Biased epitope selection by recombinant vaccinia-virus (rVV)-infected mature or immature dendritic cells

Nagorsen, Dirk; Panelli, Monica C.; Dudley, Mark E.; Finkelstein, Steven E.; Rosenberg, S A; Marincola, Francesco M.

doi:10.1038/sj.gt.3302066

Cited by 18 publications

(10 citation statements)

References 64 publications

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“…In a variety of vectors, vaccinia virus has more recently been used as a versatile eukaryotic expression vector and is important in tumor gene transfecting. Indeed, several studies have shown that vaccinia gene has successfully transfered into human DCs and results in induction of a T-cell response against tumor (27,28). Our results showed that the expression of LMP2A in transfection DCs reached a high level of 80.69%, which indicated efficient gene transfection.…”

Section: Discussionsupporting

confidence: 58%

Computational Prediction and Identification of Epstein-Barr Virus Latent Membrane Protein 2A Antigen-Specific CD8+ T-Cell Epitopes

et al. 2009

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Section: Discussionsupporting

confidence: 58%

Computational Prediction and Identification of Epstein-Barr Virus Latent Membrane Protein 2A Antigen-Specific CD8+ T-Cell Epitopes

et al. 2009

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“…Because mature dendritic cells mainly contain IPs, vaccination modalities that are based on full-length proteins or full-length recombinant vectors should induce CTL responses against peptides produced by the IP but not against those only produced by the SP. The poor presentation of peptide gp100 209 -217 by dendritic cells infected with a full-length gp100 recombinant virus was confirmed in a recent study (48). The induction of CTL responses against such peptides might require an immunization procedure that bypasses intracellular processing by dendritic cells.…”

Section: Discussionmentioning

confidence: 64%

Destructive Cleavage of Antigenic Peptides Either by the Immunoproteasome or by the Standard Proteasome Results in Differential Antigen Presentation

Chapiro

Claverol

Piette

et al. 2006

The Journal of Immunology

136

131

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The immunoproteasome (IP) is usually viewed as favoring the production of antigenic peptides presented by MHC class I molecules, mainly because of its higher cleavage activity after hydrophobic residues, referred to as the chymotrypsin-like activity. However, some peptides have been found to be better produced by the standard proteasome. The mechanism of this differential processing has not been described. By studying the processing of three tumor antigenic peptides of clinical interest, we demonstrate that their differential processing mainly results from differences in the efficiency of internal cleavages by the two proteasome types. Peptide gp100209–217 (ITDQVPSFV) and peptide tyrosinase369–377 (YMDGTMSQV) are destroyed by the IP, which cleaves after an internal hydrophobic residue. Conversely, peptide MAGE-C2336–344 (ALKDVEERV) is destroyed by the standard proteasome by internal cleavage after an acidic residue, in line with its higher postacidic activity. These results indicate that the IP may destroy some antigenic peptides due to its higher chymotrypsin-like activity, rather than favor their production. They also suggest that the sets of peptides produced by the two proteasome types differ more than expected. Considering that mature dendritic cells mainly contain IPs, our results have implications for the design of immunotherapy strategies.

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“…This may be potentially mitigated through various immunological approaches. [34][35][36][37][38][39][40][41][42] Finally, the paradoxical "worsening" of the immunophenotype in the short term after IL-2 therapy, as measured by several cell-surface markers or by the falling DCto-MDSC ratio, was observed. This was despite the eventual excellent, complete, durable response shown in some of our patients.…”

Section: Immunological Versus Tumor-based Patient Selectionmentioning

confidence: 93%

Changes in Dendritic Cell Phenotype After a New High-dose Weekly Schedule of Interleukin-2 Therapy for Kidney Cancer and Melanoma

Finkelstein¹,

Carey²,

Fricke³

et al. 2010

Journal of Immunotherapy

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High-dose intravenous interleukin-2 (IL-2) therapy (14 doses/course, 2 courses/cycle) for metastatic melanoma or kidney cancer induces infrequent, although major responses. In this trial, we evaluated a new schedule (dose of 600,000 IU/kg, 8 h between doses, 5 doses/course, 4 courses at weekly intervals/cycle) of high-dose IL-2, in which we inserted more planned breaks while maintaining high cumulative dose delivery, and investigated the relationship between dendritic cells (DC) and response to treatment. Target dose delivery was attained: median IL-2 cumulative dose per patient was 11.4 and 10.8 million units/kg (cycles 1 and 2, respectively). Major responses were observed in patients with kidney cancer (n=20; 3 complete and 2 partial responses) and melanoma (n=16; 1 partial response). Adverse events appeared comparable with those typically associated with high-dose IL-2. From this data set, we introduce the hypothesis-generating observation that patients who had more favorable outcomes had high pretreatment DC-to-myeloid-derived suppressor cell (MDSC) ratios, similar to the ratio observed in healthy individuals. However, even in patients with the most favorable outcome, after treatment, there were IL-2-induced changes in the DC-to-MDSC ratio, specifically increases in MDSCs. This modified IL-2 schedule is a feasible option, with a more uniform dose delivery over the treatment cycle, a similar toxicity profile, and observed complete, durable response in patients with renal cancer. Pretreatment assessment of DC phenotypic or maturational status may be a starting point to predicting response to high-dose IL-2 cytokine immunotherapy in patients with melanoma and kidney cancer.

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Biased epitope selection by recombinant vaccinia-virus (rVV)-infected mature or immature dendritic cells

Cited by 18 publications

References 64 publications

Computational Prediction and Identification of Epstein-Barr Virus Latent Membrane Protein 2A Antigen-Specific CD8+ T-Cell Epitopes

Computational Prediction and Identification of Epstein-Barr Virus Latent Membrane Protein 2A Antigen-Specific CD8+ T-Cell Epitopes

Destructive Cleavage of Antigenic Peptides Either by the Immunoproteasome or by the Standard Proteasome Results in Differential Antigen Presentation

Changes in Dendritic Cell Phenotype After a New High-dose Weekly Schedule of Interleukin-2 Therapy for Kidney Cancer and Melanoma

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