Off-the-shelf CAR–engineered natural killer cells targeting FLT3 enhance killing of acute myeloid leukemia

Mansour, Anthony G.; Teng, Kun-Yu; Li, Zhiyao; Zhu, Zheng; Chen, H L; Tian, Lei; Ali, Aliya; Zhang, Jianying; Lu, Ting; Ma, Shoubao; Lin, Chunshui; Caligiuri, Michael A.; Yu, Jianhua

doi:10.1182/bloodadvances.2022007405

Cited by 12 publications

(4 citation statements)

References 59 publications

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“…Anti-CD117 CAR-T therapy shows preclinical efficacy ( Myburgh et al, 2020 ) but also eliminates healthy HSCs, necessitating novel approaches such as terminating “safety switches” ( Magnani et al, 2023 ). Both CAR-T ( Wang et al, 2018c ) and CAR-NK ( Mansour et al, 2023 ) cells have been used to target FLT3. Anti-CD123 CAR-T therapy has been used in early-stage clinical trials, appearing safe and potentially effective ( Yao et al, 2019 ; Wermke et al, 2021 ).…”

Section: Targeting Aberrant Stem Cell Programs In Leukemia For Therapymentioning

confidence: 99%

Aberrant stem cell and developmental programs in pediatric leukemia

Ling,

Cross,

Roy

2024

Front. Cell Dev. Biol.

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Hematopoiesis is a finely orchestrated process, whereby hematopoietic stem cells give rise to all mature blood cells. Crucially, they maintain the ability to self-renew and/or differentiate to replenish downstream progeny. This process starts at an embryonic stage and continues throughout the human lifespan. Blood cancers such as leukemia occur when normal hematopoiesis is disrupted, leading to uncontrolled proliferation and a block in differentiation of progenitors of a particular lineage (myeloid or lymphoid). Although normal stem cell programs are crucial for tissue homeostasis, these can be co-opted in many cancers, including leukemia. Myeloid or lymphoid leukemias often display stem cell-like properties that not only allow proliferation and survival of leukemic blasts but also enable them to escape treatments currently employed to treat patients. In addition, some leukemias, especially in children, have a fetal stem cell profile, which may reflect the developmental origins of the disease. Aberrant fetal stem cell programs necessary for leukemia maintenance are particularly attractive therapeutic targets. Understanding how hijacked stem cell programs lead to aberrant gene expression in place and time, and drive the biology of leukemia, will help us develop the best treatment strategies for patients.

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Section: Targeting Aberrant Stem Cell Programs In Leukemia For Therapymentioning

confidence: 99%

Aberrant stem cell and developmental programs in pediatric leukemia

Ling,

Cross,

Roy

2024

Front. Cell Dev. Biol.

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“…Engineered NK cells are showing great promise in preclinical settings. [ 109 , 110 ] Investigators are addressing the challenges of NK cell source, manufacturing, and in vivo persistence for optimal clinical efficacy. Importantly, like many other cancers, relapsed lung cancer is aggressive and very complicated.…”

Section: Future Directionsmentioning

confidence: 99%

Recent advances and remaining challenges in lung cancer therapy

Barr,

Ma,

et al. 2024

Chinese Medical Journal

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Lung cancer remains the most common cause of cancer death. Given the continued research into new drugs and combination therapies, outcomes in lung cancer have been improved, and clinical benefits have been expanded to a broader patient population. However, the overall cure and survival rates for lung cancer patients remain low, especially in metastatic cases. Among the available lung cancer treatment options, such as surgery, radiation therapy, chemotherapy, targeted therapies, and alternative therapies, immunotherapy has shown to be the most promising. The exponential progress in immuno-oncology research and recent advancements made in the field of immunotherapy will further increase the survival and quality of life for lung cancer patients. Substantial progress has been made in targeted therapies using tyrosine kinase inhibitors and monoclonal antibody immune checkpoint inhibitors with many FDA-approved drugs targeting the programmed cell death ligand-1 (PD-L1) protein (e.g., durvalumab, atezolizumab), the programmed cell death-1 (PD-1) receptor (e.g., nivolumab, pembrolizumab), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) (e.g., tremelimumab, ipilimumab). Cytokines, cancer vaccines, adoptive T cell therapies, and NK cell mono- and combinational therapies are rapidly being studied, yet to date, there are currently none that are FDA-approved for the treatment of lung cancer. In this review, we discuss the current lung cancer therapies with an emphasis on immunotherapy, including the challenges for future research and clinical applications.

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“…In addition, NK cells are not subject to clonal expansion after activation by tumor-specific antigens, which limits their neurological and off-target toxicity. Mansour et al developed allogeneic FLT3 CAR_sIL-15 NK cells from cord blood NK-92 cell line transduced with lentivirus [52]. The activity of these cells is sustained by the CD28/CD3ζ costimulatory domain, boosted by the release of sIL-15 through a paracrine mechanism, and can be extinguished by cetuximab through the inhibition of the truncated epidermal growth factor receptor inserted into the construct.…”

Section: New Technologiesmentioning

confidence: 99%

FLT3-Mutated Leukemic Stem Cells: Mechanisms of Resistance and New Therapeutic Targets

Capelli

2024

Cancers

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Despite the availability of target drugs in the first and second line, only 30% of FLT3mut AMLs are cured. Among the multiple mechanisms of resistance, those of FLT3mut LSC are the most difficult to eradicate because of their metabolic and genomic characteristics. Reactivation of glycogen synthesis, inhibition of the RAS/MAPK pathway, and degradation of FLT3 may be potential aids to fight the resistance of LSC to FLT3i. LSC is also characterized by the expression of a CD34+/CD25+/CD123+/CD99+ immunophenotype. The receptor and ligand of FLT3, the natural killer group 2 member D ligand (NKGD2L), and CD123 are some of the targets of chimeric antigen receptor T cells (CAR-T), bispecific T-cell engager molecules (BiTEs), CAR-NK and nanoparticles recently designed and reported here. The combination of these new therapeutic options, hopefully in a minimal residual disease (MRD)-driven approach, could provide the future answer to the challenge of treating FLT3mut AML.

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Off-the-shelf CAR–engineered natural killer cells targeting FLT3 enhance killing of acute myeloid leukemia

Cited by 12 publications

References 59 publications

Aberrant stem cell and developmental programs in pediatric leukemia

Aberrant stem cell and developmental programs in pediatric leukemia

Recent advances and remaining challenges in lung cancer therapy

FLT3-Mutated Leukemic Stem Cells: Mechanisms of Resistance and New Therapeutic Targets

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