Vaccine-Induced Memory CD8+ T Cells Provide Clinical Benefit in HER2 Expressing Breast Cancer: A Mouse to Human Translational Study
| Autor: | Zachary C. Hartman, Veronica Lubkov, Erika J. Crosby, Joshua C. Snyder, Sungjin Kim, Kimberly L. Blackwell, Takuya Osada, William R. Gwin, Amy Hobeika, Gloria Broadwater, Terry Hyslop, H. Kim Lyerly, Michael A. Morse, Serena Chang, Paul K. Marcom, Andre Rogatko, Holden T. Maecker |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Oncology Cancer Research medicine.medical_specialty 03 medical and health sciences 0302 clinical medicine Immune system Breast cancer Immunity Internal medicine medicine Cytotoxic T cell skin and connective tissue diseases neoplasms biology business.industry medicine.disease Metastatic breast cancer Vaccination 030104 developmental biology 030220 oncology & carcinogenesis Cohort biology.protein Antibody business |
| Zdroj: | Clinical Cancer Research. 25:2725-2736 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | 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 such as the genomic amplification of HER2. We constructed a vaccine based on a novel alphaviral vector encoding a portion of HER2 (VRP-HER2). Patients and Methods: 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. 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 1 partial response and 2 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 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. |
| Databáze: | OpenAIRE |
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