Pre-existent immunity to the HER-2/neu oncogenic protein in patients with HER-2/neu overexpressing breast and ovarian cancer

Abstract

Immunomodulatory strategies, such as antibody therapy and cancer vaccines, are increasingly being considered as potential adjuvant therapies in patients with advanced stage breast cancer to either treat minimal residual disease or prevent relapse. However, little is known concerning the incidence and magnitude of the pre-existent breast cancer specific immune response in this patient population. Using the HER-2/neu oncogenic protein as a model, a well-defined tumor antigen in breast cancer, we questioned whether patients with advanced stage HER-2/neu overexpressing breast and ovarian cancers (III/IV) had evidence of pre-existent immunity to HER-2/neu. Forty-five patients with stage III or IV HER-2/neu overexpressing breast or ovarian cancer were evaluated for HER-2/neu specific T cell and antibody immunity. Patients enrolled had not received immunosuppressive chemotherapy for at least 30 days (median 5 months, range 1-75 months). All patients were documented to be immune competent prior to entry by DTH testing using a skin test anergy battery. Five of 45 patients (11%) were found to have a significant HER-2/neu specific T cell response as defined by a stimulation index > or = 2.0 (range 2.0-7.9). None of eight patients who were HLA-A2 had a detectable IFNgamma secreting T-cell precursor frequency to a well-defined HER-2/neu HLA-A2 T cell epitope, p369-377. Three of 45 patients (7%) had detectable HER-2/neu specific IgG antibodies, range 1.2-8.9 microg/ml. These findings suggest that patients with advanced stage HER-2/neu overexpressing breast and ovarian cancer can mount a T cell and/or antibody immune response to their tumor. However, in the case of the HER-2/neu antigen, the pre-existent tumor specific immune response is found only in a minority of patients.

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

“…These populations are considered for cancer vaccination with the HER-2 peptide in oesophageal SCC. 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).…”

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

“…Although the immunogenicity of HER-2(9 369 ) has been merely shown in studies aiming at generation of peptide-specific CTL in vitro, and also in vivo, in the course of vaccination protocols assessing the efficacy of the HER-2/neu peptide vaccines, very low PF to this peptide could be detected in HER-2/neu-overexpressing HLA-A2 patients (Disis et al, 2000;Knutson et al, 2001). Given the fact that HER-2(9 369 ) binds with high affinity to HLA-A2 allele, we assumed that T-cell clones recognising this particular bimolecular complex (i.e., HLA-A2 þ HER-2(9 369 )) might have been partially tolerised, suggesting that boosting or generating an immune response via immunisation could represent a reasonable approach for reactivating such clones.…”

A virosomal formulated Her-2/neu multi-peptide vaccine induces Her-2/neu-specific immune responses in patients with metastatic breast cancer: a phase I study

“…Unlike many peptide vaccines against cancers which have been designed to induce cytotoxic T cell responses using class I restricted peptides [18][19][20][21][22][23], we used putative B cell epitopes from the extracellular domain of the Her-2/ neu protein being HLA type independent. In order to induce CD4?…”