Potent preclinical activity of FLT3-directed chimeric antigen receptor T-cell immunotherapy against <i>FLT3</i>- mutant acute myeloid leukemia and <i>KMT2A</i>-rearranged acute lymphoblastic leukemia
Lisa M. Niswander,
Zachary T. Graff,
Christopher D. Chien,
John A. Chukinas,
Christina A. Meadows,
Lillie C. Leach,
Joseph P. Loftus,
M. Eric Kohler,
Sarah K. Tasian,
Terry J. Fry
Affiliations
Lisa M. Niswander
Children’s Hospital of Philadelphia, Division of Oncology and Center for Childhood Cancer Research; Philadelphia PA
Zachary T. Graff
Center for Cancer and Blood Disorders, Children's Hospital Colorado; Aurora, CO, USA; Department of Pediatrics, University of Colorado Anschutz Medical Campus; Aurora, CO
Christopher D. Chien
Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health; Bethesda, MD
John A. Chukinas
Children’s Hospital of Philadelphia, Division of Oncology and Center for Childhood Cancer Research; Philadelphia PA
Christina A. Meadows
Department of Pediatrics, University of Colorado Anschutz Medical Campus; Aurora, CO
Lillie C. Leach
Department of Pediatrics, University of Colorado Anschutz Medical Campus; Aurora, CO
Joseph P. Loftus
Children’s Hospital of Philadelphia, Division of Oncology and Center for Childhood Cancer Research; Philadelphia, PA
M. Eric Kohler
Center for Cancer and Blood Disorders, Children's Hospital Colorado; Aurora, CO, USA; Department of Pediatrics, University of Colorado Anschutz Medical Campus; Aurora, CO
Sarah K. Tasian
Children’s Hospital of Philadelphia, Division of Oncology and Center for Childhood Cancer Research; Philadelphia PA, USA; University of Pennsylvania Perelman School of Medicine and Abramson Cancer Center; Philadelphia PA
Terry J. Fry
Center for Cancer and Blood Disorders, Children's Hospital Colorado; Aurora, CO, USA; Department of Pediatrics, University of Colorado Anschutz Medical Campus; Aurora, CO
Chimeric antigen receptor (CAR) T-cell immunotherapies targeting CD19 or CD22 induce remissions in the majority of patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL), although relapse due to target antigen loss or downregulation has emerged as a major clinical dilemma. Accordingly, great interest exists in developing CAR T cells directed against alternative leukemia cell surface antigens that may help to overcome immunotherapeutic resistance. The fms-like tyrosine kinase 3 receptor (FLT3) is constitutively activated via FLT3 mutation in acute myeloid leukemia (AML) or wild-type FLT3 overexpression in KMT2A (lysine-specific methyltransferase 2A)-rearranged ALL, which are associated with poor clinical outcomes in children and adults. We developed monovalent FLT3-targeted CAR T cells (FLT3CART) and bispecific CD19xFLT3CART and assessed their anti-leukemia activity in preclinical models of FLT3-mutant AML and KMT2A-rearranged infant ALL. We report robust in vitro FLT3CART-induced cytokine production and cytotoxicity against AML and ALL cell lines with minimal cross-reactivity against normal hematopoietic and non-hematopoietic tissues. We also observed potent in vivo inhibition of leukemia proliferation in xenograft models of both FLT3-mutant AML and KMT2A-rearranged ALL, including a post-tisagenlecleucel ALL-to-AML lineage switch patient-derived xenograft model pairing. We further demonstrate significant in vitro and in vivo activity of bispecific CD19xFLT3CART against KMT2Arearranged ALL and posit that this additional approach might also diminish potential antigen escape in these high-risk leukemias. Our preclinical data credential FLT3CART as a highly effective immunotherapeutic strategy for both FLT3- mutant AML and KMT2A-rearranged ALL which is poised for further investigation and clinical translation.
