A pilot study in prostate cancer patients treated with the AE37 Ii-key-HER-2/neu polypeptide vaccine suggests that HLA-A*24 and HLA-DRB1*11 alleles may be prognostic and predictive biomarkers for clinical benefit

Abstract

Recently, several types of immunotherapies have been shown to induce encouraging clinical results, though in a restricted number of patients. Consequently, there is a need to identify immune biomarkers to select patients who will benefit from such therapies. Such predictive biomarkers may be also used as surrogates for overall survival (OS). We have recently found correlations between immunologic parameters and clinical outcome in prostate cancer patients who had been vaccinated with a HER-2/neu hybrid polypeptide vaccine (AE37) and received one booster 6 months post-primary vaccinations. Herein, we aimed to expand these retrospective analyses by studying the predictive impact of HLA-A*24 and HLA-DRB1*11 alleles, which are expressed at high frequencies among responders in our vaccinated patients, for clinical and immunological responses to AE37 vaccination. Our data show an increased OS of patients expressing the HLA-DRB1*11 or HLA-A*24 alleles, or both. Vaccine-induced immunological responses, measured as interferon γ (IFN-γ) responses in vitro or delayed-type hypersensitivity reactions in vivo, were also higher in these patients and inversely correlated with suppressor elements. Preexisting (i.e., before vaccinations with AE37) levels of vaccine-specific IFN-γ immunity and plasma TGF-β, among the HLA-A*24 and/or HLA-DRB1*11 positive patients, were strong indicators for immunological responses to AE37 treatment. These data suggest that HLA-DRB1*11 and HLA-A*24 are likely to be predictive factors for immunological and clinical responses to vaccination with AE37, though prospective validation in larger cohorts is needed.

Unraveling the role of preexisting immunity in prostate cancer patients vaccinated with a HER-2/neu hybrid peptide

“…The present study involves prostate cancer patients enrolled in the phase I clinical trial of the AE37 vaccine (Ii-Key/HER-2 /neu (776–790) :Ac-LRMKGVGSPYVSRLLGICL-NH2), EudraCT2006-003299-37 [9, 11, 27]. The current study was approved by the Institutional Review Board of Saint Savas Cancer Hospital.…”

“…HLA typing was performed by PCR-SSP (polymerase chain reaction-sequence specific primers) as described previously [11]. Patients' clinicopathological characteristics are presented in Table 1.…”

“…In our previous prostate cancer phase I vaccination clinical trial, we showed that AE37 not only induced potent immunologic responses [9], but also generated specific antitumor responses that could be detected even 3 years post booster inoculation [10]. Patients expressing HLA-DRB1*11 and/or HLA-A24 alleles showed an increased vaccine induced immunological response which was followed by an increased overall survival (OS) [11]. Additionally, we found that the AE37 vaccine has the potential to induce HER-2 specific CD4 + T helper cells (Th) that belong to the in vivo immunological memory repertoire and could even be detected 5 years after the first vaccine inoculation [12].…”

The Present and Future of Biomarkers in Prostate Cancer: Proteomics, Genomics, and Immunology Advancements

“…Such strategies hold high potential and are beginning to emerge in the specific context of PC. For example, Anastasopoulou et al 240 showed that patients with HLA-A * 24 and HLA-DRB * 11 alleles had increased immune responses as well as a higher OS after treatment with the AE37 li-key-HER-2/neu polypeptide vaccine, suggesting the potential prognostic and predictive impact of these alleles.…”

Further Insight into AE37 Peptide Vaccination in Prostate Cancer

“…It is important to underline that the antitumor immune response is influenced by the respective immunological status and tumor-cell characteristics, thus implying heterogeneity among patients [ 4 ]. In respect to this, T-cell responses against certain peptides, including those derived from tumors, are mediated by specific human leukocyte antigen (HLA) molecules, therefore, the HLA polymorphism is another factor reflecting this variation in patients’ immunological response [ 5 ]. Given that, patients’ selection in vaccination studies requires careful consideration, so as to achieve therapeutic efficacy.…”