Therapeutic Targeting of Mesothelin with Chimeric Antigen Receptor T Cells in Acute Myeloid Leukemia

Le, Quy; Castro, Sommer; Tang, Thao T.; Loeb, Anisha; Hylkema, Tiffany; McKay, Cyd Nourigat; Perkins, LaKeisha; Srivastava, Shivani; Call, Lindsey; Smith, Jenny L.; Leonti, Amanda R.; Ries, Rhonda E.; Pardo, Laura; Loken, Michael R.; Correnti, Colin; Fiorenza, Salvatore; Turtle, Cameron J.; Riddell, Stanley R.; Tarlock, Katherine; Meshinchi, Soheil

doi:10.1158/1078-0432.ccr-21-1546

Cited by 19 publications

(24 citation statements)

References 51 publications

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“…Among the 7 reported R/R AML patients, the CR/CRi rate was 42% (157). Moreover, CAR-T cells redirected to several novel targets [FLT3 (158,159), CLL-1 (160), CD70 (161), IL-10R (162), mesothelin (163), Siglec-6 (164), etc.] have shown potent efficacy in preclinical studies, and some of them (eg., CLL-1) are currently being assessed in clinical trials (150).…”

Section: Car-t and Car-nk Cellsmentioning

confidence: 99%

Optimization of Donor Lymphocyte Infusion for AML Relapse After Allo-HCT in the Era of New Drugs and Cell Engineering

Yang

Yuan

et al. 2022

Front. Oncol.

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Donor lymphocyte infusion (DLI) is a key strategy for the treatment of AML relapse after allogeneic hematopoietic cell transplantation (allo-HCT) and has been used for either prophylactic, pre-emptive, or therapeutic purposes. However, the prognosis of these patients remains dismal even after DLI infusion (2-year overall survival, ~25%), and the efficacy is achieved at the cost of toxicities such as graft-versus-host (GVH) disease. Attempts to optimize DLI efficacy and safety, such as dose/timing modification and the use of cytoreduction, before DLI have been performed previously. Recently, a great number of novel targeted and immunomodulatory agents have emerged. Some of them, such as hypomethylating agents, FLT3 and Bcl-2 inhibitors, have been used in combination with DLI, aiming to enhance the graft-versus-leukemia effect. Moreover, manipulation of the DLI graft through cell selection (e.g., donor NK cells) or cell engineering (donor CAR-T cells) has shown potentially superior anti-tumor effects but less GVH effect than conventional DLI in clinical trials. This review summarizes the recent advances on the use of DLI for the prophylaxis/treatment of AML relapse and discusses future strategies which may further improve the treatment efficacy.

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Section: Car-t and Car-nk Cellsmentioning

confidence: 99%

Optimization of Donor Lymphocyte Infusion for AML Relapse After Allo-HCT in the Era of New Drugs and Cell Engineering

Yang

Yuan

et al. 2022

Front. Oncol.

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“…Multiple additional antigens have been tested preclinically or in a clinical setting in the quest for better CAR-T cell target proteins. Apart from those described above, the following antigens have either been examined for AML or are being investigated: CD7, CD13, CD19, CD34, CD38, CD56, CD117, B7-H3, mesothelin, NKG2D ligands, IL-10 receptor, GM-CSF receptor, ILT3, TIM-3, MUC-1, Lewis Y, and folate receptor β [ 46 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 ] ( Table 1 ).…”

Section: Aml Target Antigens Under Investigationmentioning

confidence: 99%

Current Limitations and Perspectives of Chimeric Antigen Receptor-T-Cells in Acute Myeloid Leukemia

Maucher

Srour

Danhof

et al. 2021

Cancers

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Adoptive transfer of gene-engineered chimeric antigen receptor (CAR)-T-cells has emerged as a powerful immunotherapy for combating hematologic cancers. Several target antigens that are prevalently expressed on AML cells have undergone evaluation in preclinical CAR-T-cell testing. Attributes of an ‘ideal’ target antigen for CAR-T-cell therapy in AML include high-level expression on leukemic blasts and leukemic stem cells (LSCs), and absence on healthy tissues, normal hematopoietic stem and progenitor cells (HSPCs). In contrast to other blood cancer types, where CAR-T therapies are being similarly studied, only a rather small number of AML patients has received CAR-T-cell treatment in clinical trials, resulting in limited clinical experience for this therapeutic approach in AML. For curative AML treatment, abrogation of bulk blasts and LSCs is mandatory with the need for hematopoietic recovery after CAR-T administration. Herein, we provide a critical review of the current pipeline of candidate target antigens and corresponding CAR-T-cell products in AML, assess challenges for clinical translation and implementation in routine clinical practice, as well as perspectives for overcoming them.

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“…Similar MSLN expression patterns (MFI, 70.4 ± 24.0%) were also seen in bulk AML cells from MSLN-positive patients, while MSLN expression was entirely absent in normal hematopoietic cells. 31 These results…”

Section: Msln and Secondary Diseases Of Amlmentioning

confidence: 71%

“…Recent research has shown that MSLN is highly expressed in LSCs. 31 The CD34 + CD38fraction of LSCs from 5 MSLNpositive patients was MSLN + (MFI, 67.1 ± 26.6%) by flow cytometry.…”

Section: Msln and Secondary Diseases Of Amlmentioning

confidence: 90%

Immunotherapy targeting mesothelin in acute myeloid leukemia

Wang

Gong

2022

Journal of Leukocyte Biology

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Mesothelin (MSLN) is an emerging target that exists in soluble and membrane‐associated forms. It is usually used for the diagnosis and treatment of MSLN‐positive solid tumors. Interestingly, recent studies have shown that MSLN is highly expressed in 36% of acute myeloid leukemia (AML) patients and barely expressed in normal hematopoietic cells, which makes MSLN a promising target for the treatment of AML. It has been shown that MSLN is detectable as a diagnostic marker in its soluble form. Although the mechanism of action is unclear, MSLN remains a promising target for immunotherapy. Most MSLN research has been conducted in solid tumors, and less research has been conducted in hematopoietic tumors. Increasing research on MSLN is underway in AML, a hematopoietic neoplasm. For example, MSLN is related to extramedullary disease, minimal residual disease, and relapse in AML patients. Decreasing the expression of MSLN reduces the severity of the disease course. This information suggests that MSLN may be an ideal target for the treatment of many AML‐related diseases to improve the prognosis and survival rate. At present, there are a few immunotherapies targeting MSLN in AML in preclinical and clinical trials, such as antibody‒drug conjugates, bispecific T‐cell engagers, and chimeric antigen receptor‐T cells, which opens new room for the treatment of MSLN‐related AML.

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Therapeutic Targeting of Mesothelin with Chimeric Antigen Receptor T Cells in Acute Myeloid Leukemia

Cited by 19 publications

References 51 publications

Optimization of Donor Lymphocyte Infusion for AML Relapse After Allo-HCT in the Era of New Drugs and Cell Engineering

Optimization of Donor Lymphocyte Infusion for AML Relapse After Allo-HCT in the Era of New Drugs and Cell Engineering

Current Limitations and Perspectives of Chimeric Antigen Receptor-T-Cells in Acute Myeloid Leukemia

Immunotherapy targeting mesothelin in acute myeloid leukemia

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