AE37 peptide vaccination in prostate cancer: identification of biomarkers in the context of prognosis and prediction

Abstract

A fundamental challenge in administering immunotherapies for cancer is the establishment of biomarkers that can predict patients' responsiveness to treatment. In this study, our aim was to predict the immunologic and clinical responses of vaccination therapy with an Ii-key-modified HER-2/neu peptide (Ii-key/HER-2(776-790) or AE37), applied in our recent phase I study in patients with prostate cancer. To this end, we retrospectively analyzed our data derived from immunologic determinations before, during and after primary series of vaccinations with AE37, as well as after one AE37 booster injection. Using the obtained data, we then observed the relationship between the immunologic parameters and clinical outcome of patients. We found that preexisting levels of transforming growth factor beta (TGF-β) had an inverse correlation with in vivo and in vitro immunologic responses to the AE37 vaccine which were measured as delayed-type hypersensitivity (DTH) and interferon gamma (IFN-γ) production in response to the native HER-2(776-790) (or AE36) peptide, respectively. Patients with preexistent IFN-γ immunity to AE36 developed positive DTH reactions after primary vaccinations and booster. Moreover, we could detect a direct correlation between IFN-γ production and DTH reactions in response to AE36 challenge in our vaccinated patients. DTH reactions were a stronger indicator for patients' overall survival (OS) than preexistent or vaccine-induced IFN-γ immunity. In contrast, we found that preexisting TGF-β levels were correlated with shorter patients' OS. These retrospective analyses suggest that the above biomarkers at the time-points measured offer promise for evaluating immunologic and clinical responses to AE37-based vaccinations.

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

“…As a cutoff, we considered the 17 specific spots/10 6 PBMCs, which was the median IFN-γ immunity at R0 for the 23 patients who received the AE37 booster, as determined by Perez et al [20][21][22]. Patients bearing either the HLA-A*24 or HLA-DRB1*11/HLA-A*24 alleles experienced statistically increased preexistent IFN-γ immunity to AE36 vs patients lacking these alleles (Fig.…”

“…We also made estimations for the proportions of patients who responded with increased DTH reactions post-primary AE37 vaccinations (R6) as well as postbooster (LTB). The cutoff for positive DTH responses was 5 mm [20][21][22]. As depicted in Fig.…”

“…To understand how immunity develops during and postvaccination as well as after booster, we first analyzed the levels of in vitro immunity in the three groups of patients, which was measured as frequencies of IFN-γ producing PBMCs in response to AE36 in the ELISPOT assay [20][21][22]. As shown in Fig.…”

“…Long-term immunity to AE37 was still detectable 6 months post-vaccinations and could be considerably prolonged for an additional period of 36 months after a single AE37 booster inoculation [21]. Retrospective analyses revealed that preexisting IFN-γ immunity to the vaccine and plasma TGF-β levels correlated with DTH reactions and overall survival (OS) [22]. The data from our studies have demonstrated the important role of HER-2 as a therapeutic target in prostate cancer and implied a significant role for AE37 as a therapeutic vaccine that should be studied to prevent disease progression both at early and late stages (i.e., castrate-sensitive and castrate-resistant prostate cancer, respectively).…”

Reinstating endogenous antitumor immunity: The concept of therapeutic management of cancer

“…AE37 induced strong immunological responses in vivo (delayed-type hypersensitivity) and in vitro (IFNγ production) and it could be measured in majority of the patients. Long-term immunity to AE37 was still detectable 6 months post-vaccinations, and it could be considerably prolonged for an additional period of 36 months after one single booster AE37 injection [71][72][73]. AE37 has also been utilised to vaccinate breast cancer patients in a randomised phase II trial.…”