Vaccine-induced memory CD8+ T cells provide clinical benefit in HER2 expressing breast cancer: a mouse to human translational study.
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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.
Published Version (Please cite this version)10.1158/1078-0432.ccr-18-3102
Publication InfoLyerly, Herbert; Hartman, Zachary; Crosby, Erika J; Gwin, William R; Blackwell, Kimberly; Marcom, Paul Kelly; ... Morse, Michael A (2019). Vaccine-induced memory CD8+ T cells provide clinical benefit in HER2 expressing breast cancer: a mouse to human translational study. Clinical cancer research : an official journal of the American Association for Cancer Research. pp. clincanres.3102.2018-clincanres.3102.2018. 10.1158/1078-0432.ccr-18-3102. Retrieved from https://hdl.handle.net/10161/17931.
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Assistant Professor of Surgery
My research interests encompass studies of immunity and inflammation in the context of developing and established cancers. These research interests involve studies of inflammation in the genesis and maintenance of specific cancer types (principally breast and ovarian), as well as the impact of inflammation on tumor metastasis and the tumor microenvironment. My group is also involved in strategies to modulate the immune response to tumors, which involves the use of novel immunotherapeutic s
George Barth Geller Professor
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