The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China.
Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
J Transl Med. 2023 Sep 12;21(1):619. doi: 10.1186/s12967-023-04504-w.
In situ tumor vaccine has been gradually becoming a hot research field for its advantage of achieving personalized tumor therapy without prior antigen identification. Various in situ tumor vaccine regimens have been reported to exert considerable antitumor efficacy in preclinical and clinical studies. However, the design of in situ tumor vaccines still needs further optimization and the underlying immune mechanism also waits for deeper investigation.
A novel triple in situ vaccine strategy that combining local radiation with intratumoral injection of TLR9 agonist CpG and OX40 agonist was established in this sturdy. Local and abscopal antitumor efficacy as well as survival benefit were evaluated in the bilateral tumors and pulmonary metastasis model of B16F10 melanoma. In situ vaccine-induced immune responses and immune-associated variation in tumor environment were further investigated using multiparameter flow cytometry and RNA sequencing. Base on the analysis, the RT + CpG + αOX40 triple in situ vaccine was combined with checkpoint blockade therapy to explore the potential synergistic antitumor efficacy.
Enhanced tumor suppression was observed with minimal toxicity in both treated and untreated abscopal tumors after receiving RT + CpG + αOX40 triple vaccine. The introduction of local radiation and OX40 agonist benefit more to the inhibition of local and abscopal lesions respectively, which might be partially attributed to the increase of effector memory T cells in the tumor microenvironment. Further analysis implied that the triple in situ vaccine did not only activate the microenvironment of treated tumors, with the upregulation of multiple immune-associated pathways, but also enhanced systemic antitumor responses, thus achieved superior systemic tumor control and survival benefit. Moreover, the triple in situ vaccine synergized with checkpoint blockade therapy, and significantly improved the therapeutic effect of anti-programmed cell death protein (PD)-1 antibody.
This triple combining in situ vaccine induced intensive antitumor responses, mediated effective systemic tumor control and survival benefit, and displayed impressive synergistic antitumor effect with checkpoint blockade therapy. These data preliminary confirmed the efficacy, feasibility and safety of the triple combining in situ vaccine, suggesting its great application potential as both monotherapy and a part of combined immunotherapeutic regimens in clinical scenario.
原位肿瘤疫苗因其无需预先进行抗原鉴定即可实现个体化肿瘤治疗的优势，逐渐成为研究热点。各种原位肿瘤疫苗方案在临床前和临床研究中均显示出相当大的抗肿瘤疗效。然而，原位肿瘤疫苗的设计仍需要进一步优化，其潜在的免疫机制也需要进一步研究。
本研究构建了一种新型三联原位疫苗策略，该策略将局部放疗与肿瘤内注射 TLR9 激动剂 CpG 和 OX40 激动剂相结合。在 B16F10 黑色素瘤的双侧肿瘤和肺转移模型中，评估了局部和远隔抗肿瘤疗效以及生存获益。采用多参数流式细胞术和 RNA 测序进一步研究了原位疫苗诱导的免疫反应和肿瘤微环境中的免疫相关变化。基于分析结果，将 RT+CpG+αOX40 三联原位疫苗与检查点阻断治疗相结合，以探索潜在的协同抗肿瘤疗效。
在接受 RT+CpG+αOX40 三联原位疫苗治疗后，治疗和未治疗的远隔肿瘤均观察到增强的肿瘤抑制作用，且毒性最小。局部放疗和 OX40 激动剂的引入分别更有利于局部和远隔病变的抑制，这可能部分归因于肿瘤微环境中效应记忆 T 细胞的增加。进一步分析表明，三联原位疫苗不仅激活了治疗肿瘤的微环境，上调了多个免疫相关通路，而且增强了全身抗肿瘤反应，从而实现了更好的全身肿瘤控制和生存获益。此外，三联原位疫苗与检查点阻断治疗具有协同作用，显著提高了抗程序性细胞死亡蛋白（PD）-1 抗体的治疗效果。
该三联原位疫苗诱导了强烈的抗肿瘤反应，介导了有效的全身肿瘤控制和生存获益，并与检查点阻断治疗显示出令人印象深刻的协同抗肿瘤作用。这些数据初步证实了三联原位疫苗的疗效、可行性和安全性，表明其作为单一疗法和联合免疫治疗方案的一部分在临床应用中有很大的应用潜力。
