Therapeutic Vaccination of Chronic Hepatitis C Nonresponder Patients With the Peptide Vaccine IC41

Klade, Christoph; Wedemeyer, Heiner; Berg, Thomas; Hinrichsen, Holger; Cholewińska, Grażyna; Zeuzem, Stefan; Blum, Hubert E.; Buschle, Michael; Jelovcan, Sandra; Buerger, Vera; Tauber, Erich; Frisch, Juergen; Manns, Michael P.

doi:10.1053/j.gastro.2008.02.058

Cited by 138 publications

(103 citation statements)

References 32 publications

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“…The T cell response to HCV core protein was determined using a number of FACS-based T cell assays. PBMC samples were cultured in vitro for a period of 7 days in the presence of IL-2 and HCV core antigen (i.e., either protein or three known HLA-A*0201-restricted peptides, YLLPRRGPRL [35][36][37][38][39][40][41][42][43][44] , DLMGYIPLV 132-140 and FLLALLSCL [177][178][179][180][181][182][183][184][185] ) to stimulate and expand antigen-specific CD4 + and/or CD8 + T cells, respectively. A complete analysis of the T cell responses was evaluated in the highest protein dose group only (i.e., 50 μg) as the lower dose groups were predominantly for safety evaluation.…”

Section: Resultsmentioning

confidence: 99%

“…Cryopreserved PBMC from all time points for a given subject were thawed and assayed in parallel. CD8 T cell assays were performed using three HLA-A*0201-restricted HCV Core peptides: HCV Core 132-140 (DLMGYIPLV), HCV Core [35][36][37][38][39][40][41][42][43][44] (YLLPRRGPRL) and HCV Core 177-185 (FLLALLSCL). A subject's recall response to a HLA-A*0201-restricted Epstein-Barr virus (EBV) peptide, EBV BMLF1 280-288 (GLCTLVAML), was used as an internal positive control in the ICS assay to monitor PBMC culture sensitivity across the bleed time points (all peptides were purchased from Mimotopes, Vic, Australia).…”

Section: Methodsmentioning

confidence: 99%

“…In a healthy volunteer study the CD8 + T cell responder rate for IC41 ranged from 0 to 40% depending on the dose of peptide and adjuvant. 37 In the Phase Ib study CD8 + T cell responder rate with IC41 ranged from 33 to 42% however there was minimal impact on the viral load. 38 The authors of the Phase Ib study manuscript highlight the potential limitations of peptide vaccines and the need for more powerful adjuvants although there was some evidence that the strongest T-cell responses were associated with transient reduction in HCV RNA.…”

Section: Wwwlandesbiosciencecom Human Vaccines 155mentioning

confidence: 99%

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Priming of CD4+ and CD8+ T cell responses using a HCV core ISCOMATRIX™ vaccine: A phase I study in healthy volunteers

Drane¹,

Maraskovsky²,

Gibson³

et al. 2009

Human Vaccines

100

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Wwwlandesbiosciencecom Human Vaccines 155mentioning

confidence: 99%

See 1 more Smart Citation

Priming of CD4+ and CD8+ T cell responses using a HCV core ISCOMATRIX™ vaccine: A phase I study in healthy volunteers

Drane¹,

Maraskovsky²,

Gibson³

et al. 2009

Human Vaccines

100

View full text Add to dashboard Cite

show abstract

“…One explanation may be that these chronic carriers have dysfunctional T cells (5)(6)(7)(8)(9). Hence, one approach to reactivate these dysfunctional T cells is therapeutic vaccination (10)(11)(12). Until now, no vaccine is available for HCV, although several candidates have been evaluated in clinical phase I/II trials (11,(13)(14)(15).…”

Section: Hronic Liver Disease Caused By the Hepatitis C Virus (Hcv)mentioning

confidence: 99%

A Synthetic Codon-Optimized Hepatitis C Virus Nonstructural 5A DNA Vaccine Primes Polyfunctional CD8+ T Cell Responses in Wild-Type and NS5A-Transgenic Mice

Holmström

Pasetto

Nähr

et al. 2013

The Journal of Immunology

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The hepatitis C virus (HCV) nonstructural (NS) 5A protein has been shown to promote viral persistence by interfering with both innate and adaptive immunity. At the same time, the HCV NS5A protein has been suggested as a target for antiviral therapy. In this study, we performed a detailed characterization of HCV NS5A immunogenicity in wild-type (wt) and immune tolerant HCV NS5A-transgenic (Tg) C57BL/6J mice. We evaluated how efficiently HCV NS5A-based genetic vaccines could activate strong T cell responses. Truncated and full-length wt and synthetic codon-optimized NS5A genotype 1b genes were cloned into eukaryotic expression plasmids, and the immunogenicity was determined after i.m. immunization in combination with in vivo electroporation. The NS5A-based genetic vaccines primed high Ab levels, with IgG titers of >104 postimmunization. With respect to CD8+ T cell responses, the coNS5A gene primed more potent IFN-γ–producing and lytic cytotoxic T cells in wt mice compared with NS5A-Tg mice. In addition, high frequencies of NS5A-specific CD8+ T cells were found in wt mice after a single immunization. To test the functionality of the CTL responses, the ability to inhibit growth of NS5A-expressing tumor cells in vivo was analyzed after immunization. A single dose of coNS5A primed tumor-inhibiting responses in both wt and NS5A-Tg mice. Finally, immunization with the coNS5A gene primed polyfunctional NS5A-specific CD8+ T cell responses. Thus, the coNS5A gene is a promising therapeutic vaccine candidate for chronic HCV infections.

