Chimeric antigen receptor (CAR) cell-based therapies have demonstrated limited success in solid tumors, including glioblastoma (GBM). GBMs exhibit high heterogeneity and create an immunosuppressive tumor microenvironment (TME). In addition, other challenges exist for CAR therapy, including trafficking and infiltration into the tumor site, proliferation, persistence of CARs once in the tumor, and reduced functionality, such as suboptimal cytokine production. Cytokine modification is of interest, as one can enhance therapy efficacy and minimize off-target toxicity by directly combining CAR therapy with cytokines, antibodies, or oncolytic viruses that alter cytokine response pathways. Alternatively, one can genetically modify CAR T-cells or CAR NK-cells to secrete cytokines or express cytokines or cytokine receptors. Finally, CARs can be genetically altered to augment or suppress intracellular cytokine signaling pathways for a more direct approach. Codelivery of cytokines with CARs is the most straightforward method, but it has associated toxicity. Alternatively, combining CAR therapy with antibodies (e.g., anti-IL-6, anti-PD1, and anti-VEGF) or oncolytic viruses has enhanced CAR cell infiltration into GBM tumors and provided proinflammatory signals to the TME. CAR T- or NK-cells secreting cytokines (e.g., IL-12, IL-15, and IL-18) have shown improved efficacy within multiple GBM subtypes. Likewise, expressing cytokine-modulating receptors in CAR cells that promote or inhibit cytokine signaling has enhanced their activity. Finally, gene editing approaches are actively being pursued to directly influence immune signaling pathways in CAR cells. In this review, we summarize these cytokine modification methods and highlight any existing gaps in the hope of catalyzing an improved generation of CAR-based therapies for glioblastoma.
嵌合抗原受体（CAR）细胞疗法在包括胶质母细胞瘤（GBM）在内的实体瘤中疗效有限。胶质母细胞瘤具有高度异质性，并形成免疫抑制性肿瘤微环境。此外，CAR疗法还面临其他挑战，包括CAR细胞向肿瘤部位的迁移与浸润、增殖能力、在肿瘤内的持久性以及功能减弱（如细胞因子产生不足）。细胞因子修饰备受关注，因为通过将CAR疗法与改变细胞因子反应通路的细胞因子、抗体或溶瘤病毒直接结合，可以增强疗效并减少脱靶毒性。另一种策略是通过基因工程改造CAR T细胞或CAR NK细胞，使其分泌细胞因子或表达细胞因子及其受体。最后，还可对CAR细胞进行基因修饰以增强或抑制细胞内细胞因子信号通路，实现更直接的调控。细胞因子与CAR的联合递送是最直接的方法，但存在相关毒性风险。此外，将CAR疗法与抗体（如抗IL-6、抗PD1和抗VEGF抗体）或溶瘤病毒联用，可增强CAR细胞对胶质母细胞瘤的浸润能力，并向肿瘤微环境提供促炎信号。分泌细胞因子（如IL-12、IL-15和IL-18）的CAR T细胞或NK细胞在多种胶质母细胞瘤亚型中显示出增强的疗效。同样，在CAR细胞中表达调控细胞因子信号通路的受体（促进或抑制信号传导）也能提升其活性。最后，通过基因编辑技术直接调控CAR细胞内免疫信号通路的研究正在积极开展。本综述系统总结了这些细胞因子修饰策略，并指出当前存在的不足，以期推动新一代胶质母细胞瘤CAR疗法的优化发展。
Cytokine Modification of Adoptive Chimeric Antigen Receptor Immunotherapy for Glioblastoma
肿瘤(癌症)患者之家