肿瘤细胞治疗研究
英文原题：hCCL19-expressing recombinant Newcastle disease virus boosts CAR T cell infiltration and efficacy in solid tumor.
rNDV19 与 CAR T 细胞的联合代表了一种有前景的策略，可克服 CAR T 细胞疗法用于实体瘤的局限性。该方法增强免疫细胞浸润与激活，有可能将「冷」肿瘤转化为「热」肿瘤，以改善治疗结局，并为实体瘤免疫治疗提供了一个稳健的转化框架。
嵌合抗原受体（CAR）T细胞疗法彻底改变了血液系统恶性肿瘤的治疗格局；然而，在治疗实体瘤方面仍面临重大挑战，包括免疫细胞向肿瘤组织浸润有限以及免疫抑制性肿瘤微环境。溶瘤病毒（OVs）能够选择性杀伤肿瘤细胞并触发抗肿瘤免疫应答，为应对这些挑战提供了极具前景的解决方案。新城疫病毒（NDV）是一种天然溶瘤病毒，在临床研究中展现出抗肿瘤活性且副作用极小。我们假设，将经过工程化改造以表达某种趋化因子的NDV与四环素诱导型CAR T细胞联合使用，可协同增强CAR T细胞疗法对实体瘤的疗效。
我们构建了表达人 CCL19 的重组 NDV（rNDV19），并在原位肺癌小鼠模型中评估了其与 doxycycline 诱导型 CAR T 细胞联合的治疗疗效。分析了肿瘤负荷、免疫细胞浸润和小鼠生存。
rNDV19保留了强效的溶瘤活性，显著降低肿瘤细胞活力，同时实现人CCL19的稳定表达。rNDV19触发了CAR T细胞向肿瘤内的显著募集，并促进其活性。机制分析显示，rNDV19与CAR T细胞联合治疗重塑了肿瘤微环境。转录组分析突出显示，联合治疗激活了关键免疫通路——包括白细胞趋化、T细胞分化、细胞因子产生以及免疫反应激活信号传导。这些发现进一步得到T细胞活化标志物如IL-2、TNF-、IFN-以及细胞毒性效应分子如颗粒酶A和穿孔素表达上调的佐证。在治疗方面，该联合方案协同将中位生存时间从22天延长至36天，优于各单药治疗。
BACKGROUND: Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of hematological malignancies; however, it faces significant challenges in treating solid tumors, including limited immune infiltration into tumor tissues and immunosuppressive tumor microenvironment. Oncolytic viruses (OVs), which selectively destroy cancer cells and trigger antitumor immune responses, offer a compelling solution to these challenges. Newcastle disease virus (NDV) is a natural OV that exhibits antitumor activity with minimal side effects in clinical studies. We hypothesized that combining NDV, engineered to express a chemokine, with tetracycline-inducible CAR T cells could synergistically enhance CAR T cell therapy efficacy against solid tumors. METHODS: We constructed a recombinant NDV expressing human CCL19 (rNDV19) and evaluated its therapeutic efficacy alongside doxycycline-inducible CAR T cells in an orthotopic lung cancer mouse model. Tumor burden, immune cell infiltration, and mouse survival were analyzed. RESULTS: rNDV19 retained potent oncolytic activity, significantly reducing tumor cell viability while achieving stable expression of human CCL19. rNDV19 triggered significant recruitment of CAR T cells into tumors and promoted their activity. Mechanistic analysis revealed that rNDV19 and CAR T cell combination therapy remodeled the tumor microenvironment. Transcriptomic profiling highlighted activation of critical immune pathways-including leukocyte chemotaxis, T cell differentiation, cytokine production, and immune response-activating signaling in combination therapy. These findings were further corroborated by upregulated expression of T cell activation markers like IL-2, TNF- , IFN- , and cytotoxic effector molecules such as granzyme A and perforin. Therapeutically, the combination synergistically extended median survival time from 22 to 36 days, outperforming monotherapies. CONCLUSIONS: The combination of rNDV19 and CAR T cells represents a promising strategy for overcoming the limitations of CAR T cell therapy for solid tumors. This approach enhances immune cell infiltration and activation, potentially converting "cold" tumors into "hot" tumors to improve therapeutic outcomes and offering a robust translational framework for solid tumor immunotherapy.
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