Results from a Phase I Clinical Study of the Novel Ii-Key/HER-2/neu(776–790) Hybrid Peptide Vaccine in Patients with Prostate Cancer

Abstract

Purpose: Active immunotherapy is emerging as a potential therapeutic approach for prostate cancer. We conducted the first phase I trial of an Ii-Key/HER-2/neu(776-790) hybrid peptide vaccine (AE37) with recombinant granulocyte macrophage colony-stimulating factor as adjuvant in patients with HER-2/neu + prostate cancer. The primary end points of the study were to evaluate toxicity and monitor patients' immune responses to the vaccine.Experimental Design: Thirty-two HER-2/neu + , castrate-sensitive, and castrate-resistant prostate cancer patients were enrolled. Of these, 29 patients completed all six vaccination cycles with AE37. Immunologic responses in the total patient population were monitored by delayed-type hypersensitivity and IFN-γ ELISPOT and intracellular staining. Regulatory T-cell (Treg) frequency and plasma HER-2/neu and transforming growth factor-β levels were also determined. Immunologic responses were also analyzed among groups of patients with different clinical characteristics. Local/systemic toxicities were monitored throughout the study. Results: Toxicities beyond grade 2 were not observed. Seventy-five percent of patients developed augmented immunity to the AE37 vaccine and 65% to the unmodified AE36 peptide as detected in the IFN-γ-based ELISPOT assay. Intracellular IFN-γ analyses revealed that AE37 elicited both CD4 + and CD8 + T-cell responses. Eighty percent of the patients developed a positive delayed-type hypersensitivity reaction to AE36. Additionally, significant decreases could be detected in circulating Treg frequencies, plasma HER-2/neu, and serum transforming growth factor-β levels. Patients with less extensive disease developed better immunologic responses on vaccination. Conclusion: AE37 vaccine is safe and can induce HER-2/neu-specific cellular immune responses in patients with castrate-sensitive and castrate-resistant prostate cancer, thus emphasizing the potential of AE37 to target HER-2/neu for the immunotherapy of prostate cancer. Clin Cancer Res; 16(13); 3495-506.

A new era in anticancer peptide vaccines

“…Only grade 1 toxicity has been observed in 10% of patients, whereas the majority of patients have achieved increased immunologic responses to the vaccine in vivo, measured as delayed-type hypersensitivity, and in vitro (as determined with the IFNc-based enzyme-linked immunospot assay). 55 We are observing similar results using this Ii-Key-conjugated HER-2/neu peptide in an ongoing phase 2 study of patients with HER-2/neu-positive/lymph node-positive and high-risk/lymph node-negative breast cancer for the prevention of recurrences (unpublished observations). In a randomized, double-blind study, patients with stage II breast cancer but no evidence of disease received injections with oxidized mannan-mucin 1 (MUC1) to immunize against MUC1 and to prevent cancer recurrence/metastases.…”

Anti-tumor activity of dendritic cell-cytokine induced killer cells (DC-CIKs) sensitized to HER2 against HER-positive breast cancer cells

“…However, novel and more efficient treatment options need to be developed. AE37 has been tested in phase I and II clinical trials as a potential therapeutic vaccine against breast and prostate cancers Perez et al, 2010). The research indicates that AE37 is safe and effective and inhibits the growth of Her2+ and ++ breast cancer.…”

“…Therefore, it might be necessary to induce and establish the long-term immunity using a CD4+T auxiliary polypeptide (Hirschhorn-Cymerman et al, 2012;Tussiwand et al, 2012). As indicated by phase I clinical trials, AE37, a polypeptide inducing CD4+T cells, can be used to treat breast or prostate cancer patients in whom HER-2/neu protein is overexpressed Perez et al, 2010).…”

HER2/neu: an increasingly important therapeutic target. Part 1: basic biology & therapeutic armamentarium

“…These moved into early-phase clinical studies in the first decade of the 2000s including: several early-phase clinical studies of the immunodominant E75 peptide with granulocyte macrophage colony-stimulating factor as a biological adjuvant (now referred to as NeuVax™) [221][222][223]; of an improved E75 vaccine, AE37 (NCT00524277) [224][225][226][227]; and of the subdominant G2 peptide (NCT00524277) [228][229][230]. Other groups have ongoing Phase I and II clinical studies examining other peptides, other adjuvants and/or combinations of immunomodulatory agents (NCT00058526, NCT00194714, NCT00791037, NCT00952692, NCT01355393, NCT01376505 and NCT01632332).…”