title: Murine allogeneic CD19 CAR T cells harbor potent antileukemic activity but have the potential to mediate lethal GVHD.
abstract: Acute lymphoblastic leukemia (ALL) persisting or relapsing following bone marrow transplantation (BMT) has a dismal prognosis. Success with chimeric antigen receptor (CAR) T cells offers an opportunity to treat these patients with leukemia-redirected donor-derived T cells, which may be more functional than T cells derived from patients with leukemia but have the potential to mediate graft-versus-host disease (GVHD). We, together with others, have previously demonstrated tumor-specific T-cell dysfunction in the allogeneic environment. Here, we studied CAR T-cell function following BMT using an immunocompetent murine model of minor mismatched allogeneic transplantation followed by donor-derived CD19-CAR T cells. Allogeneic donor-derived CD19-CAR T cells eliminated residual ALL with equal potency to those administered after syngeneic BMT. Surprisingly, allogeneic CAR T cells mediated lethal acute GVHD with early mortality, which is atypical for this minor mismatch model. We demonstrated that both allogeneic and syngeneic CAR T cells show initial expansion as effector T cells, with a higher peak but rapid deletion of allogeneic CAR T cells. Interestingly, CAR-mediated acute GVHD was only seen in the presence of leukemia, suggesting CAR-target interactions induced GVHD. Indeed, serum interleukin (IL)-6 was elevated only in the presence of both leukemia and CAR T cells, and IL-6 neutralization ameliorated the severity of GVHD in a delayed donor lymphocyte infusion model. Finally, allogeneic CD4(+) CAR T cells were responsible for GVHD, which correlated with their ability to produce IL-6 upon CAR stimulation. Altogether, we demonstrate that donor-derived allogeneic CAR T cells are active but have the capacity to drive GVHD.
authors.affiliation: Pediatric Oncology Branch and.
authors.forename: Elad
authors.initials: E
authors.lastname: Jacoby
authors.affiliation: Pediatric Oncology Branch and.
authors.forename: Yinmeng
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Pediatric Oncology Branch and.
authors.forename: Haiying
authors.initials: H
authors.lastname: Qin
authors.affiliation: Pediatric Oncology Branch and.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Chien
authors.affiliation: Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: James N
authors.initials: JN
authors.lastname: Kochenderfer
authors.affiliation: Pediatric Oncology Branch and.
authors.forename: Terry J
authors.initials: TJ
authors.lastname: Fry
mesh_terms: D064591:Allografts; D000818:Animals; D018941:Antigens, CD19 / Q000235:genetics / Q000276:immunology*; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D017710:Lymphocyte Transfusion; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D044169:Receptors, Calcium-Sensing; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000637:transplantation
chemical_list: D018941:Antigens, CD19; C577923:CASR protein, mouse; D015850:Interleukin-6; D044169:Receptors, Calcium-Sensing; D043562:Receptors, G-Protein-Coupled; D011993:Recombinant Fusion Proteins