Trastuzumab (Herceptin) Enhances Class I-Restricted Antigen Presentation Recognized by HER-2/<b><i>neu</i></b>-Specific T Cytotoxic Lymphocytes

Kono, Koji; Sato, Eiji; Naganuma, Hirofumi; Takahashi, Akihiro; Mimura, Kousaku; Nukui, Hideaki; Fujii, Hideki

doi:10.1158/1078-0432.ccr-03-0424

Cited by 54 publications

(49 citation statements)

References 28 publications

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“…In fact, we and others reported that clinical vaccination trials in gastric or breast cancer patients using DCs pulsed with HER-2 peptides confirmed the fact that vaccination with HER-2 peptides is immunogenic, and that HER-2 could be a good target for immunotherapy (Disis et al, 1999;Kono et al, 2002c). Furthermore, we have recently shown that Herceptin enhances MHC class Irestricted antigen presentation in HER-2-overexpressing tumours, resulting in a higher susceptibility of HER-2-overexpressing tumours to lysis by HER-2-specific CTL (Kono et al, 2004). These results suggested that the combination of Herceptin and anti-HER-2-specific CTLs may result in a synergic antitumour effect in oesophageal SCC.…”

Section: Discussionmentioning

confidence: 88%

Frequencies of HER-2/neu expression and gene amplification in patients with oesophageal squamous cell carcinoma

et al. 2005

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The utilisation of antitumour T cells induced by cancer vaccination with HER-2 peptides or antibodies (Herceptin) against HER-2, as immunotherapy for oesophageal cancer, is a novel and attractive approach. It is important to clarify the frequencies of HER-2 expression and gene amplification in patients with oesophageal squamous cell carcinoma (SCC) and to evaluate the relationship between HER-2 status and HLA haplotype, since the candidates for HER-2 peptide-based vaccination are restricted to a certain HLA haplotype. We determined the frequency of HER-2 expression using the HercepTestt for immunohistochemistry and HER-2 gene amplification by fluorescence in situ hybridisation (FISH) assay in oesophageal SCC (n ¼ 66). HER-2-positive tumours (1 þ /2 þ /3 þ ) analysed by a HercepTest were observed in 30.3% of all the patients and HER-2 gene amplification evaluated by FISH was observed in 11.0% of all the patients, in which all HercepTest (3 þ ) tumours were found to have gene amplification and three of six moderately positive (2 þ ) tumours showed gene amplification. Furthermore, HER-2-positive cells were present more diffusely and were larger within each tumour in the patients who were HercepTest 3 þ than those who were HercepTest 1 þ . Moreover, the survival rate in HER-2-positive group was significantly worse than that in HER-2-negative group. Also, the survival rate in the patients with HER-2 gene amplification was significantly worse than that without HER-2 gene amplification. In addition, oesophageal SCC patients with both HLA-A24-positive and HER-2-positive tumours (1 þ /2 þ /3 þ ) accounted for 26% of these cases, and both HLA-A2-and HER-2-positive tumours accounted for 18% of them.

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Section: Discussionmentioning

confidence: 88%

Frequencies of HER-2/neu expression and gene amplification in patients with oesophageal squamous cell carcinoma

et al. 2005

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“…Interestingly, trastuzumab has been shown to enhance the cytotoxicity of ErbB-2-specific cytotoxic T lymphocytes (CTLs). Through enhanced endocytic degradation of ErbB-2, trastuzumab was shown to enhance MHC class I presentation of ErbB-2 epitopes, resulting in a higher susceptibility of ErbB-2 tumors to lysis by CTLs (30,31). Taken together, these data suggest that the combined administration of anti-DR5 mAb and trastuzumab may synergize in the generation of antitumor adaptive immune responses.…”

Section: Discussionmentioning

confidence: 99%

Antibodies targeted to TRAIL receptor-2 and ErbB-2 synergize in vivo and induce an antitumor immune response

