Vaccine-induced memory CD8+ T cells provide clinical benefit in HER2 expressing breast cancer: a mouse to human translational study.
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2019-01-11
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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.
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Crosby, Erika J, William Gwin, Kimberly Blackwell, Paul K Marcom, Serena Chang, Holden T Maecker, Gloria Broadwater, Terry Hyslop, et al. (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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Scholars@Duke
Erika J Crosby
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.
Kimberly Lynn Blackwell
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.
Principal Investigator, Use of Plasma D-Dimer as a Predictive Marker in Colorectal Carcinoma: Correlative Science Study with Genentech, Inc.
Principal Investigator, A randomized, Phase II study of gabapentin or glutamine to prevent the peripheral neuropathy/myalgia associated with weekly taxol administration in metastatic breast and lung cancer.
Investigator, A Phase 2, Randomized, Double-Masked, Multicenter Study of Two Dose Levels of ERA-923 for the treatment of Metastatic Breast Cancer in Postmenopausal Women who have failed Tamoxifen therapy. Genetics Institute.
Investigator, A Phase I Study of Combined Doxil/Hyperthermia in Stage IV Breast Cancer.
Paul Kelly Marcom
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 multidisciplinary breast cancer clinic. He participates in clinical trials investigating new chemotherapeutic and biologic treatments.
Terry Hyslop
Joshua Clair Snyder
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 Center for Applied therapeutics where we share our models as tools for preclinical and translational research. To learn more about our research please visit the Cancer Initiation and Cancer Cell Behavior Lab's homepage.
Takuya Osada
Amy Claudine Hobeika
Michael Aaron Morse
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 transfer of tumor and viral antigen-specific T cells.
Our current clinical trials include phase I and II studies of immunotherapy for: patients with metastatic malignancies expressing CEA, pancreatic cancer, colorectal cancer, breast cancer, and ovarian cancer, and leukemias following HSCT. My clinical area of expertise is in gastrointestinal oncology, in particular, the treatment of hepatic malignancies, and malignant melanoma.
Key words: dendritic cells, immunotherapy, vaccines, T cells, gastrointestinal oncology, melanoma, hepatoma
Herbert Kim Lyerly
Zachary Conrad Hartman
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 strategies and development of vaccines to specific oncogenic targets. The major focus of my lab is in uncovering strategies to modulate tumor-derived inflammation and tumor-specific immunity that will translate into clinically efficacious therapies in patients.
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