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Combining SiRPα decoy-coengineered T cells and antibodies augments macrophage-mediated phagocytosis of tumor cells.
Stefanidis, Evangelos; Semilietof, Aikaterini; Pujol, Julien; Seijo, Bili; Scholten, Kirsten; Zoete, Vincent; Michielin, Olivier; Sandaltzopoulos, Raphael; Coukos, George; Irving, Melita.
Afiliación
  • Stefanidis E; Ludwig Institute for Cancer Research, Department of Oncology, University of Lausanne (UNIL) and University Hospital of Lausanne (CHUV), Lausanne, Switzerland.
  • Semilietof A; Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece.
  • Pujol J; Ludwig Institute for Cancer Research, Department of Oncology, University of Lausanne (UNIL) and University Hospital of Lausanne (CHUV), Lausanne, Switzerland.
  • Seijo B; Swiss Institute of Bioinformatics, Lausanne, Switzerland.
  • Scholten K; Ludwig Institute for Cancer Research, Department of Oncology, University of Lausanne (UNIL) and University Hospital of Lausanne (CHUV), Lausanne, Switzerland.
  • Zoete V; Ludwig Institute for Cancer Research, Department of Oncology, University of Lausanne (UNIL) and University Hospital of Lausanne (CHUV), Lausanne, Switzerland.
  • Michielin O; Ludwig Institute for Cancer Research, Department of Oncology, University of Lausanne (UNIL) and University Hospital of Lausanne (CHUV), Lausanne, Switzerland.
  • Sandaltzopoulos R; Ludwig Institute for Cancer Research, Department of Oncology, University of Lausanne (UNIL) and University Hospital of Lausanne (CHUV), Lausanne, Switzerland.
  • Coukos G; Swiss Institute of Bioinformatics, Lausanne, Switzerland.
  • Irving M; Ludwig Institute for Cancer Research, Department of Oncology, University of Lausanne (UNIL) and University Hospital of Lausanne (CHUV), Lausanne, Switzerland.
J Clin Invest ; 134(11)2024 Apr 23.
Article en En | MEDLINE | ID: mdl-38828721
ABSTRACT
The adoptive transfer of T cell receptor-engineered (TCR-engineered) T cells (ACT) targeting the HLA-A2-restricted cancer-testis epitope NY-ESO-1157-165 (A2/NY) has yielded favorable clinical responses against several cancers. Two approaches to improve ACT are TCR affinity optimization and T cell coengineering to express immunomodulatory molecules that can exploit endogenous immunity. By computational design we previously developed a panel of binding-enhanced A2/NY-TCRs including A97L, which augmented the in vitro function of gene-modified T cells as compared with WT. Here, we demonstrated higher persistence and improved tumor control by A97L-T cells. In order to harness macrophages in tumors, we further coengineered A97L-T cells to secrete a high-affinity signal regulatory protein α (SiRPα) decoy (CV1) that blocks CD47. While CV1-Fc-coengineered A97L-T cells mediated significantly better control of tumor outgrowth and survival in Winn assays, in subcutaneous xenograft models the T cells, coated by CV1-Fc, were depleted. Importantly, there was no phagocytosis of CV1 monomer-coengineered T cells by human macrophages. Moreover, avelumab and cetuximab enhanced macrophage-mediated phagocytosis of tumor cells in vitro in the presence of CV1 and improved tumor control upon coadministration with A97L-T cells. Taken together, our study indicates important clinical promise for harnessing macrophages by combining CV1-coengineered TCR-T cells with targeted antibodies to direct phagocytosis against tumor cells.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fagocitosis / Receptores Inmunológicos / Macrófagos Límite: Animals / Female / Humans / Male Idioma: En Revista: J Clin Invest Año: 2024 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fagocitosis / Receptores Inmunológicos / Macrófagos Límite: Animals / Female / Humans / Male Idioma: En Revista: J Clin Invest Año: 2024 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Estados Unidos