Induction of anti-self-immunity to cure cancer

Nanda, Nivedita; Sercarz, Eli E.

doi:10.1016/0092-8674(95)90047-0

Cited by 187 publications

(107 citation statements)

References 20 publications

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“…Consequently, during natural immunogenic processing of the intact HER-2/neu protein, HER-2(9 369 ) may be presented in the context of HLA-A2 or HLA-A26 in an immunodominant manner and be recognised by high-affinity CD8 þ T-cell clones, which will be tolerised by the immune system in order to prevent the induction of an immune response to nonmalignant epithelial cells also expressing HER-2/neu. Indeed, dominantly processed self-determinants are thought to be efficient in tolerance induction (Nanda and Secarz, 1995;Sercarz, 2000).…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic T-cell precursor frequencies to HER-2 (369 – 377) in patients with HER-2/neu-positive epithelial tumours

et al. 2003

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HER-2/neu oncoprotein contains several major histocompatibility complex class I-restricted epitopes, which are recognised by cytotoxic T lymphocyte (CTL) on autologous tumours and therefore can be used in immune-based cancer therapies. Of these, the most extensively studied is HER-2(9 369 ). In the present report, we used dendritic cells pulsed with HER-2(9 369 ) to stimulate, in the presence of IL-7 and IL-12, the production of IFN-g by patients' CTL detected by the enzyme-linked immunosorbent spot-assay. Frequencies of peptide-specific precursors were estimated in HLA-A2, HLA-A3 and HLA-A26 patients with HER-2/neu-positive ( þ ) breast, ovarian, lung, colorectal and prostate cancers and healthy individuals. We found increased percentages of such precursors in HLA-A2 (25%) and HLA-A26 (30%) patients, which were significantly higher (60%) in HLA-A3 patients. Our results demonstrate for the first time that pre-existing immunity to HER-2(9 369 ) occurs in patients with colorectal, lung and prostate cancer. They also suggest that HER-2(9 369 ) can be recognised by CTL, besides HLA-A2, also in the context of HLA-A3 and HLA-A26, thus increasing the applicability of HER-2(9 369 )-based vaccinations in a considerably broader patients' population.

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Section: Discussionmentioning

confidence: 99%

Cytotoxic T-cell precursor frequencies to HER-2 (369 – 377) in patients with HER-2/neu-positive epithelial tumours

et al. 2003

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“…25 Cancer-vaccine strategies for self-tumor antigens need to overcome this immune tolerance to self-proteins. 26,27 In the present study, the infiltrating grade of TILs did not differ between tumors overexpressing HER-2/neu and those that did not in patients with gastric cancer.…”

Section: Relationship Between Clinicopathological Features and Hla Hamentioning

confidence: 99%

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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“…It should be noted, however, that both humoral and cell-mediated immune responses to overexpressed tumor-associated Ags such as Her2 and Melan-A/Mart1, which are expressed in normal tissues as well, can be documented in cancer patients. [23][24][25][26] Indeed, a variety of current immunotherapeutic strategies actively seek to target such Ags. 27 Hrg--expressing T cells will be tested in an animal model of a cancer that overexpresses Her3/Her4.…”

Section: Resultsmentioning

confidence: 99%

Ligand-mediated cytolysis of tumor cells: Use of heregulin-ζ chimeras to redirect cytotoxic T lymphocytes

Muniappan¹,

Banapour²,

Lebkowski³

et al. 2000

Cancer Gene Ther

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New specificities may be engrafted onto lymphocytes by the transfer of genes for chimeric receptors that combine antigen recognition and signal-transducing elements. We have engineered and evaluated a new class of chimeric receptors that use the natural ligands of receptors found to be frequently overexpressed by cancer cells. The heregulin molecule, a ligand for Her3 and Her4 receptors when fused with the CD3 -chain, was capable of redirecting T lymphocytes to recognize and respond to cancer cell lines that overexpress these receptors. Thus, CD8 ϩ T lymphocytes were isolated from a healthy individual and transduced to express the chimeric heregulin-receptor. These modified effector cells acquired the ability to specifically lyse a breast cancer cell line that overexpresses Her3 and Her4. A new class of chimeric receptors, such as heregulin-, endowing anti-cancer effector cells with the potential to recognize and eliminate tumor targets, are likely to increase the effectiveness of adoptive immunotherapy for the treatment of cancer. Cancer Gene Therapy (2000) 7, 128 -134

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Induction of anti-self-immunity to cure cancer

Cited by 187 publications

References 20 publications

Cytotoxic T-cell precursor frequencies to HER-2 (369 – 377) in patients with HER-2/neu-positive epithelial tumours

Cytotoxic T-cell precursor frequencies to HER-2 (369 – 377) in patients with HER-2/neu-positive epithelial tumours

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

Ligand-mediated cytolysis of tumor cells: Use of heregulin-ζ chimeras to redirect cytotoxic T lymphocytes

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