Cancer immunotherapy is rapidly advancing in the treatment of a variety of hematopoietic cancers, including pediatric acute lymphoblastic leukemia and diffuse large B cell lymphoma, with chimeric antigen receptor (CAR)-T cells. CARs are genetically encoded artificial T cell receptors that combine the antigen specificity of an antibody with the machinery of T cell activation. However, implementation of CAR technology in the treatment of solid tumors has been progressing much slower. Solid tumors are characterized by a number of challenges that need to be overcome, including cellular heterogeneity, immunosuppressive tumor microenvironment (TME), and, in particular, few known cancer-specific targets. Post-translational modifications that differentially occur in malignant cells generate valid cell surface, cancer-specific targets for CAR-T cells. We previously demonstrated that CAR-T cells targeting an aberrant O-glycosylation of MUC1, a common cancer marker associated with changes in cell adhesion, tumor growth and poor prognosis, could control malignant growth in mouse models. Here, we discuss the field of glycan-directed CAR-T cells and review the different classes of antibodies specific for glycan-targeting, including the generation of high affinity O-glycopeptide antibodies. Finally, we discuss historic and recently investigated glycan targets for CAR-T cells and provide our perspective on how targeting the tumor glycoproteome and/or glycome will improve CAR-T immunotherapy.

中文翻译：

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聚糖定向的CAR-T细胞

癌症免疫疗法在利用嵌合抗原受体（CAR）-T细胞治疗各种造血系统癌症中迅速发展，包括小儿急性淋巴细胞白血病和弥漫性大B细胞淋巴瘤。CAR是由基因编码的人工T细胞受体，将抗体的抗原特异性与T细胞活化机制结合在一起。但是，CAR技术在实体瘤治疗中的实施进展缓慢得多。实体瘤的特点是需要克服许多挑战，包括细胞异质性，免疫抑制肿瘤微环境（TME），尤其是很少有已知的癌症特异性靶标。在恶性细胞中差异发生的翻译后修饰为CAR-T细胞产生有效的细胞表面，癌症特异性靶标。我们以前证明，靶向MUC1异常O-糖基化的CAR-T细胞可以控制小鼠模型中的恶性生长，MUC1是与细胞粘附，肿瘤生长和不良预后相关的常见癌症标志物。在这里，我们讨论了针对聚糖的CAR-T细胞领域，并综述了针对聚糖靶向的不同类别的抗体，包括高亲和力O-糖肽抗体的产生。最后，我们讨论了CAR-T细胞的历史性和最近研究过的聚糖靶标，并就靶向肿瘤糖蛋白组和/或糖原将如何改善CAR-T免疫疗法提供了我们的观点。可以控制小鼠模型的恶性生长。在这里，我们讨论了针对聚糖的CAR-T细胞领域，并综述了针对聚糖靶向的不同类别的抗体，包括高亲和力O-糖肽抗体的产生。最后，我们讨论了CAR-T细胞的历史性和最近研究过的聚糖靶标，并就靶向肿瘤糖蛋白组和/或糖原将如何改善CAR-T免疫疗法提供了我们的观点。可以控制小鼠模型的恶性生长。在这里，我们讨论了针对聚糖的CAR-T细胞领域，并综述了针对聚糖靶向的不同类别的抗体，包括高亲和力O-糖肽抗体的产生。最后，我们讨论了CAR-T细胞的历史性和最近研究过的聚糖靶标，并就靶向肿瘤糖蛋白组和/或糖原将如何改善CAR-T免疫疗法提供了我们的观点。