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Leukemia vaccine overcomes limitations of checkpoint blockade by evoking clonal T cell responses in a murine acute myeloid leukemia model.
Stroopinsky, Dina; Liegel, Jessica; Bhasin, Manoj; Cheloni, Giulia; Thomas, Beena; Bhasin, Swati; Panchal, Ruchit; Ghiasuddin, Haider; Rahimian, Maryam; Nahas, Myrna; Orr, Shira; Capelletti, Marzia; Torres, Daniela; Tacettin, Cansu; Weinstock, Matthew; Bisharat, Lina; Morin, Adam; Mahoney, Kathleen M; Ebert, Benjamin; Stone, Richard; Kufe, Donald; Freeman, Gordon J; Rosenblatt, Jacalyn; Avigan, David.
Afiliação
  • Stroopinsky D; Beth Israel Deaconess Medical Center, Harvard Medical School. dstroopi@bidmc.harvard.edu.
  • Liegel J; Beth Israel Deaconess Medical Center, Harvard Medical School.
  • Bhasin M; Beth Israel Deaconess Medical Center, Harvard Medical School.
  • Cheloni G; Beth Israel Deaconess Medical Center, Harvard Medical School.
  • Thomas B; Beth Israel Deaconess Medical Center, Harvard Medical School.
  • Bhasin S; Beth Israel Deaconess Medical Center, Harvard Medical School.
  • Panchal R; Beth Israel Deaconess Medical Center, Harvard Medical School.
  • Ghiasuddin H; Beth Israel Deaconess Medical Center, Harvard Medical School.
  • Rahimian M; Beth Israel Deaconess Medical Center, Harvard Medical School.
  • Nahas M; Beth Israel Deaconess Medical Center, Harvard Medical School.
  • Orr S; Beth Israel Deaconess Medical Center, Harvard Medical School.
  • Capelletti M; Beth Israel Deaconess Medical Center, Harvard Medical School.
  • Torres D; Beth Israel Deaconess Medical Center, Harvard Medical School.
  • Tacettin C; Beth Israel Deaconess Medical Center, Harvard Medical School.
  • Weinstock M; Beth Israel Deaconess Medical Center, Harvard Medical School.
  • Bisharat L; Beth Israel Deaconess Medical Center, Harvard Medical School.
  • Morin A; Beth Israel Deaconess Medical Center, Harvard Medical School.
  • Mahoney KM; Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School.
  • Ebert B; Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School.
  • Stone R; Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School.
  • Kufe D; Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School.
  • Freeman GJ; Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School.
  • Rosenblatt J; Beth Israel Deaconess Medical Center, Harvard Medical School.
  • Avigan D; Beth Israel Deaconess Medical Center, Harvard Medical School.
Haematologica ; 106(5): 1330-1342, 2021 05 01.
Article em En | MEDLINE | ID: mdl-33538148
ABSTRACT
We have developed a personalized vaccine whereby patient derived leukemia cells are fused to autologous dendritic cells, evoking a polyclonal T cell response against shared and neo-antigens. We postulated that the dendritic cell (DC)/AML fusion vaccine would demonstrate synergy with checkpoint blockade by expanding tumor antigen specific lymphocytes that would provide a critical substrate for checkpoint blockade mediated activation. Using an immunocompetent murine leukemia model, we examined the immunologic response and therapeutic efficacy of vaccination in conjunction with checkpoint blockade with respect to leukemia engraftment, disease burden, survival and the induction of tumor specific immunity. Mice treated with checkpoint blockade alone had rapid leukemia progression and demonstrated only a modest extension of survival. Vaccination with DC/AML fusions resulted in the expansion of tumor specific lymphocytes and disease eradication in a subset of animals, while the combination of vaccination and checkpoint blockade induced a fully protective tumor specific immune response in all treated animals. Vaccination followed by checkpoint blockade resulted in upregulation of genes regulating activation and proliferation in memory and effector T cells. Long term survivors exhibited increased T cell clonal diversity and were resistant to subsequent tumor challenge. The combined DC/AML fusion vaccine and checkpoint blockade treatment offers unique synergy inducing the durable activation of leukemia specific immunity, protection from lethal tumor challenge and the selective expansion of tumor reactive clones.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucemia Mieloide Aguda / Vacinas Anticâncer Limite: Animals / Humans Idioma: En Revista: Haematologica Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucemia Mieloide Aguda / Vacinas Anticâncer Limite: Animals / Humans Idioma: En Revista: Haematologica Ano de publicação: 2021 Tipo de documento: Article