title: Mechanisms of Acute Toxicity in NKG2D Chimeric Antigen Receptor T Cell-Treated Mice.
abstract: Targeting cancer through the use of effector T cells bearing chimeric Ag receptors (CARs) leads to elimination of tumors in animals and patients, but recognition of normal cells or excessive activation can result in significant toxicity and even death. CAR T cells based on modified NKG2D receptors are effective against many types of tumors, and their efficacy is mediated through direct cytotoxicity and cytokine production. Under certain conditions, their ligands can be expressed on nontumor cells, so a better understanding of the potential off-tumor activity of these NKG2D CAR T cells is needed. Injection of very high numbers of activated T cells expressing CARs based on murine NKG2D or DNAM1 resulted in increased serum cytokines (IFN-γ, IL-6, and MCP-1) and acute toxicity similar to cytokine release syndrome. Acute toxicity required two key effector molecules in CAR T cells-perforin and GM-CSF. Host immune cells also contributed to this toxicity, and mice with severe immune cell defects remained healthy at the highest CAR T cell dose. These data demonstrate that specific CAR T cell effector mechanisms and the host immune system are required for this cytokine release-like syndrome in murine models.
authors.affiliation: Center for Synthetic Immunity and the Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756.
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Sentman
authors.affiliation: Celdara Medical, LLC, Lebanon, NH 03766.
authors.forename: Joana M
authors.initials: JM
authors.lastname: Murad
authors.affiliation: Center for Synthetic Immunity and the Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756.
authors.forename: W James
authors.initials: WJ
authors.lastname: Cook
authors.affiliation: Center for Synthetic Immunity and the Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756.
authors.forename: Ming-Ru
authors.initials: MR
authors.lastname: Wu
authors.affiliation: Celdara Medical, LLC, Lebanon, NH 03766.
authors.forename: Jake
authors.identifier: 0000-0002-7975-9874
authors.initials: J
authors.lastname: Reder
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215.|Division of Hematology-Oncology, Boston Children's Hospital, Boston, MA 02115.|Harvard Medical School, Boston, MA 02115; and.
authors.forename: Susanne H
authors.identifier: 0000-0003-3846-5156
authors.initials: SH
authors.lastname: Baumeister
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215.|Exploratory Immuno-oncology, Novartis Institutes for BioMedical Research, Cambridge, MA 02139.
authors.forename: Glenn
authors.initials: G
authors.lastname: Dranoff
authors.affiliation: Celdara Medical, LLC, Lebanon, NH 03766.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Fanger
authors.affiliation: Center for Synthetic Immunity and the Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756; charles.sentman@dartmouth.edu.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sentman
mesh_terms: D000818:Animals; D017252:CD3 Complex / Q000235:genetics; D019496:Cancer Vaccines / Q000276:immunology*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008213:Lymphocyte Activation; D016399:Lymphoma, T-Cell / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000378:metabolism*; D009374:Neoplasms, Experimental; D054353:Perforin / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics; D013601:T-Lymphocytes / Q000502:physiology* / Q000637:transplantation
chemical_list: D017252:CD3 Complex; D019496:Cancer Vaccines; C485468:Cd3e protein, mouse; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011993:Recombinant Fusion Proteins; D054353:Perforin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor