Murine allogeneic CD19 CAR T cells harbor potent antileukemic activity but have the potential to mediate lethal GVHD
Blood, The Journal of the American Society of Hematology, 2016•ashpublications.org
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 …
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 …
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.
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