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“…17 Briefly, the HLA-A2:immunoglobulin (Ig) dimer (Pharmingen, San Diego, Calif) was loaded with the E75 or control peptide (folate binding protein peptide-E37 [25][26][27][28][29][30][31][32][33] RIA-WARTEL) by incubating 1 lg of dimer with an excess (5 lg) of peptide and 0.5 lg of b 2 -microglobulin (Sigma Chemical Co, St Louis, Mo) at 37 C overnight, then storing it at 4 C until used. PBMCs were washed and resuspended in Pharmingen Stain Buffer and were added at 5 Â 10 5 cells/100 lL/tube in 5 mL round-bottom polystyrene tubes (Becton Dickinson) and stained with the loaded dimers and antibodies as described previously.…”

Section: Hla-a2: Immunoglobulin Dimer Assaymentioning

confidence: 99%

Use of booster inoculations to sustain the clinical effect of an adjuvant breast cancer vaccine

Holmes

Clifton

Patil

et al. 2010

Cancer

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BACKGROUND:The authors are conducting clinical trials of the HER-2/neu E75-peptide vaccine in clinically diseasefree breast cancer (BC) patients. Their phase 1-2 trials revealed that the E75 þ granulocyte-macrophage colony-stimulating factor (GM-CSF) vaccine is safe and effective in stimulating clonal expansion of E75-specific CD8 þ T cells.They assessed the need for and response to a booster after completion of primary vaccination series. METHODS: BC patients enrolled in the E75 vaccine trials who were !6 months from completion of their primary vaccination series were offered boosters with E75 þ GM-CSF. Patients were monitored for toxicity. E75-specific CD8 þ T cells were quantified using the human leukocyte antigen-A2:immunoglobulin G dimer before and after boosting. RESULTS: Fiftythree patients received the vaccine booster. Median time from primary vaccination series was 9 months (range, 6-35 months), and median residual E75-specific immunity was 0.70% (range, 0-3.49%) CD8 þ lymphocytes. Elevated residual immunity (ERI) (CD8 þ E75-specific T cells >0.5%) was seen in 94.4% of patients at 6 months from primary vaccination series versus 48% of patients at >6 months (P ¼ .002). The booster was well tolerated, with only grade 1 and 2 toxicity observed. Local reactions were more robust in patients receiving the booster at 6 months from primary vaccination series compared with those at >6 months (99.4 AE 6.1 mm vs 81.8 AE 4.1 mm, P ¼ .01). In patients lacking ERI, 85% had increased ERI after vaccination (P ¼ .0014). CONCLUSIONS: The HER-2/neu E75 peptide vaccine E75 stimulates specific immunity in disease-free BC patients. However, immunity wanes with time. A vaccine booster is safe and effective in stimulating E75-specific immunity in those patients without ERI. These results suggest that the booster may be most effective at 6 months after completion of the primary vaccination series. Peptide-based vaccines are being used in clinical trials either to treat 1,2 or to prevent recurrence of malignancy. 3,4Peptide-based vaccination techniques involve inoculating patients with immunogenic epitopes from tumor-associated antigens, typically given with an immunoadjuvant, to stimulate proliferation of peptide-specific lymphocytes. Peptidespecific lymphocytes then identify and eliminate tumor cells presenting the vaccine-targeted epitope. Peptide-based vaccines are attractive immunotherapeutic options because they have no malignant potential, have low toxicity profiles, are simple and inexpensive, are easily monitored and studied, and eventually will be easily exportable to the community. The individual peptides used in cancer vaccine preparations are often major histocompatibility complex (MHC) class-restricted and human leukocyte antigen (HLA) type-specific, thus stimulating either CD4 þ or CD8 þ lymphocytes and sometimes limiting the applicability of peptides to patients with the correct HLA type. Peptide vaccination techniques

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Therapeutic Vaccination of Chronic Hepatitis C Nonresponder Patients With the Peptide Vaccine IC41

Cited by 138 publications

References 32 publications

Priming of CD4+ and CD8+ T cell responses using a HCV core ISCOMATRIX™ vaccine: A phase I study in healthy volunteers

Priming of CD4+ and CD8+ T cell responses using a HCV core ISCOMATRIX™ vaccine: A phase I study in healthy volunteers

A Synthetic Codon-Optimized Hepatitis C Virus Nonstructural 5A DNA Vaccine Primes Polyfunctional CD8+ T Cell Responses in Wild-Type and NS5A-Transgenic Mice

Use of booster inoculations to sustain the clinical effect of an adjuvant breast cancer vaccine

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