Vaccinating HER2-transgenic mice with viral-like particles of an alphaviral vector encoding two HER2 domains (VRP-HER2), Crosby and Gwin et al. observed an increase in HER2-specific T cells, humoral immunity, and antitumor efficacy. In a small Phase I clinical trial of patients with previously treated HER2+ breast cancer, VRP-HER2 expanded perforin+ HER2-specific memory CD8+ T cells, which correlated with progression-free survival. Vaccination also increased HER2 antibodies capable of cellular cytotoxicity, inducing HER2 receptor internalization, and binding to regions of HER2 not recognized by standard-of-care trastuzumab and pertuzumab.

PURPOSE: Immune-based therapy for metastatic breast cancer has had limited success, particularly in molecular subtypes with low somatic mutations rates. Strategies to augment T cell infiltration of tumors include vaccines targeting established oncogenic drivers like the genomic amplification of HER2. We constructed a vaccine based on a novel alphaviral vector encoding a portion of HER2 (VRP-HER2). EXPERIMENTAL DESIGN: In preclinical studies, mice were immunized with VRP-HER2 before or after implantation of hHER2+ tumor cells and HER2-specific immune responses and anti-tumor function were evaluated. We tested VRP-HER2 in a Phase I clinical trial where subjects with advanced HER2-overexpressing malignancies in cohort 1 received VRP-HER2 every 2 weeks for a total of three doses. In cohort 2, subjects received the same schedule concurrently with a HER2-targeted therapy. RESULTS: Vaccination in preclinical models with VRP-HER2 induced HER2-specific T cells and antibodies while inhibiting tumor growth. VRP-HER2 was well tolerated in patients and vaccination induced HER2-specific T cells and antibodies. Although a phase I study, there was one partial response and two patients with continued stable disease. Median OS was 50.2 months in cohort 1 (n=4) and 32.7 months in cohort 2 (n=18). Perforin expression by memory CD8 T cells post-vaccination significantly correlated with improved PFS. CONCLUSIONS: VRP-HER2 increased HER2-specific memory CD8 T cells and had anti-tumor effects in preclinical and clinical studies. The expansion of HER2-specific memory CD8 T cells in vaccinated patients was significantly correlated with increased PFS. Subsequent studies will seek to enhance T cell activity by combining with anti-PD-1.

Author Info: (1) Department of Surgery, Duke University Medical Center. (2) Department of Medicine, University of Washington. (3) Medicine, Duke University Medical Center. (4) Medicine, Duke University

Author Info: (1) Department of Surgery, Duke University Medical Center. (2) Department of Medicine, University of Washington. (3) Medicine, Duke University Medical Center. (4) Medicine, Duke University Medical Center. (5) Immunity, Transplantation, Infection, Stanford University Medical School. (6) Immunity, Transplantation, Infection, Stanford University Medical School. (7) Duke Cancer Institute, Duke University Medical Center. (8) Department of Biostatistics and Bioinformatics, Duke University Medical Center. (9) Biostatistics and Bioinformatics Research Center, Cedars-Sinai Medical Center. (10) Biostatistics and Bioinformatics Research Center, Cedars-Sinai Medical Center. (11) Department of Surgery, Duke University Medical Center. (12) Department of Surgery, Duke University Medical Center. (13) Surgery, Duke University Medical Center. (14) Surgery, Duke University Medical Center. (15) Division of Medical Oncology, Duke Cancer Institute, Duke University Medical Center. (16) Surgery, Duke University Medical Center lyerl001@mc.duke.edu. (17) Department of Surgery, Duke University Medical Center.

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