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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-\u03b3, IL-6, and MCP-1) and acute toxicity similar to cytokine release syndrome. Acute toxicity required two key effector molecules in CAR T cells\u2014perforin 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\u2013like syndrome in murine models.<\/jats:p>","DOI":"10.4049\/jimmunol.1600769","type":"journal-article","created":{"date-parts":[[2016,11,15]],"date-time":"2016-11-15T02:15:26Z","timestamp":1479176126000},"page":"4674-4685","source":"Crossref","is-referenced-by-count":53,"title":["Mechanisms of Acute Toxicity in NKG2D Chimeric Antigen Receptor T Cell\u2013Treated Mice"],"prefix":"10.1093","volume":"197","author":[{"given":"Marie-Louise","family":"Sentman","sequence":"first","affiliation":[{"name":"Center for Synthetic Immunity and the Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth , Lebanon, NH 03756"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joana M","family":"Murad","sequence":"additional","affiliation":[{"name":"Celdara Medical, LLC , Lebanon, NH 03766"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W James","family":"Cook","sequence":"additional","affiliation":[{"name":"Center for Synthetic Immunity and the Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth , Lebanon, NH 03756"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Ru","family":"Wu","sequence":"additional","affiliation":[{"name":"Center for Synthetic Immunity and the Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth , Lebanon, NH 03756"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7975-9874","authenticated-orcid":false,"given":"Jake","family":"Reder","sequence":"additional","affiliation":[{"name":"Celdara Medical, LLC , Lebanon, NH 03766"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3846-5156","authenticated-orcid":false,"given":"Susanne H","family":"Baumeister","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute , Boston, MA 02215"},{"name":"Department of Pediatric Oncology, Dana-Farber Cancer Institute , Boston, MA 02215"},{"name":"Division of Hematology-Oncology, Boston Children\u2019s Hospital , Boston, MA 02115"},{"name":"Harvard Medical School , Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Glenn","family":"Dranoff","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute , Boston, MA 02215"},{"name":"Exploratory Immuno-oncology, Novartis Institutes for BioMedical Research , Cambridge, MA 02139"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael W","family":"Fanger","sequence":"additional","affiliation":[{"name":"Celdara Medical, LLC , Lebanon, NH 03766"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles L","family":"Sentman","sequence":"additional","affiliation":[{"name":"Center for Synthetic Immunity and the Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth , Lebanon, NH 03756"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,12,15]]},"reference":[{"key":"2025030618360601700_r1","doi-asserted-by":"crossref","first-page":"177ra38","DOI":"10.1126\/scitranslmed.3005930","article-title":"CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia","volume":"5","author":"Brentjens","year":"2013","journal-title":"Sci. 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