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Vaccine-Induced Memory CD8 + T Cells Provide Clinical Benefit in HER2 Expressing Breast Cancer: A Mouse to Human Translational Study

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

Clinical cancer research, 2019-05, Vol.25 (9), p.2725-2736 [Periódico revisado por pares]

United States

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  • Título:
    Vaccine-Induced Memory CD8 + T Cells Provide Clinical Benefit in HER2 Expressing Breast Cancer: A Mouse to Human Translational Study
  • Autor: 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
  • É parte de: Clinical cancer research, 2019-05, Vol.25 (9), p.2725-2736
  • Notas: ObjectType-Article-1
    SourceType-Scholarly Journals-1
    ObjectType-Feature-2
    content type line 23
    These authors contributed equally to this work
  • Descrição: 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). 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. 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 ( = 4) and 32.7 months in cohort 2 ( = 18). Perforin expression by memory CD8 T cells post-vaccination significantly correlated with improved PFS. 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.
  • Editor: United States
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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