AE37 peptide vaccination in prostate cancer: a 4-year immunological assessment updates on a phase I trial

Abstract

In our recent phase I trial, we demonstrated that the AE37 vaccine is safe and induces HER-2/neu-specific immunity in a heterogeneous population of HER-2/neu (+) prostate cancer patients. Herein, we tested whether one AE37 boost can induce long-lasting immunological memory in these patients. Twenty-three patients from the phase I study received one AE37 boost 6-month post-primary vaccinations. Local/systemic toxicities were evaluated following the booster injection. Immunological responses were monitored 1-month (long-term booster; LTB) and 3-year (long-term immunity; LTI) post-booster by delayed-type hypersensitivity, IFN-γ ELISPOT and proliferation assays. Regulatory T cell (Treg) frequencies, plasma transforming growth factor-β (TGF-β) and indoleamine 2,3-deoxygenase (IDO) activity levels were also determined at the same time points. The AE37 booster was safe and well tolerated. Immunological monitoring revealed vaccine-specific long-term immunity in most of the evaluated patients during both LTB and LTI, although individual levels of immunity during LTI were decreased compared with those measured 3 years earlier during LTB. This was paralleled with increased Tregs, TGF-β levels and IDO activity. One AE37 booster generated long-term immunological memory in HER-2/neu (+) prostate cancer patients, which was detectable 3 years later, albeit with a tendency to decline. Boosted patients had favorable clinical outcome in terms of overall and/or metastasis-free survival compared with historical groups with similar clinical characteristics at diagnosis. We suggest that more boosters and/or concomitant disarming of suppressor circuits may be necessary to sustain immunological memory, and therefore, further studies to optimize the AE37 booster schedule are warranted.

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

“…A detailed description of the phase I clinical trial (EudraCT 2006-003299-37) design has been reported recently [20,21]. In brief, androgen-dependent and androgen-independent prostate cancer patients with primary tumors expressing HER-2/neu + (score 1+ to 3+) and ECOG 0 or 1, were eligible.…”

“…Twelve of these patients developed increased immunity in response to AE37 vaccinations and were classified as high responders (HR) (Table 1 and [20,21]). Interestingly, of the 12 HR patients, nine (75 %) were HLA-DRB1*11 positive (+) and seven (58 %) were HLA-A*24+ (Table 1).…”

“…IDO activity was estimated by quantifying tryptophan (Trp) and its metabolite kynurenine (Kyn) as previously described [21]. Patient's plasmas were tested in duplicates, and samples of three donors without cancer were also systematically included.…”

“…AE37-induced strong immunological responses in vivo (DTH) and in vitro (INF-γ production) could be measured in the majority of patients and were correlated with decreases in TGF-β plasma levels [20]. 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].…”

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.…”