Jiang Tingting, Yang Zailin, Su Qiuyu, Fang Liang, Xiang Qing, Tian Cheng, Gao Qinlin, Mao Chengde, Huang Cheng Zhi, Zuo Hua
College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China.
Department of Hematology-Oncology, Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, China.
ACS Appl Mater Interfaces. 2025 Feb 5;17(5):7353-7362. doi: 10.1021/acsami.4c18550. Epub 2025 Jan 22.
Cancer immunotherapy has revolutionized cancer treatment by harnessing the body's immune system to recognize and attack tumors. Over the past 25 years, the use of blocking antibodies has fundamentally transformed the landscape of cancer therapy. However, despite extensive research, agonist antibodies targeting costimulatory receptors such as ICOS, GITR, OX40, CD27, and 4-1BB have consistently underperformed in clinical trials over the past 15 years, failing to meet the anticipated success. One reason the agonist antibodies failed is that researchers escalated the dose to the highest tolerable level, which can lead to cell exhaustion, especially when used as a single agent. In this study, we introduced novel therapeutic agents by combining a bivalent RNA aptamer of OX40, biR, which binds to two copies of the OX40 receptor as an agonist, with CpG, a toll-like receptor 9 (TLR9) immune stimulator. These agents were specifically designed for lymphoma treatment, with the dose reduced to the lowest bioactive amount to maximize efficacy while minimizing potential side effects. BiR and CpG exhibited a dual immune activation effect and demonstrated a synergistic response even at extremely low dose of 0.32 mg/kg (5.75 μg per mouse) for biR and moderate dose of 1.39 mg/kg (25 μg per mouse) for CpG, resulting in remarkable antitumor efficacy. This effect was achieved through the promotion of intratumoral CD8+ T cell proliferation and cytokine secretion, inhibition of regulatory T cell (Treg) proliferation, and enhanced generation and proliferation of memory T cells in immune organs. The agonistic effects of these reagents led to tumor regression not only at the treated sites but also at distant, nontreated locations in the animal models. This outcome highlighted the induction of a robust systemic antitumor immune response, which effectively suppressed tumor recurrence. This combination therapy, utilizing low-dose biR alongside CpG, offers a straightforward and widely applicable strategy to enhance immune responses in cancer immunotherapy. This approach overcomes the limitations of high-dose single-agent anti-OX40 therapies (whether antibodies or aptamers), including immune cell exhaustion and diminished efficacy.
癌症免疫疗法通过利用人体免疫系统来识别和攻击肿瘤，彻底改变了癌症治疗方式。在过去25年里，阻断抗体的使用从根本上改变了癌症治疗的格局。然而，尽管进行了广泛研究，但在过去15年的临床试验中，靶向共刺激受体（如ICOS、GITR、OX40、CD27和4-1BB）的激动剂抗体一直表现不佳，未能取得预期的成功。激动剂抗体失败的一个原因是研究人员将剂量提高到了最高耐受水平，这可能导致细胞耗竭，尤其是在作为单一药物使用时。在本研究中，我们引入了新型治疗药物，将OX40的二价RNA适配体biR（作为激动剂与两个OX40受体拷贝结合）与Toll样受体9（TLR9）免疫刺激剂CpG相结合。这些药物是专门为淋巴瘤治疗设计的，剂量降低到最低生物活性量，以在最大限度减少潜在副作用的同时最大化疗效。biR和CpG表现出双重免疫激活作用，即使在biR极低剂量0.32mg/kg（每只小鼠5.75μg）和CpG中等剂量1.39mg/kg（每只小鼠25μg）时也表现出协同反应，产生了显著的抗肿瘤疗效。这种效果是通过促进肿瘤内CD8+T细胞增殖和细胞因子分泌、抑制调节性T细胞（Treg）增殖以及增强免疫器官中记忆T细胞的产生和增殖来实现的。这些试剂的激动作用不仅导致动物模型中治疗部位的肿瘤消退，还导致远处未治疗部位的肿瘤消退。这一结果突出了强大的全身抗肿瘤免疫反应的诱导，有效抑制了肿瘤复发。这种利用低剂量biR与CpG的联合疗法，为增强癌症免疫疗法中的免疫反应提供了一种简单且广泛适用的策略。这种方法克服了高剂量单药抗OX40疗法（无论是抗体还是适配体）的局限性，包括免疫细胞耗竭和疗效降低。
