Department of Radiation Oncology, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong Cancer Hospital and Institute, Jinan, Shandong, China.
Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
J Exp Clin Cancer Res. 2024 Sep 2;43(1):251. doi: 10.1186/s13046-024-03165-x.
BACKGROUND: Combining interleukin-2 (IL-2) with radiotherapy (RT) and immune checkpoint blockade (ICB) has emerged as a promising approach to address ICB resistance. However, conventional IL-2 cytokine therapy faces constraints owing to its brief half-life and adverse effects. RDB 1462, the mouse ortholog of Nemvaleukin alfa, is an engineered IL-2 with an intermediate affinity that selectively stimulates antitumor CD8 T and NK cells while limiting regulatory T cell expansion. This study aimed to evaluate the antitumor activity and mechanism of action of the combination of RDB 1462, RT, and anti-PD1 in mouse tumor models. METHODS: Two bilateral lung adenocarcinoma murine models were established using 344SQ-Parental and 344SQ anti-PD1-resistant cell lines. Primary tumors were treated with RT, and secondary tumors were observed for evidence of abscopal effects. We performed immune phenotyping by flow cytometry, analyzed 770 immune-related genes using NanoString, and performed T cell receptor (TCR) repertoire analysis. Serum pro-inflammatory cytokine markers were analyzed by 23-plex kit. RESULTS: Compared to native IL-2 (RDB 1475), RDB 1462 demonstrated superior systemic antitumoral responses, attributable, at least in part, to augmented levels of CD4 and CD8 T cells with the latter. Our findings reveal substantial reductions in primary and secondary tumor volumes compared to monotherapy controls, with some variability observed among different dosing schedules of RDB 1462 combined with RT. Blood and tumor tissue-based flow cytometric phenotyping reveals an increase in effector memory CD8 and CD4 T cells and a decrease in immunosuppressive cells accompanied by a significant increase in IL-2, IFN-γ, and GM-CSF levels in the combination group. Transcriptomic profiling and TCR sequencing reveal favorable gene expression and T cell repertoire patterns with the dual combination. Furthermore, integrating anti-PD1 therapy with RT and RDB 1462 further reduced primary and secondary tumor volumes, prolonged survival, and decreased lung metastasis. Observations of immune cell profiles indicated that RT with escalating doses of RDB 1462 significantly reduced tumor growth and increased tumor-specific immune cell populations. CONCLUSION: The addition of Nemvaleukin therapy may enhance responses to RT alone and in combination with anti-PD1.
背景：将白细胞介素-2 (IL-2) 与放射治疗 (RT) 和免疫检查点阻断 (ICB) 相结合，已成为解决 ICB 耐药性的一种很有前途的方法。然而，由于其半衰期短和副作用，传统的 IL-2 细胞因子治疗受到限制。RDB 1462 是 Nemvaleukin alfa 的鼠同源物，是一种具有中间亲和力的工程化 IL-2，可选择性刺激抗肿瘤 CD8 T 和 NK 细胞，同时限制调节性 T 细胞的扩增。本研究旨在评估 RDB 1462、RT 和抗 PD1 联合治疗在小鼠肿瘤模型中的抗肿瘤活性和作用机制。
方法：使用 344SQ-Parental 和 344SQ 抗 PD1 耐药细胞系建立了两个双侧肺腺癌小鼠模型。对原发性肿瘤进行 RT 治疗，并观察继发性肿瘤有无远隔效应。我们通过流式细胞术进行免疫表型分析，使用 NanoString 分析 770 个免疫相关基因，并进行 T 细胞受体 (TCR) 谱分析。通过 23 聚体试剂盒分析血清促炎细胞因子标志物。
结果：与天然 IL-2 (RDB 1475) 相比，RDB 1462 表现出更好的全身抗肿瘤反应，这至少部分归因于 CD4 和 CD8 T 细胞水平的增加，尤其是后者。与单药对照组相比，我们发现原发性和继发性肿瘤体积有显著减少，而不同剂量的 RDB 1462 与 RT 联合使用时，观察到一些变化。血液和肿瘤组织的流式细胞术表型分析显示，效应记忆 CD8 和 CD4 T 细胞增加，免疫抑制细胞减少，同时组合组中 IL-2、IFN-γ 和 GM-CSF 水平显著增加。转录组谱分析和 TCR 测序显示，双重联合具有有利的基因表达和 T 细胞库模式。此外，将抗 PD1 治疗与 RT 和 RDB 1462 联合使用进一步减少了原发性和继发性肿瘤体积，延长了生存期，并减少了肺转移。免疫细胞谱观察表明，随着 RDB 1462 剂量的增加，RT 显著降低了肿瘤生长并增加了肿瘤特异性免疫细胞群体。
结论：Nemvaleukin 治疗的加入可能增强 RT 单独和与抗 PD1 联合治疗的效果。
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