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Vaccine-induced memory CD8+ T cells provide clinical benefit in HER2 expressing breast cancer: a mouse to human translational study.

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Date
2019-01-11
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
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(17 total)
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Abstract
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.
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Journal article
Permalink
https://hdl.handle.net/10161/17931
Published Version (Please cite this version)
10.1158/1078-0432.ccr-18-3102
Publication Info
Crosby, Erika J; Gwin, William; Blackwell, Kimberly; Marcom, Paul K; Chang, Serena; Maecker, Holden T; ... Hartman, Zachary C (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.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Blackwell

Kimberly Lynn Blackwell

Adjunct Professor in the Department of Medicine
Breast cancer angiogenesis Breast cancer in younger women Hormonal therapy Neoadjurant therapy for breast cancer Current Clinical Investigations Principal Investigator, A Phase I-II Study of Neoadjuvant Evacet/Paclitaxel/Hyperthermia in Locally Advanced Breast Cancer Patients. Investigator, Development of Screening Markers for Breast Cancer using Circulating Immune Complexes: Collaborative Study with Diagen Medical Technologies. <br
Crosby

Erika J Crosby

Assistant Professor in Surgery
Dr. Crosby received her PhD in Immunology from the University of Pennsylvania where she used models of chronic infection to understand how the immune system causes damage to healthy tissue. She arrived at Duke for a postdoctoral fellowship where she applied this knowledge to test new therapies that bypass this immune system regulation to treat breast cancer. Dr. Crosby remained at Duke to start her own research program in 2021.
Hartman

Zachary Conrad Hartman

Associate Professor in 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
Hobeika

Amy Claudine Hobeika

Assistant Professor in Surgery
Hyslop

Terry Hyslop

Adjunct Professor in the Department of Biostatistics & Bioinformatics
Lyerly

Herbert Kim Lyerly

George Barth Geller Distinguished Professor of Immunology
Marcom

Paul Kelly Marcom

Adjunct Professor in the Department of Medicine
Basic Science: -Germline and somatic genetic changes in breast cancer. Translational: -Identification and management of individuals and families with hereditary cancer risk. -Communication of cancer risk information to individuals and families. -Breast cancer prevention. -Optimizing management of early breast cancer. -Treatment of metastatic breast cancer Clinically, Dr. Marcom works as a medical oncologist in the multidisciplina
Morse

Michael Aaron Morse

Professor of Medicine
We are studying the use of immune therapies to treat various cancers, including gastrointestinal, breast, and lung cancers and melanoma. These therapies include vaccines based on dendritic cells developed in our laboratory as well as vaccines based on peptides, viral vectors, and DNA plasmids. Our group is also a national leader in the development and use of laboratory assays for demonstrating immunologic responses to cancer vaccines. Finally, we are developing immunotherapies based on adoptive
Osada

Takuya Osada

Adjunct Associate Professor in the Department of Surgery
Snyder

Joshua Clair Snyder

Associate Professor in Surgery
I am the PI of the Cancer Initiation and Cancer Cell Behavior lab. Our research objective is to determine how cancer cells adapt and grow before cancer is diagnosed. Our lab is also part of the <a href="https://surgery.duke.edu/divisions/surgical-sciences/research/research-laboratories/cente
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