of a Novel Immunogenic HLA-A0201-Binding Epitope of HER-2/neu* with Potent Antitumor Properties

Identification of a Novel Immunogenic HLA-A0201-Binding Epitope of HER-2/neu* with Potent Antitumor Properties