Vaccine-induced memory CD8+ T cells provide clinical benefit in HER2 expressing breast cancer: a mouse to human translational study.
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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https://hdl.handle.net/10161/17931Published Version (Please cite this version)
10.1158/1078-0432.ccr-18-3102Publication 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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Show full item recordScholars@Duke
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
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.
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
Amy Claudine Hobeika
Assistant Professor in Surgery
Terry Hyslop
Adjunct Professor in the Department of Biostatistics & Bioinformatics
Herbert Kim Lyerly
George Barth Geller Distinguished Professor of Immunology
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
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
Takuya Osada
Adjunct Associate Professor in the Department of Surgery
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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