Redirection of CAR‑T Cell Cytotoxicity Using Metabolic Glycan Labeling with Unnatural Sugars

T cells expressing chimeric antigen receptors (CAR-T cells) have shown unprecedented clinical responses against hematological malignancies. However, some patients relapse after CAR-T cell therapy due to antigen-negative escape variants. Additionally, CAR-T cell therapies showed limited clinical effi...

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Published inJournal of medicinal chemistry Vol. 66; no. 12; pp. 7804 - 7812
Main Authors Cha, Jeong Hyeon, Kim, Eunsu, Lee, Hyeong Ji, Lee, Young-Ho, Lee, Jeonghyun, Kim, Eunha, Kim, Chan Hyuk
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 22.06.2023
Amer Chemical Soc
Subjects
Chemistry, Medicinal
Humans
Immunotherapy
Immunotherapy, Adoptive - adverse effects
Life Sciences & Biomedicine
Neoplasm Recurrence, Local - etiology
Neoplasm Recurrence, Local - metabolism
Pharmacology & Pharmacy
Receptors, Antigen, T-Cell
Receptors, Chimeric Antigen - metabolism
Science & Technology
T-Lymphocytes - metabolism
Xenograft Model Antitumor Assays
IMMUNOTHERAPY
SIALIC-ACID
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Summary:T cells expressing chimeric antigen receptors (CAR-T cells) have shown unprecedented clinical responses against hematological malignancies. However, some patients relapse after CAR-T cell therapy due to antigen-negative escape variants. Additionally, CAR-T cell therapies showed limited clinical efficacy in solid tumors with high antigen heterogeneity. To overcome this, we metabolically labeled the glycans on cancer cells to redirect CAR-T cell cytotoxicity regardless of the endogenous antigen expression status of the cancer cells. We found that modifying cancer cells with N-azidoacetylmannosamine and bicyclo[6.1.0]­non-4-yne-fluorescein isothiocyanate can elicit selective and durable cytotoxicity of anti-FITC CAR-T cells. Furthermore, we demonstrated that dinitrophenyl-conjugated sialic acid (Sia-DNP) generated DNP-modified glycans on cancer cells in situ that could be effectively targeted by anti-DNP CAR-T cells to eradicate established tumors in xenograft models. Our study illustrates that metabolic glycan labeling using unnatural sugars can be combined with CAR-T cell therapy to provide novel cancer immunotherapy for solid tumors that lack viable target antigens.
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ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.3c00048