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CAR T cells redirected against tumor-specific antigen glycoforms: can low-sugar antigens guarantee a sweet success?

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Abstract

Immune-based therapies have experienced a pronounced breakthrough in the past decades as they acquired multiple US Food and Drug Administration (FDA) approvals for various indications. To date, six chimeric antigen receptor T cell (CAR-T) therapies have been permitted for the treatment of certain patients with relapsed/refractory hematologic malignancies. However, several clinical trials of solid tumor CAR-T therapies were prematurely terminated, or they reported life-threatening treatment-related damages to healthy tissues. The simultaneous expression of target antigens by healthy organs and tumor cells is partly responsible for such toxicities. Alongside targeting tumor-specific antigens, targeting the aberrantly glycosylated glycoforms of tumor-associated antigens can also minimize the off-tumor effects of CAR-T therapies. Tn, T, and sialyl-Tn antigens have been reported to be involved in tumor progression and metastasis, and their expression results from the dysregulation of a series of glycosyltransferases and the endoplasmic reticulum protein chaperone, Cosmc. Moreover, these glycoforms have been associated with various types of cancers, including prostate, breast, colon, gastric, and lung cancers. Here, we discuss how underglycosylated antigens emerge and then detail the latest advances in the development of CAR-T-based immunotherapies that target some of such antigens.

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  1. These authors share first authorship.

Authors and Affiliations

  1. Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, P.O. Box 14115/111, Iran

    Pooria Safarzadeh Kozani & Fatemeh Rahbarizadeh

  2. Department of Medical Biotechnology, Faculty of Paramedicine, Guilan University of Medical Sciences, Rasht, P.O. Box 44771/66595, Iran

    Pouya Safarzadeh Kozani

  3. Research and Development Center of Biotechnology, Tarbiat Modares University, Tehran, P.O. Box 14115/111, Iran

    Fatemeh Rahbarizadeh

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  1. Pooria Safarzadeh Kozani
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Pooria Safarzadeh Kozani, Pouya Safarzadeh Kozani, and Fatemeh Rahbarizadeh declare that they have no conflict of interest. This manuscript is a review article and does not involve a research protocol that requires the approval of the relevant institutional review board or ethics committee.

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Safarzadeh Kozani, P., Safarzadeh Kozani, P. & Rahbarizadeh, F. CAR T cells redirected against tumor-specific antigen glycoforms: can low-sugar antigens guarantee a sweet success?. Front. Med. 16, 322–338 (2022). https://doi.org/10.1007/s11684-021-0901-2

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