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Stimulation of Oncogene-Specific Tumor-Infiltrating T Cells through Combined Vaccine and αPD-1 Enable Sustained Antitumor Responses against Established HER2 Breast Cancer.
Crosby, Erika J; Acharya, Chaitanya R; Haddad, Anthony-Fayez; Rabiola, Christopher A; Lei, Gangjun; Wei, Jun-Ping; Yang, Xiao-Yi; Wang, Tao; Liu, Cong-Xiao; Wagner, Kay U; Muller, William J; Chodosh, Lewis A; Broadwater, Gloria; Hyslop, Terry; Shepherd, Jonathan H; Hollern, Daniel P; He, Xiaping; Perou, Charles M; Chai, Shengjie; Ashby, Benjamin K; Vincent, Benjamin G; Snyder, Joshua C; Force, Jeremy; Morse, Michael A; Lyerly, Herbert K; Hartman, Zachary C.
Afiliação
  • Crosby EJ; Department of Surgery, Division of Surgical Sciences, Duke University, Durham North Carolina.
  • Acharya CR; Department of Surgery, Division of Surgical Sciences, Duke University, Durham North Carolina.
  • Haddad AF; Department of Surgery, Division of Surgical Sciences, Duke University, Durham North Carolina.
  • Rabiola CA; Department of Surgery, Division of Surgical Sciences, Duke University, Durham North Carolina.
  • Lei G; Department of Surgery, Division of Surgical Sciences, Duke University, Durham North Carolina.
  • Wei JP; Department of Surgery, Division of Surgical Sciences, Duke University, Durham North Carolina.
  • Yang XY; Department of Surgery, Division of Surgical Sciences, Duke University, Durham North Carolina.
  • Wang T; Department of Surgery, Division of Surgical Sciences, Duke University, Durham North Carolina.
  • Liu CX; Department of Surgery, Division of Surgical Sciences, Duke University, Durham North Carolina.
  • Wagner KU; Department of Oncology, Wayne State University, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan.
  • Muller WJ; Departments of Biochemistry and Medicine, Goodman Cancer Center, McGill University, Montreal, Quebec.
  • Chodosh LA; Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania.
  • Broadwater G; Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina.
  • Hyslop T; Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina.
  • Shepherd JH; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
  • Hollern DP; Department of Genetics, University of North Carolina, Chapel Hill, North Carolina.
  • He X; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
  • Perou CM; Department of Genetics, University of North Carolina, Chapel Hill, North Carolina.
  • Chai S; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
  • Ashby BK; Department of Genetics, University of North Carolina, Chapel Hill, North Carolina.
  • Vincent BG; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
  • Snyder JC; Department of Genetics, University of North Carolina, Chapel Hill, North Carolina.
  • Force J; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
  • Morse MA; Department of Medicine, Division of Hematology/Oncology, University of North Carolina, Chapel Hill, North Carolina.
  • Lyerly HK; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
  • Hartman ZC; Department of Medicine, Division of Hematology/Oncology, University of North Carolina, Chapel Hill, North Carolina.
Clin Cancer Res ; 26(17): 4670-4681, 2020 09 01.
Article em En | MEDLINE | ID: mdl-32732224
PURPOSE: Despite promising advances in breast cancer immunotherapy, augmenting T-cell infiltration has remained a significant challenge. Although neither individual vaccines nor immune checkpoint blockade (ICB) have had broad success as monotherapies, we hypothesized that targeted vaccination against an oncogenic driver in combination with ICB could direct and enable antitumor immunity in advanced cancers. EXPERIMENTAL DESIGN: Our models of HER2+ breast cancer exhibit molecular signatures that are reflective of advanced human HER2+ breast cancer, with a small numbers of neoepitopes and elevated immunosuppressive markers. Using these, we vaccinated against the oncogenic HER2Δ16 isoform, a nondriver tumor-associated gene (GFP), and specific neoepitopes. We further tested the effect of vaccination or anti-PD-1, alone and in combination. RESULTS: We found that only vaccination targeting HER2Δ16, a driver of oncogenicity and HER2-therapeutic resistance, could elicit significant antitumor responses, while vaccines targeting a nondriver tumor-specific antigen or tumor neoepitopes did not. Vaccine-induced HER2-specific CD8+ T cells were essential for responses, which were more effective early in tumor development. Long-term tumor control of advanced cancers occurred only when HER2Δ16 vaccination was combined with αPD-1. Single-cell RNA sequencing of tumor-infiltrating T cells revealed that while vaccination expanded CD8 T cells, only the combination of vaccine with αPD-1 induced functional gene expression signatures in those CD8 T cells. Furthermore, we show that expanded clones are HER2-reactive, conclusively demonstrating the efficacy of this vaccination strategy in targeting HER2. CONCLUSIONS: Combining oncogenic driver targeted vaccines with selective ICB offers a rational paradigm for precision immunotherapy, which we are clinically evaluating in a phase II trial (NCT03632941).
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Receptor ErbB-2 / Vacinas Anticâncer / Inibidores de Checkpoint Imunológico / Neoplasias Mamárias Experimentais Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Receptor ErbB-2 / Vacinas Anticâncer / Inibidores de Checkpoint Imunológico / Neoplasias Mamárias Experimentais Idioma: En Ano de publicação: 2020 Tipo de documento: Article