The Multi-epitope Approach for Immunotherapy for Cancer: Identification of Several CTL Epitopes from Various Tumor-Associated Antigens Expressed on Solid Epithelial Tumors

Kawashima, Ichiro; Hudson, Stephen J.; Tsai, Van; Southwood, Scott; Takesako, Kazutoh; Appella, Ettore; Sette, Alessandro; Celis, Esteban

doi:10.1016/s0198-8859(97)00255-3

Cited by 196 publications

(132 citation statements)

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“…We conclude that this recognition was MHC class I-restricted, as a HER-2 expressing, but HLA-A2.1-negative, tumor was not recognized. In line with these findings, Kawashima et al (34) were able to identify double-substitution analogues from CEA with strong tumor-specific immunogenicity in vitro, and others have found that double or single substitution of CTL epitopes is able to induce tumor-specific T cells (8 -11, 17, 29, 30).…”

Section: Discussionmentioning

confidence: 75%

Improved Immunogenicity of an Immunodominant Epitope of the Her-2/neu Protooncogene by Alterations of MHC Contact Residues

Vertuani

Sette

Sidney

et al. 2004

The Journal of Immunology

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The HER-2/neu (HER-2) oncogene is expressed in normal epithelial surfaces at low levels and overexpressed in several types of tumors. The low immunogenicity against this self tumor Ag can be improved by developing epitopes with amino acid replacements in their sequences. In this study, three HER-2/neu.369 (HER-2.369) analogue peptides, produced by modifying both anchor positions by introducing L, V, or T at position 2 and V at the C terminus, were analyzed for their capacity to induce CTLs in vitro from human PBMC and in vivo in HLA-A2.1/Kb transgenic mice. One of the analogues (HER-2.369 V2V9) sensitized target cells for HER-2-specific recognition by human CTLs and induced specific CTLs in vitro at 100-fold lower concentrations than the HER-2.369 wild-type epitope. These CTLs were also able to recognize the wild-type epitope and HER-2-expressing tumors in an MHC-restricted manner. Furthermore, a 100-fold lower amount of the HER-2.369 V2V9 analogue compared with the wild-type epitope was required to induce CTLs in HLA-A2.1/Kb transgenic mice. However, the V2V9 analogue demonstrated only marginally better binding to the MHC class I A2 allele compared with wild type. To establish thermodynamic parameters, we developed radiolabeled F3*Y analogues from both the HER-2.369 epitope and the V2V9 analogue. Our results indicate that the high biological activity of the HER-2.369 V2V9 epitope is associated with a slower dissociation kinetic profile, resulting in an epitope with greater HLA-A2 stability.

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Section: Discussionmentioning

confidence: 75%

Improved Immunogenicity of an Immunodominant Epitope of the Her-2/neu Protooncogene by Alterations of MHC Contact Residues

Vertuani

Sette

Sidney

et al. 2004

The Journal of Immunology

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“…The identification of several new HLA-A2-restricted CTL epitopes from HER-2/neu that can activate CTLs from healthy donors and patients with advanced ovarian carcinoma has also been reported. 14,15 These results indicate that HER-2/neu-derived peptides could be broad targets for immunotherapy against these types of cancers. It is important to evaluate candidates for tumor vaccination with HER-2/neu-derived peptides in patients with gastric cancer.…”

mentioning

confidence: 96%

Frequencies of HER‐2/neu overexpression relating to HLA haplotype in patients with gastric cancer

