TRUCKS, the fourth-generation CAR T cells: Current developments and clinical translation

Markus Chmielewski, Hinrich Abken
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引用次数: 74

Abstract

The overriding goal of adoptive cell therapy with chimeric antigen receptor (CAR) redirected T cells in oncology is to eliminate cancer cells from infiltrated tissues. Clinical trials document that this form of immunotherapy can induce lasting remissions of hematologic malignancies; however, the successes could not yet be transferred to the treatment of solid tumors. In this situation, modulating the immune regulation within the solid tumor tissue is thought to be a key point. In order to induce a pro-inflammatory milieu CAR T cells were additionally engineered to release a transgenic cytokine upon CAR signaling in the targeted tumor tissue. Such TRUCKs (“T cells redirected for antigen-unrestricted cytokine-initiated killing”), also called “4th generation” CAR T cells, combine the direct antitumor attack of the CAR T cell with the immune modulating capacities of the delivered cytokine. Through CAR-induced release, the cytokine is ideally deposited in the targeted tissue alleviating systemic side effects. The TRUCK concept is currently explored using a panel of cytokines, including IL-7, IL-12, IL-15, IL-18, IL-23, and combinations thereof, and is entering early phase trials. Future developments will expand the application to a broader panel of released proteins converting CAR T cells to “living factories” of therapeutically active, locally deposited products with the potential to eliminate some clinical deficits of the currently used CAR T cells in the field of solid tumors.

Abstract Image

卡车,第四代CAR - T细胞:目前的发展和临床转化
嵌合抗原受体(CAR)重定向T细胞过继细胞治疗在肿瘤中的首要目标是消除浸润组织中的癌细胞。临床试验证明,这种形式的免疫疗法可以诱导血液恶性肿瘤的持久缓解;然而,成功还不能转移到实体瘤的治疗上。在这种情况下,调节实体瘤组织内的免疫调节被认为是一个关键点。为了诱导促炎环境,CAR - T细胞被额外改造,在靶向肿瘤组织中的CAR信号传导上释放转基因细胞因子。这种卡车(“T细胞重定向用于抗原不受限制的细胞因子启动的杀伤”),也被称为“第四代”CAR - T细胞,将CAR - T细胞的直接抗肿瘤攻击与传递的细胞因子的免疫调节能力结合起来。通过car诱导释放,细胞因子理想地沉积在靶组织中,减轻全身副作用。TRUCK概念目前正在使用一组细胞因子进行探索,包括IL-7、IL-12、IL-15、IL-18、IL-23及其组合,并正在进入早期试验阶段。未来的发展将扩大应用到更广泛的释放蛋白,将CAR - T细胞转化为具有治疗活性的“活工厂”,局部沉积产品,有可能消除目前在实体肿瘤领域使用的CAR - T细胞的一些临床缺陷。
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