Vaccine-Induced Memory CD8+ T Cells Provide Clinical Benefit in HER2 Expressing Breast Cancer: A Mouse to Human Translational Study

• Published in: Clinical cancer research Vol. 25; no. 9; pp. 2725 - 2736
• Main Authors: Crosby, Erika J., Gwin, William, Blackwell, Kimberly, Marcom, Paul K., Chang, Serena, Maecker, Holden T., Broadwater, Gloria, Hyslop, Terry, Kim, Sungjin, Rogatko, Andre, Lubkov, Veronica, Snyder, Joshua C., Osada, Takuya, Hobeika, Amy C., Morse, Michael A., Lyerly, H. Kim, Hartman, Zachary C.
• Format: Journal Article
• Language: English
• Published: United States 01.05.2019
• Subjects: Adult; Aged; Alphavirus - genetics; Animals; Apoptosis; Breast Neoplasms - immunology; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Breast Neoplasms - therapy; Cancer Vaccines - administration & dosage; Cancer Vaccines - immunology; CD8-Positive T-Lymphocytes - immunology; Cell Proliferation; Dendritic Cells - immunology; Female; Follow-Up Studies; Genetic Vectors - administration & dosage; Humans; Immunity, Humoral - immunology; Immunologic Memory - immunology; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Prognosis; Receptor, ErbB-2 - immunology; Receptor, ErbB-2 - metabolism; Survival Rate; Tumor Cells, Cultured; Vaccines, Subunit - administration & dosage; Vaccines, Subunit - immunology; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-18-3102

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 such as the genomic amplification of HER2. We constructed a vaccine based on a novel alphaviral vector encoding a portion of HER2 (VRP-HER2). In preclinical studies, mice were immunized with VRP-HER2 before or after implantation of hHER2 tumor cells and HER2-specific immune responses and antitumor 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 3 doses. In cohort 2, subjects received the same schedule concurrently with a HER2-targeted therapy. 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 1 partial response and 2 patients with continued stable disease. Median OS was 50.2 months in cohort 1 ( = 4) and 32.7 months in cohort 2 ( = 18). Perforin expression by memory CD8 T cells post-vaccination significantly correlated with improved PFS. VRP-HER2 increased HER2-specific memory CD8 T cells and had antitumor 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.