研究动态
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检查点阻滞与基因治疗相结合:提高治疗反应与降低毒性的机会

Checkpoint blockade meets gene therapy: Opportunities to improve response and reduce toxicity.

发表日期:2023
作者: Noelia Silva-Pilipich, Ángela Covo-Vergara, Lucía Vanrell, Cristian Smerdou
来源: International Review of Cell and Molecular Biology

摘要:

免疫检查点抑制剂(ICIs)是基于单克隆抗体的癌症治疗的突破。然而,它们的疗效因肿瘤类型和患者而异,并且由于在高剂量下全身给药,它们可能导致因靶向/非肿瘤活性而产生不良反应。ICIs的一种替代和有吸引力的给药途径是利用基因治疗载体能够在体内表达它们。本综述主要关注最近在癌症临床前模型中使用能够局部或全身表达ICIs的病毒载体的研究。这些载体包括非复制病毒、仅在肿瘤细胞中特异性复制和破坏它们的溶瘤病毒以及携带不同格式的抗免疫检查点抗体的自我扩增RNA载体。非复制载体通常导致长期ICIs表达,可能消除了重复给药的需要。虽然具有复制能力的载体表达窗口较短,但能诱导炎症,从而增强抗肿瘤效应。最后,这些改造后的载体可以与其他免疫刺激分子或CAR-T细胞结合使用,进一步增强抗肿瘤免疫应答。版权所有 © 2023. 由Elsevier Inc.出版。
Immune checkpoint inhibitors (ICIs) based on monoclonal antibodies represent a breakthrough for the treatment of cancer. However, their efficacy varies among tumor types and patients, and they can lead to adverse effects due to on-target/off-tumor activity, since they are administered systemically at high doses. An alternative and attractive approach for the delivery of ICIs is the use of gene therapy vectors able to express them in vivo. This review focuses on the most recent studies using viral vectors able to express ICIs locally or systemically in preclinical models of cancer. These vectors include non-replicating viruses, oncolytic viruses able to propagate specifically in tumor cells and destroy them, and self-amplifying RNA vectors, armed with different formats of antibodies against immune checkpoints. Non-replicating vectors usually lead to long-term ICI expression, potentially eliminating the need for repeated administration. Vectors with replication capacity, although they have a shorter window of expression, can induce inflammation which enhances the antitumor effect. Finally, these engineered vectors can be used in combination with other immunostimulatory molecules or with CAR-T cells, further boosting the antitumor immune responses.Copyright © 2023. Published by Elsevier Inc.