Cancer Therapy: Clinical 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 Sonia A. Perez 1 , Nikoletta L. Kallinteris 4 , Stratos Bisias 2 , Panagiotis K. Tzonis 1 , Katerina Georgakopoulou 1 , Marighoula Varla-Leftherioti 3 , Michael Papamichail 1 , Anastasios Thanos 2 , Eric von Hofe 4 , and Constantin N. Baxevanis 1 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 trans- forming 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 through- out 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 hypersensi- tivity reaction to AE36. Additionally, significant decreases could be detected in circulating Treg frequen- cies, 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. ©2010 AACR. Despite conventional treatments for prostate cancer, such as surgical resection and radiotherapy, many patients will fi- nally develop metastases. Hormone deprivation is initially effective in the majority of patients with metastatic disease (1). Eventually, however, prostate cancer patients will relapse due to progression of prostate cancer toward hormone-independent growth of the tumor. Unfortunately, advanced prostate cancer responds poorly to chemothera- peutic agents of which taxane-based treatments are now- adays considered as the common treatment of castrate- resistant prostate cancer (2). Therefore, novel approaches are required for the prevention and/or effective management of patients with advanced prostate cancer. Prostate glands are frequently diffusely infiltrated with both CD4 + and CD8 + T cells (3, 4), suggesting that pros- tate cancer may represent an attractive target for immu- notherapy. Indeed, several prostate-specific gene products have been reported that may function as tumor/tissue antigens (5–7). Active immunotherapies in prostate cancer have used a variety of methods to augment immune re- sponses to prostate cancer–associated antigens. Of these, the most promising agents include PROSTVAC and APC8015 (Provenge). PROSTVAC-VF comprises two re- combinant viral vectors, each encoding transgenes for prostate-specific antigen (PSA). In two phase II studies, PROSTVAC-VF immunotherapy was well tolerated and Authors' Affiliations: 1 Cancer Immunology and Immunotherapy Center and 2 Urology Department, Saint Savas Cancer Hospital; 3 Immunobiology Department, “Helena Venizelou” Maternity Hospital of Athens, Athens, Greece; and 4 Antigen Express, Inc., Worcester, Massachusetts Corresponding Author: Constantin N. Baxevanis, Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, 171 Alexandras Avenue, Athens 11522, Greece. Phone: 30-210-6409380; Fax: 30-210- 6409516; E-mail: baxevanis@ciic.gr. doi: 10.1158/1078-0432.CCR-10-0085 ©2010 American Association for Cancer Research. Clinical Cancer Research www.aacrjournals.org 3495 Research. on April 19, 2017. © 2010 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst May 13, 2010; DOI: 10.1158/1078-0432.CCR-10-0085