Overview of LeY-Targeted CAR Cell Therapies

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Background of LeY

Lewis Y tetrasaccharide, also known as Lewis Y or LeY, is a carbohydrate antigen that falls under the Lewis blood group system. It comprises a fucose residue attached to an oligosaccharide chain of type 2. This chain consists of galactose and N-acetylglucosamine linked by a beta-1,4 glycosidic bond. LeY is present on the surface of different cells and tissues, including red blood cells, epithelial cells, endothelial cells, and some immune cells. Its roles in biological processes such as cell adhesion, inflammation, angiogenesis, and tumor progression are significant. LeY plays a crucial part in several biological processes that are essential for cancer cell growth and seeding, such as cell adhesion, differentiation, migration, and signaling. It interacts with various receptors and ligands such as selectins, galectins and antibodies. LeY has been linked to numerous diseases like cancer, inflammation and infection.

Fig.1 Structure of LeY

LeY Signaling Pathways

LeY is involved in regulating various signaling pathways that contribute to cancer progression, including the transforming growth factor beta (TGF-β) pathway. This pathway has a dual function in cancer, acting as either a tumor suppressor or promoter depending on the cellular context. TGF-β signals through two transmembrane receptors - TGF-β receptor I (TβRI) and TGF-β receptor II (TβRII), which activate downstream effectors like Smad, ERK/MAPK and PI3K/Akt.

LeY has the ability to modulate the TGF-β pathway by altering the expression, structure, and function of TβRI and TβRII. Studies indicate that LeY can enhance ERK and Akt phosphorylation, which is associated with cell proliferation and survival. Additionally, it inhibits Smad2/3 phosphorylation involved in growth inhibition and apoptosis. Furthermore, LeY affects the interaction between TβRI/TβRII ligands or antibodies by changing receptor glycosylation status. Therefore, LeY may act as a positive regulator of the TGF-β pathway in ovarian cancer cells promoting their growth and survival. It may also influence other signaling pathways related to cancer development such as selectin-mediated adhesion pathway and Wnt/ β-catenin pathway. As a potential biomarker for ovarian cancer diagnosis and treatment target, LeY holds significant therapeutic value.

Clinical Status of LeY-Targeted CAR Cell Therapies

Four clinical trials have been conducted on LeY-targeted chimeric antigen receptor (CAR) cell therapies. The first trial, published in 2013 by Ritchie et al., demonstrated the biological activity of second generation CD28-ζ CAR-T cells against the Lewis Y antigen in acute myeloid leukemia (AML) patients. Although limited efficacy was observed, this study is significant as it showed that CAR-T cells can be biologically active in AML patients without causing hematopoietic toxicity.

Currently, all FDA-approved CAR cell therapies are only used to treat hematologic malignancies and not solid tumors. However, recent research has shown that LeY is highly expressed, mutated, and amplified in most solid organs. This makes it a potential target for CAR therapy in the treatment of solid cancers such as lung cancer, liver cancer, and breast cancer. Two clinical trials are currently underway to explore the efficacy of this approach.

Table 1. Ongoing LeY-Targeted CAR Cell Therapy Clinical Trials

NCT Number	Title	Status	Conditions	Phases	Sponsor/Collaborators
NCT03198052	GPC3/Mesothelin/Claudin18.2/GUCY2C/B7-H3/PSCA/PSMA/MUC1/TGFβ/HER2/Lewis-Y/AXL/EGFR-CAR-T Cells Against Cancers	Recruiting	Lung Cancer Cancer Immunotherapy CAR-T Cell	Phase 1	Second Affiliated Hospital of Guangzhou Medical University/ Hunan Zhaotai Yongren Medical Innovation Co. Ltd./ Guangdong Zhaotai InVivo Biomedicine Co. Ltd.
NCT03851146	A Study of Anti-Lewis Y Chimeric Antigen Receptor-T Cells (LeY-CAR-T) in Patients With Solid Tumours	Completed	Advanced Cancer	Phase 1	Peter MacCallum Cancer Centre, Australia
NCT04842812	Engineered TILs/CAR-TILs to Treat Advanced Solid Tumors	Recruiting	Liver Cancer Lung Cancer Breast Cancer	Phase 1	Second Affiliated Hospital of Guangzhou Medical University/ Guangdong Zhaotai InVivo Biomedicine Co. Ltd
NCT01716364	Safety Study of Anti LewisY Chimeric Antigen Receptor in Myeloma, Acute Myeloid Leukemia or Myelodysplastic Syndrome	Unknown	Multiple Myeloma Acute Myeloid Leukaemia Myelodysplastic Syndrome	Phase 1	Peter MacCallum Cancer Centre, Australia

References

Hao, Yingying, et al. "c-Fos mediates α1, 2-fucosyltransferase 1 and Lewis y expression in response to TGF-β1 in ovarian cancer." Oncology Reports 38.6 (2017): 3355-3366.
Kukowska-Latallo, Jolanta F., et al. "A cloned human cDNA determines expression of a mouse stage-specific embryonic antigen and the Lewis blood group alpha (1, 3/1, 4) fucosyltransferase." Genes & Development 4.8 (1990): 1288-1303.
Cameron, H. Scott, Dorota Szczepaniak, and Brent W. Weston. "Expression of Human Chromosome 19p α (1, 3)-Fucosyltransferase Genes in Normal Tissues: ALTERNATIVE SPLICING, POLYADENYLATION, AND ISOFORMS (∗)." Journal of Biological Chemistry 270.34 (1995): 20112-20122.
Mardiana, Sherly, and Saar Gill. "CAR T cells for acute myeloid leukemia: state of the art and future directions." Frontiers in oncology 10 (2020): 697.