Potent preclinical activity of FLT3-directed chimeric antigen receptor T-cell immunotherapy against FLT3 - mutant acute myeloid leukemia and KMT2A -rearranged acute lymphoblastic leukemia

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. Accor...

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Published inHaematologica (Roma) Vol. 108; no. 2; pp. 457 - 471
Main Authors Niswander, Lisa M, Graff, Zachary T, Chien, Christopher D, Chukinas, John A, Meadows, Christina A, Leach, Lillie C, Loftus, Joseph P, Kohler, M Eric, Tasian, Sarah K, Fry, Terry J
Format Journal Article
LanguageEnglish
Published Italy Fondazione Ferrata Storti 01.02.2023
Ferrata Storti Foundation
Subjects
Adult
Cell Therapy & Immunotherapy
Child
fms-Like Tyrosine Kinase 3 - genetics
Humans
Immunotherapy
Leukemia, Myeloid, Acute - genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Receptors, Chimeric Antigen - genetics
T-Lymphocytes - metabolism
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Summary: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.
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Disclosures
CDC and TJF have a United States Department of Health and Human Services patent application for FLT3 chimeric antigen receptors (WO2017205747A1). SKT is receiving or has received research funding for unrelated studies from Beam Therapeutics, Gilead Sciences, Incyte Corporation, and Kura Oncology, has consulted for bluebird bio, and serves on the scientific advisory boards of Aleta Biotherapeutics, Kura Oncology, and Syndax Pharmaceuticals. TJF is a part-time employee of and owns stock options in Sana Biotechnology. The remaining authors have no conflicts of interest to disclose.
Contributions
LMN performed experiments, analyzed and interpreted data, and wrote the manuscript. ZTG and CDC performed experiments, analyzed and interpreted data, and contributed to writing the manuscript. JAC, CAM, LCL, JPL, and MEK performed experiments and analyzed and interpreted data. SKT and TJF conceived and directed the study, analyzed and interpreted data, and wrote and/or edited the manuscript. All authors approved the final version of the manuscript.
Data-sharing statement
Human leukemia cell lines used in these studies are publicly available through commercial sources and may be made available from the authors upon written request and material transfer agreement approval. The authors are also glad to share guidance regarding protocols and assays used in these studies upon written request.
ISSN:0390-6078
1592-8721
DOI:10.3324/haematol.2022.281456