Targeting FLT3 by chimeric antigen receptor T cells for the treatment of acute myeloid leukemia

Chen, Lichao; Mao, Hsiaoyin; Zhang, Jianying; Chu, Jianhong; Devine, Steven M.; Caligiuri, Michael A.; Yu, Jianhua

doi:10.1038/leu.2017.147

Cited by 48 publications

(62 citation statements)

References 14 publications

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“…Anti FLT3‐41BB‐CD3ζ CAR T‐cells showed impressive cytotoxicity against AML cell lines in‐vitro and in xenografted NSG‐SGM3 mice . Similar results were also found by another group which developed a second‐generation anti‐FLT3 CAR T‐cells with CD28 as the co‐stimulating domain . Crenolanib has been shown to increase surface expression of FLT3 receptors which enhanced the potency of CD4+ and CD8+ CAR T‐cells against FLT3‐ITD+ as well as wild type AML cells .…”

Section: Introductionsupporting

confidence: 78%

Finding new lanes: Chimeric antigen receptor (CAR) T‐cells for myeloid leukemia

Pratap

Zhao

2020

Cancer Reports

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Background: Myeloid leukemia represents a heterogeneous group of cancers of blood and bone marrow which arise from clonal expansion of hematopoietic myeloid lineage cells. Acute myeloid leukemia (AML) has traditionally been treated with multiagent chemotherapy, but conventional therapies have not improved the long-term survival for decades. Chronic myeloid leukemia (CML) is an indolent disease which requires lifelong treatment, is associated with significant side effects, and carries a risk of progression to potentially lethal blast crises.Recent Findings: Recent advances in molecular biology, virology, and immunology have enabled researchers to grow and modify T lymphocytes ex-vivo. Chimeric antigen receptor (CAR) T-cell therapy has been shown to specifically target cells of lymphoid lineage and induce remission in acute lymphoblastic leukemia (ALL) patients.

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Section: Introductionsupporting

confidence: 78%

Finding new lanes: Chimeric antigen receptor (CAR) T‐cells for myeloid leukemia

Pratap

Zhao

2020

Cancer Reports

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“…In a previous study parental antibody 4G8 on its own did not affect colony formation and was not cytotoxic toward CD34‐positive human bone marrow cells . Likewise, two prior studies with T cells carrying CARs based on FLT3‐specific scFv antibody or FLT3 ligand reported normal human hematopoiesis in NSG mice transplanted with HSCs after treatment with the FLT3‐specific CAR T cells, and undisturbed colony formation of cord blood derived HSCs in the presence of CAR T cells, respectively . In contrast, in another recent report, a marked reduction in colony formation and HSC viability was observed upon exposure of HSCs to FLT3‐targeted CAR T cells .…”

Section: Discussionmentioning

confidence: 88%

Genetically engineered CAR NK cells display selective cytotoxicity against FLT3‐positive B‐ALL and inhibit in vivo leukemia growth

Oelsner

Waldmann

Billmeier

et al. 2019

Intl Journal of Cancer

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Chimeric antigen receptor (CAR)‐engineered natural killer (NK) cells represent a promising effector cell type for adoptive cancer immunotherapy. Both, genetically modified donor‐derived NK cells as well as continuously expanding NK‐92 cells are currently under clinical development. To enhance their therapeutic utility for the treatment of pre‐B‐cell acute lymphoblastic leukemia (B‐ALL), we engineered NK‐92 cells by lentiviral gene transfer to express a FMS‐like tyrosine kinase 3 (FLT3)‐specific CAR that contains a composite CD28‐CD3ζ signaling domain. FLT3 has primarily been described as a therapeutic target for acute myeloid leukemia, but overexpression of FLT3 has also been reported in B‐ALL. Exposure of FLT3‐positive targets to CAR NK‐92 cells resulted in conjugate formation between NK and leukemia cells, NK‐cell degranulation and selective cytotoxicity toward established B‐ALL cell lines and primary blasts that were resistant to parental NK‐92. In a SEM B‐ALL xenograft model in NOD‐SCID IL2R γnull mice, treatment with CAR NK‐92 but not parental NK‐92 cells markedly inhibited disease progression, demonstrating high antileukemic activity in vivo. As FLT3 is known to be also expressed on precursor cells, we assessed the feasibility of incorporating an inducible caspase‐9 (iCasp9) suicide switch to enhance safety of our approach. Upon addition of the chemical dimerizer AP20187 to NK‐92 cells coexpressing the FLT3‐specific CAR and iCasp9, rapid iCasp9 activation was observed, precluding further CAR‐mediated cytotoxicity. Our data demonstrate that B‐ALL can be effectively targeted by FLT3‐specific CAR NK cells which may complement CD19‐directed immunotherapies, particularly in cases of inherent or acquired resistance to the latter.

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“…After demonstrating significant activity of the construct in vitro and in a mouse model, and after proving the efficacy of alemtuzumab as safety switch, Liu and colleagues presented the results of the first patient treated, who achieved a minimal residual disease (MRD)-negative CR and could be successfully bridged to alloHSCT (91). Other AML targets have been studied in preclinical models with encouraging results, including folate receptor ß (92), CD7 (93), CD44v6 (54), CD38 (94), CLL1 (95), FLT3 (96), and LILRB4 (97), but CAR T cells directed toward these antigens have not entered clinical development or are tested in early trials whose results are not available yet.…”

Section: Car T Cells For Myeloid Diseasesmentioning

confidence: 98%

Adoptive immunotherapy with CAR modified T cells in cancer current landscape and future perspectives

Coscia¹

2019

Front Biosci

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Targeting FLT3 by chimeric antigen receptor T cells for the treatment of acute myeloid leukemia

Cited by 48 publications

References 14 publications

Finding new lanes: Chimeric antigen receptor (CAR) T‐cells for myeloid leukemia

Finding new lanes: Chimeric antigen receptor (CAR) T‐cells for myeloid leukemia

Genetically engineered CAR NK cells display selective cytotoxicity against FLT3‐positive B‐ALL and inhibit in vivo leukemia growth

Adoptive immunotherapy with CAR modified T cells in cancer current landscape and future perspectives

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