Phase I Immunotherapy Trial with Two Chimeric HER-2 B-Cell Peptide Vaccines Emulsified in Montanide ISA 720VG and Nor-MDP Adjuvant in Patients with Advanced Solid Tumors

• Type of Material: Article
• Authors: Tanios Bekaii-Saab, Mayo Clinic; Robert Wesolowski, Ohio State University; Daniel H. Ahn, Mayo Clinic; Christina Wu, Emory University; Amir Mortazavi, Ohio State University; Maryam Lustberg, Ohio State University; Bhuvaneswari Ramaswamy, Ohio State University; Jeffrey Fowler, Ohio State University; Lai Wei, Ohio State University; Jay Overholser, Ohio State University; Pravin T. P. Kaumaya, Ohio State University
• Language: English
• Date: 2019-06-15
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 American Association for Cancer Research.
• Final Published Version (URL): http://dx.doi.org/10.1158/1078-0432.CCR-18-3997
• Title of Journal or Parent Work: Clinical Cancer Research
• Volume: 25
• Issue: 12
• Start Page: 3495
• End Page: 3507
• Grant/Funding Information: This study was funded by NIH/NCI R01 CA CA84356 to PTPK; NIH R21 CA13508 to PTPK.
• Keywords: Chemotherapy; Expression; Docetaxel; Metastatic breast cancer; Endometrial cancer; Trastuzumab resistant; Oncology; Antibody; Plus trastuzumab; Gene amplification; Science & Technology; Therapy; Life Sciences & Biomedicine
• Research Categories: Health Sciences, Oncology; Health Sciences, Obstetrics and Gynecology; Biology, Cell; Health Sciences, Immunology; Health Sciences, Rehabilitation and Therapy

Abstract

PURPOSE: This first-in-human Phase 1 study (NCT 01417546) evaluated the safety profile, optimal immunologic/biologic dose (OID/OBD) and immunogenicity of the combination of two peptide B-cell epitope vaccines engineered to represent the trastuzumab and pertuzumab binding sites. While trastuzumab and pertuzumab have been approved for clinical use, patients often develop resistance to these therapies. We have advanced a new paradigm in immunotherapy that focuses on humoral responses based on conformational B-cell epitope vaccines. METHODS: The vaccine is comprised of two chimeric HER-2 B-cell peptide vaccines incorporating a “promiscuous T cell epitope.” Patients were immunized with the vaccine constructs emulsified with nor-muramyl-dipeptide adjuvant in a water-in-oil Montanide ISA 720VG vehicle. Eligible patients with metastatic and/or recurrent solid tumors received three inoculations every 3 weeks. RESULTS: Forty-nine patients with a median of 4 prior lines of chemotherapy received at least 1 vaccination. Twenty-eight patients completed the 3 vaccination regimen. Six patients received 1 six-month boost after the regimen, and one patient received 7 six-month boosts. No serious adverse reactions or dose-limiting toxicities were observed. The vaccine was well tolerated with dose level 2 as the recommended phase II dose. The most common related toxicity in all patients was injection site reactions (24%). Two patients had a partial response (PR), 14 had stable disease (SD), and 19 had progressive disease (PD). CONCLUSIONS: The study vaccine is safe, exhibits anti-tumor activity and shows preliminary indication that peptide vaccination may avoid therapeutic resistance and offer a promising alternative to monoclonal antibody therapies.