Stagg

Sharkey

Pommey

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Despite the development of human epidermal growth factor receptor-2 (ErbB-2/HER2)-targeted therapies, there remains an unmet medical need for breast cancer patients with ErbB-2 overexpression. We investigated the therapeutic activity of an agonist mAb to mouse tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-2 (DR5) against ErbB2-driven breast cancer. Established tumors in BALB/c transgenic mice expressing a constitutively active ErbB-2/neuT were treated with anti-DR5 mAb and/or anti-ErbB-2 mAb and monitored for tumor progression. Treatment with anti-DR5 or anti-ErbB2 mAb as single agents significantly delayed tumor growth, although all tumors eventually progressed. Remarkably, treatment with a combination of anti-DR5 and anti-ErbB-2 mAbs induced complete response in a majority of mice. In vivo blockade of CD11b ؉ cells, but not natural killer cell depletion, significantly abrogated the early antitumor response. Notably, depletion of CD8 ؉ T cells provoked primary and secondary tumor relapse, revealing the induction of antitumor immunity by the combination treatment. Combined therapy with anti-DR5 and anti-ErbB-2 mAbs further significantly suppressed the growth of advanced spontaneous tumors in ErbB-2/neuT transgenic mice, even when treatment was delayed until tumors were palpable. We thus demonstrated that the combination of anti-DR5 and anti-ErbB2 mAbs might be an effective form of treatment for ErbB-2-overexpressing breast cancer.apoptosis ͉ breast cancer ͉ herceptin ͉ immunity H uman epidermal growth factor receptor-2 (ErbB-2/HER2) is overexpressed in 20-30% of patients with breast cancer and is associated with a poor prognosis (1). The use of trastuzumab (Herceptin; Genentech), a mAb that blocks the activity of ErbB-2, in combination with chemotherapy has been associated with an increased median survival in patients with advanced ErbB-2-positive breast cancer (2-4). In addition to its inhibitory effect on ErbB-2 signaling, trastuzumab mediates its therapeutic effect through the recruitment of immune cells such as monocytes and natural killer (NK) cells (1, 5). Accordingly, trastuzumab-like mAb unable to bind Fc receptors has less therapeutic activity (6), and complete or partial remission induced by trastuzumab correlates with higher antibody-dependent cell cytotoxicity (7-9).Although the development of trastuzumab constitute a major advance in the treatment of ErbB-2-overexpressing breast cancer, there remains an unmet medical need for new therapies. Proapoptotic receptor agonists (PARAs), including recombinant Apo2L/ tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and mAbs, have now emerged as promising anticancer agents (10, 11). PARAs exploit the enhanced susceptibility of cancer cells versus nontransformed cells to TRAIL-mediated apoptosis. Activation of TRAIL-R1 (DR4) or TRAIL-R2 (DR5) triggers the formation of a death-inducing signaling complex (DISC) that activates caspase-8. In some cells (type I), the activation of the ensuing caspase cascade is sufficient t...

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“…The Her2/neu receptor is considered a good target for Ab-mediated immunotherapeutic approaches because it is expressed at high levels in many tumors but at low levels in normal cells (28). Within the Her2/neu protein there are multiple HLA-A2 binding peptide epitopes that can induce CTL responses against autologous tumor cells (15,29).…”

Section: Discussionmentioning

confidence: 99%

“…In our study, drugtreated cells showed a 2-fold increase in HLA-A2 surface expression and a 15% increase in 1B8 staining (data not shown), suggesting that factors such as chaperones may provide protection from the proteasomal degradation pathway and that dissociation of these complexes may lead to enhanced lysis by CTLs. Other studies have shown that the internalization of Her2/neu mediated by trastuzumab can enhance tumor cell sensitivity to CTL-mediated lysis, and it is hypothesized that this is due to an increase in Her2/ neu peptide-HLA-A2 complexes on the cell surface (28). This theory can now be tested directly using the 1B8 TCRm to assess the presentation of the dominant Her2 (369) -A2 epitope.…”

Section: Discussionmentioning

confidence: 99%

Levels of Specific Peptide-HLA Class I Complex Predicts Tumor Cell Susceptibility to CTL Killing

Weidanz

Nguyen²,

Woodburn³

et al. 2006

The Journal of Immunology

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Recognition of tumor-associated Ags (TAAs) on tumor cells by CTLs and the subsequent tumor cell death are assumed to be dependent on TAA protein expression and to correlate directly with the level of peptide displayed in the binding site of the HLA class I molecule. In this study we evaluated whether the levels of Her-2/neu protein expression on human tumor cell lines directly correlate with HLA-A*0201/Her2/neu peptide presentation and CTL recognition. We developed a TCR mimic (TCRm) mAb designated 1B8 that specifically recognizes the HLA-A2.1/Her2/neu peptide (369–377) (Her2(369)-A2) complex. TCRm mAb staining intensity varied for the five human tumor cell lines analyzed, suggesting quantitative differences in levels of the Her2(369)-A2 complex on these cells. Analysis of tumor cell lines pretreated with IFN-γ and TNF-α for Her2/neu protein and HLA-A2 molecule expression did not reveal a direct correlation between the levels of Her2/neu Ag, HLA-A2 molecule, and Her2(369)-A2 complex expression. However, compared with untreated cells, cytokine-treated cell lines showed an increase in Her2(369)-A2 epitope density that directly correlated with enhanced tumor cell death (p = 0.05). Although a trend was observed between tumor cell lysis and the level of the Her2(369)-A2 complex for untreated cells, the association was not significant. These findings suggest that tumor cell susceptibility to CTL-mediated lysis may be predicted based on the level of specific peptide-MHC class I expression rather than on the total level of TAA expression. Further, these studies demonstrate the potential of the TCRm mAb for validation of endogenous HLA-peptide epitopes on tumor cells.

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Trastuzumab (Herceptin) Enhances Class I-Restricted Antigen Presentation Recognized by HER-2/neu-Specific T Cytotoxic Lymphocytes

Cited by 54 publications

References 28 publications

Frequencies of HER-2/neu expression and gene amplification in patients with oesophageal squamous cell carcinoma

Frequencies of HER-2/neu expression and gene amplification in patients with oesophageal squamous cell carcinoma

Antibodies targeted to TRAIL receptor-2 and ErbB-2 synergize in vivo and induce an antitumor immune response

Levels of Specific Peptide-HLA Class I Complex Predicts Tumor Cell Susceptibility to CTL Killing

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