Department of Neurosurgery, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, USA.
Department of Neurosurgery, College of Medicine, Asan Medical Center, University of Ulsan, Songpa-gu, Seoul, Republic of Korea.
Oncoimmunology. 2021 Jul 8;10(1):1940673. doi: 10.1080/2162402X.2021.1940673. eCollection 2021.
Despite the advent of immunotherapy as a promising therapeutic, glioblastoma (GBM) remains resistant to using checkpoint blockade due to its highly immunosuppressive tumor milieu. Moreover, current anti-PD-1 treatment requires multiple infusions with adverse systemic effects. Therefore, we used a PCL:PEG:PCL polymer gel loaded with anti-PD-1 and implanted at the site of lymph nodes in an attempt to maximize targeting of inactivated T cells as well as mitigate unnecessary systemic exposure.
Mice orthotopically implanted with GL261 glioma cells were injected with hydrogels loaded with anti-PD-1 in one of the following locations: cervical lymph nodes, inguinal lymph nodes, and the tumor site. Mice treated systemically with anti-PD-1 were used as comparative controls. Kaplan-Meier curves were generated for all arms, with ex vivo flow cytometric staining for L/D, CD45, CD3, CD4, CD8, TNF-α and IFN-y and co-culture ELISpots were done for immune cell activation assays.
Mice implanted with PCL:PEG:PCL hydrogels carrying anti-PD-1 at the site of their lymph nodes showed significantly improved survival outcomes compared to mice systemically treated with anti-PD-1 ( = .0185). Flow cytometric analysis of brain tissue and co-culture of lymph node T cells from mice implanted with gels demonstrated increased levels of IFN-y and TNF-α compared to mice treated with systemic anti-PD-1, indicating greater reversal of immunosuppression compared to systemic treatment.
Our data demonstrate proof of principle for using localized therapy that targets lymph nodes for GBM. We propose an alternative treatment paradigm for developing new sustained local treatments with immunotherapy that are able to eliminate the need for multiple systemic infusions and their off-target effects.
尽管免疫疗法作为一种很有前途的治疗方法已经出现，但由于胶质母细胞瘤（GBM）的肿瘤微环境具有高度免疫抑制性，其对检查点阻断仍具有抗性。此外，目前的抗 PD-1 治疗需要多次输注，会产生不良的全身效应。因此，我们使用了一种 PCL:PEG:PCL 聚合物凝胶，其中负载了抗 PD-1，并将其植入淋巴结部位，试图最大限度地靶向失活的 T 细胞，并减轻不必要的全身暴露。
将 GL261 胶质母细胞瘤细胞原位植入的小鼠分别在以下部位注射负载有抗 PD-1 的水凝胶：颈淋巴结、腹股沟淋巴结和肿瘤部位。用系统给予抗 PD-1 治疗的小鼠作为对照。所有组别均生成 Kaplan-Meier 曲线，对 L/D、CD45、CD3、CD4、CD8、TNF-α 和 IFN-y 进行体外流式细胞术染色，并进行免疫细胞激活的共培养 ELISpots 实验。
与系统给予抗 PD-1 治疗的小鼠相比，在淋巴结部位植入负载抗 PD-1 的 PCL:PEG:PCL 水凝胶的小鼠的生存结果显著改善（=0.0185）。对植入凝胶的小鼠脑组织进行流式细胞术分析和淋巴结 T 细胞共培养表明，与接受系统给予抗 PD-1 治疗的小鼠相比，IFN-y 和 TNF-α 水平升高，表明与系统治疗相比，免疫抑制的逆转程度更大。
我们的数据证明了针对 GBM 淋巴结进行局部治疗的原理。我们提出了一种替代治疗范式，用于开发新的、持续的局部免疫治疗，以消除对多次全身输注及其脱靶效应的需求。
