title: Human T cells engineered to express a programmed death 1/28 costimulatory retargeting molecule display enhanced antitumor activity.
abstract: Adoptive transfer of T cells genetically modified to express cancer-specific receptors can mediate impressive tumor regression in terminally ill patients. However, T cell function and persistence over time could be hampered by the activation of inhibitory costimulatory pathways, such as programmed death 1 (PD1)/programmed death ligand 1, leading to T cell exhaustion and providing tumor cells with an escape mechanism from immunosurveillance. In addition, the lack of positive costimulation at the tumor site can further dampen T cell response. Thus, as T cell genetic engineering has become clinically relevant, we aimed at enhancing T cell antitumor activity by genetically diverting T cell-negative costimulatory signals into positive ones using chimeric costimulatory retargeting molecules and which are composed of the PD1 extracellular domain fused to the signaling domains of positive costimulatory molecules such as CD28 and 4-1BB. After characterizing the optimal PD1 chimera, we designed and optimized a tripartite retroviral vector that enables the simultaneous expression of this chimeric molecule in conjunction with a cancer-specific TCR. Human T cells, transduced to express a PD1/28 chimeric molecule, exhibited enhanced cytokine secretion and upregulation of activation markers upon coculture with tumor cells. These engineered cells also proliferated better compared with control cells. Finally, we tested the function of these cells in two xenograft models of human melanoma tumors and show that PD1/28-engineered human T cells demonstrated superior antitumor function. Overall, we propose that engineering T cells with a costimulatory retargeting molecule can enhance their function, which bears important implications for the improvement of T cell immunotherapy.
authors.affiliation: Laboratory of Tumor Immunology and Immunotherapy, Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan 52900, Israel.
authors.forename: Chen
authors.initials: C
authors.lastname: Ankri
authors.forename: Katerina
authors.initials: K
authors.lastname: Shamalov
authors.forename: Miryam
authors.initials: M
authors.lastname: Horovitz-Fried
authors.forename: Shmuel
authors.initials: S
authors.lastname: Mauer
authors.forename: Cyrille J
authors.initials: CJ
authors.lastname: Cohen
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002642:Chick Embryo; D005260:Female; D005818:Genetic Engineering; D006801:Humans; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation; D008545:Melanoma / Q000276:immunology*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000096:biosynthesis / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D018106:CD28 Antigens; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9