Kono

Takahashi

Amemiya

et al. 2001

Intl Journal of Cancer

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We have identified that HER-2/neu-derived peptides are naturally processed as tumor rejection antigens recognized by tumor-specific, HLA-A2-restricted cytotoxic T lymphocytes in gastric cancer. To evaluate candidates for immunotherapy using HER-2/neu-derived, HLA-A2-restricted peptides, we examined the frequency of HLA-A2 relating to HER-2/neu overexpression or the infiltrating grade of tumorinfiltrating lymphocytes (TILs) in Japanese patients with gastric cancer. HER-2/neu-overexpressing tumors detected by immunohistochemistry amounted to 19% of primary gastric cancers and HLA-A2-positive patients with gastric cancer were 31% of primary gastric-cancer cases. Finally, gastriccancer patients with both HLA-A2-positive and HER-2/neuoverexpressing tumors amounted to 6.6% of these cases. There was no significant difference in the infiltrating grade of TILs between gastric cancers overexpressing HER-2/neu and those that did not. Gastric cancer is 1 of the most common cancers occurring in Japan today. The control of gastric cancer at advanced stages still remains difficult, despite various treatments such as gastrectomy with extensive lymphadenectomy 1 and surgery combined with chemotherapy. 2 We and others reported that MHC class I-restricted cytotoxic-T lymphocytes (CTLs) from gastric-cancer patients can react specifically against autologous tumor cells. [3][4][5][6] Adoptive immunotherapy based on gastric cancer-specific CTLs, or vaccinations based on the MHC class I-associated tumor antigens that they recognize, represent alternative therapeutic approaches. The presence of tumor-associated antigens recognized by gastric-cancer-specific CTLs restricted by HLA-A31 6 or HLA-A2.1 molecules 4 has been demonstrated, although the nature of these antigens has not been defined. Moreover, we have identified that HER-2/neu-derived peptides are naturally processed as tumorassociated antigens recognized by tumor-specific, HLA-A2-restricted CTLs in gastric cancer. 7 Thus, HER-2/neu-derived peptides may be considered as candidates for tumor-specific immunotherapy such as tumor vaccination in patients with gastric cancer.The HER-2/neu protooncogene encodes a 185-kDa transmembrane glycoprotein with tyrosine-specific kinase activity. 8 The HER-2/neu protooncogene is amplified and overexpressed in approximately 30% of human ovarian and breast tumors 9 and in 20% of gastric cancers. 10 HLA-A2-restricted CTL epitopes derived from HER2/neu recognized by ovarian-11,12 and breast-13 cancerspecific CTLs have previously been defined, in addition to those specific for gastric cancer. The identification of several new HLA-A2-restricted CTL epitopes from HER-2/neu that can activate CTLs from healthy donors and patients with advanced ovarian carcinoma has also been reported. 14,15 These results indicate that HER-2/neu-derived peptides could be broad targets for immunotherapy against these types of cancers. It is important to evaluate candidates for tumor vaccination with HER-2/neu-derived peptides in patients with gastric cancer. Because it has...

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“…[110][111][112][113] However, it was observed that numerous CTL that were raised against high-affinity binding peptides did not recognize tumor cells expressing the relevant TAA and restriction element. [114][115][116][117][118] A major reason for this was the lack of intracellular generation of predicted peptides by the processing machinery.…”

Section: Identification Of T-cell Epitopes For Cancer Immunotherapy Jmentioning

confidence: 99%

Identification of T-cell epitopes for cancer immunotherapy

2007

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The effectiveness of T-cell-mediated immunotherapy of cancer depends on both an optimal immunostimulatory context of the therapy and the proper selection with respect to quality and quantity of the targeted tumor-associated antigens (TAA), and, more precisely, the T-cell epitopes contained in these tumor proteins. Our progressing insight in human leukocyte antigen (HLA) class I and class II antigen processing and presentation mechanisms has improved the prediction by reverse immunology of novel cytotoxic T lymphocyte and T-helper cell epitopes within known antigens. Computer algorithms that in silico predict HLA class I and class II binding, proteasome cleavage patterns and transporter associated with antigen processing translocation are now available to expedite epitope identification. The advent of genomics allows a high-throughput screening for tumor-specific transcripts and mutations, with that identifying novel shared and unique TAA. The increasing power of mass spectrometry and proteomics will lead to the direct identification from the tumor cell surface of numerous novel tumor-specific HLA class I and class II presented ligands. Together, the expanded repertoire of tumor-specific T-cell epitopes will enable more precise immunomonitoring and the development of effective epitope-defined adoptive T-cell transfer and multi-epitope-based vaccination strategies targeting epitopes derived from a wider diversity of TAA presented in a broader array of HLA molecules.

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The Multi-epitope Approach for Immunotherapy for Cancer: Identification of Several CTL Epitopes from Various Tumor-Associated Antigens Expressed on Solid Epithelial Tumors

Cited by 196 publications

References 58 publications

Improved Immunogenicity of an Immunodominant Epitope of the Her-2/neu Protooncogene by Alterations of MHC Contact Residues

Improved Immunogenicity of an Immunodominant Epitope of the Her-2/neu Protooncogene by Alterations of MHC Contact Residues

Frequencies of HER‐2/neu overexpression relating to HLA haplotype in patients with gastric cancer

Identification of T-cell epitopes for cancer immunotherapy

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