Tian Cong, Sun Xingxing, Zhu Hongling, Zhou Meixiang, Chen Qingyu, Min Daliu, Huang Yan, Han Kun
Department of Oncology, Shanghai Jiao Tong UniversityAffiliated Sixth People' s Hospital, Shanghai 201306, China.
Department of Radiation Oncology, Tenth People's Hospital of Tongji University, Shanghai 200072, China.
Immunother Adv. 2024 Nov 28;5(1):ltae010. doi: 10.1093/immadv/ltae010. eCollection 2025.
Despite the proven clinical benefits of cytokine therapy in cancer treatment, systemic administration of cytokines such as IL-12 is constrained by dose-limiting toxicities and short half-lives. To address these challenges, we explored a localized cytokine delivery strategy using engineered neoantigen-reactive T (NRT) cells as carriers in a murine model of osteosarcoma.
We used a neoantigen from K7M2 osteosarcoma cells to retrovirally transduce NRT cells to express an inducible form of IL-12. We evaluated the engineered NRT cells' antitumor activity and the production of IL-12 and IFN-γ upon in vitro co-culture with tumor cells. We systemically administered NRT-IL-12 cells in a mouse model of osteosarcoma to assess their impact on tumor growth and survival.
assays demonstrated that the engineered NRT cells exhibited enhanced antitumor activity and produced elevated levels of IL-12 and IFN-γ. In the mouse model of osteosarcoma, systemic administration of NRT-IL-12 cells resulted in a significant reduction in tumor growth and an increase in survival rates compared to the administration of control NRT cells. Further analysis revealed that NRT-IL-12 cells induced a profound increase in CD8+ T-cell infiltration and a decrease in Treg cells within the tumor microenvironment.
Our study presents a novel and efficacious strategy for osteosarcoma immunotherapy by harnessing NRT cells as targeted cytokine delivery vehicles.
尽管细胞因子疗法在癌症治疗中已被证明具有临床益处，但诸如白细胞介素-12（IL-12）等细胞因子的全身给药受到剂量限制性毒性和短半衰期的限制。为应对这些挑战，我们在骨肉瘤小鼠模型中探索了一种局部细胞因子递送策略，即使用工程化的新抗原反应性T（NRT）细胞作为载体。
我们使用来自K7M2骨肉瘤细胞的新抗原通过逆转录病毒转导NRT细胞，使其表达可诱导形式的IL-12。我们评估了工程化NRT细胞的抗肿瘤活性以及与肿瘤细胞体外共培养时IL-12和干扰素-γ（IFN-γ）的产生情况。我们在骨肉瘤小鼠模型中全身给药NRT-IL-12细胞，以评估它们对肿瘤生长和生存的影响。
实验表明，工程化NRT细胞表现出增强的抗肿瘤活性，并产生了更高水平的IL-12和IFN-γ。在骨肉瘤小鼠模型中，与给予对照NRT细胞相比，全身给药NRT-IL-12细胞导致肿瘤生长显著减少，生存率提高。进一步分析显示，NRT-IL-12细胞诱导肿瘤微环境中CD8 + T细胞浸润显著增加，调节性T细胞减少。
我们的研究提出了一种通过利用NRT细胞作为靶向细胞因子递送载体进行骨肉瘤免疫治疗的新颖且有效的策略。
