title: Differential role of Th1 and Th2 cytokines in autotoxicity driven by CD19-specific second-generation chimeric antigen receptor T cells in a mouse model.
abstract: T cells engrafted with chimeric AgRs (CAR) are showing exciting potential for targeting B cell malignancies in early-phase clinical trials. To determine whether the second-generation CAR was essential for optimal antitumor activity, two CD28-based CAR constructs targeting CD19 were tested for their ability to redirect mouse T cell function against established B cell lymphoma in a BALB/c syngeneic model system. T cells armed with either CAR eliminated A20 B cell lymphoma in vivo; however, one construct induced a T cell dose-dependent acute toxicity associated with a raised serum Th1 type cytokine profile on transfer into preconditioned mice. Moreover, a chronic toxicity manifested as granuloma-like formation in spleen, liver, and lymph nodes was observed in animals receiving T cells bearing either CD28 CAR, albeit with different kinetics dependent upon the specific receptor used. This phenotype was associated with an expansion of CD4+ CAR+ T cells and CD11b+ Gr-1(+) myeloid cells and increased serum Th2-type cytokines, including IL-10 and IL-13. Mouse T cells engrafted with a first-generation CAR failed to develop such autotoxicity, whereas toxicity was not apparent when T cells bearing the same receptors were transferred into C57BL/6 or C3H animals. In summary, the adoptive transfer of second-generation CD19-specific CAR T cells can result in a cell dose-dependent acute toxicity, whereas the prolonged secretion of high levels of Th2 cytokines from these CAR T cells in vivo drives a granulomatous reaction resulting in chronic toxicity. Strategies that prevent a prolonged Th2-cytokine biased CAR T cell response are clearly warranted.
authors.affiliation: Clinical and Experimental Immunotherapy Group, Department of Medical Oncology, Institute of Cancer Sciences, The University of Manchester, Manchester, M20 4BX, United Kingdom;
authors.forename: Eleanor J
authors.initials: EJ
authors.lastname: Cheadle
authors.forename: Victoria
authors.initials: V
authors.lastname: Sheard
authors.forename: Dominic G
authors.initials: DG
authors.lastname: Rothwell
authors.forename: John S
authors.initials: JS
authors.lastname: Bridgeman
authors.forename: Garry
authors.initials: G
authors.lastname: Ashton
authors.forename: Vivien
authors.initials: V
authors.lastname: Hanson
authors.forename: A Wasat
authors.initials: AW
authors.lastname: Mansoor
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hawkins
authors.forename: David E
authors.initials: DE
authors.lastname: Gilham
mesh_terms: D019264:Adoptive Transfer / Q000009:adverse effects; D000818:Animals; D018941:Antigens, CD19 / Q000235:genetics / Q000276:immunology*; D016000:Cluster Analysis; D016207:Cytokines / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic; D020869:Gene Expression Profiling; D006801:Humans; D016130:Immunophenotyping; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism* / Q000637:transplantation; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D018941:Antigens, CD19; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins