Vaccine-Induced Memory CD8+ T Cells Provide Clinical Benefit in HER2 Expressing Breast Cancer: A Mouse to Human Translational Study.
Journal Article
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.
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Duke Authors
- Blackwell, Kimberly Lynn
- Hartman, Zachary Conrad
- Hobeika, Amy Claudine
- Hyslop, Terry
- Lyerly, Herbert Kim
- Marcom, Paul Kelly
- Morse, Michael Aaron
- Osada, Takuya
- Snyder, Joshua Clair
Cited Authors
- Crosby, EJ; Gwin, W; Blackwell, K; Marcom, PK; Chang, S; Maecker, HT; Broadwater, G; Hyslop, T; Kim, S; Rogatko, A; Lubkov, V; Snyder, JC; Osada, T; Hobeika, AC; Morse, MA; Lyerly, HK; Hartman, ZC
Published Date
- May 1, 2019
Published In
Volume / Issue
- 25 / 9
Start / End Page
- 2725 - 2736
PubMed ID
- 30635338
Pubmed Central ID
- 30635338
Electronic International Standard Serial Number (EISSN)
- 1557-3265
Digital Object Identifier (DOI)
- 10.1158/1078-0432.CCR-18-3102
Language
- eng
Conference Location
- United States