CAS Key Laboratory of Molecular Imaging, Beijing Key Laboratory of Molecular Imaging, the State Key Laboratory of Management and Control for Complex Systems, Institute of Automation, Chinese Academy of Sciences, Beijing, China.
The University of Chinese Academy of Sciences, Beijing, China.
J Immunother Cancer. 2022 Feb;10(2). doi: 10.1136/jitc-2021-003564.
With the rapid development of immune checkpoint inhibitors and neoantigen (NeoV)-based personalized tumor vaccines, tumor immunotherapy has shown promising therapeutic results. However, the limited efficacy of available tumor vaccines impedes the development of personalized tumor immunotherapy. In this study, we developed a novel tumor vaccine system and proposed combined therapeutic strategies for improving treatment effects.
We developed a novel tumor vaccine system comprising a newly synthesized peptidic microarchitecture (PMA) with high assembly efficacy. The PMA-trapped neoantigen vaccine was developed to codeliver tumor neoantigen and the Toll-like receptor 9 agonist CpG (NeoV), abbreviated as PMA-NeoV. A microfluidic chip was used to produce PMA particles in a uniform and precise manner. Vaccine effectiveness was investigated both in vitro and in vivo. The combined immunotherapeutic effect of PMA-NeoV with anti-programmed cell death ligand 1 antibody (aPD-L1) or with the phosphatidylinositol 3‑kinase γ (PI3Kγ) inhibitor IPI-549 was further tested in MC38 mouse tumor model.
PMA-NeoV not only promoted codelivery of the tumor vaccine but also potentiated vaccine immunogenicity. Moreover, compared with free NeoV, PMA-NeoV significantly increased the number of tumor-infiltrating lymphocytes, promoted the neoantigen-specific systemic immune response, and suppressed murine colon MC38 tumor growth. Furthermore, PMA-NeoV increased the expression of programmed cell death receptor-1 on T lymphocytes, and in combination with aPD-L1 eradicated seven of eight MC38 tumors by rescuing exhausted T lymphocytes. Moreover, we combined the PMA-NeoV with the IPI-549, a molecular switch that controls immune suppression, and found that this combination significantly suppressed tumor growth and eradicated five of eight inoculated tumors, by switching suppressive macrophages to their active state and activating T cells to prime a robust tumor immune microenvironment.
We developed a tumor vaccine delivery system and presented a promising personalized tumor vaccine-based therapeutic regimen in which a tumor vaccine delivery system is combined with an aPD-L1 or PI3Kγ inhibitor to improve tumor immunotherapy outcomes.
随着免疫检查点抑制剂和基于新抗原（NeoV）的个体化肿瘤疫苗的快速发展，肿瘤免疫治疗显示出了有前景的治疗效果。然而，现有的肿瘤疫苗疗效有限，阻碍了个体化肿瘤免疫治疗的发展。在本研究中，我们开发了一种新的肿瘤疫苗系统，并提出了联合治疗策略来提高治疗效果。
我们开发了一种新的肿瘤疫苗系统，该系统由一种具有高效组装能力的新型肽微结构（PMA）组成。PMA 捕获的新抗原疫苗被开发用于共递送肿瘤新抗原和 Toll 样受体 9 激动剂 CpG（NeoV），缩写为 PMA-NeoV。我们使用微流控芯片以均匀和精确的方式生产 PMA 颗粒。在体外和体内研究了疫苗的有效性。进一步在 MC38 小鼠肿瘤模型中测试了 PMA-NeoV 与抗程序性细胞死亡配体 1 抗体（aPD-L1）或与磷脂酰肌醇 3-激酶γ（PI3Kγ）抑制剂 IPI-549 的联合免疫治疗效果。
PMA-NeoV 不仅促进了肿瘤疫苗的共递呈，而且增强了疫苗的免疫原性。此外，与游离 NeoV 相比，PMA-NeoV 显著增加了肿瘤浸润淋巴细胞的数量，促进了新抗原特异性全身免疫反应，并抑制了小鼠结肠 MC38 肿瘤的生长。此外，PMA-NeoV 增加了 T 淋巴细胞上程序性细胞死亡受体-1 的表达，并与 aPD-L1 联合使用，通过挽救衰竭的 T 淋巴细胞，消除了 8 个 MC38 肿瘤中的 7 个。此外，我们将 PMA-NeoV 与 IPI-549 联合使用，后者是一种控制免疫抑制的分子开关，发现该联合疗法通过将抑制性巨噬细胞转换为活跃状态并激活 T 细胞来启动强大的肿瘤免疫微环境，显著抑制了肿瘤生长并消除了接种的 8 个肿瘤中的 5 个。
我们开发了一种肿瘤疫苗递送系统，并提出了一种有前途的基于个体化肿瘤疫苗的治疗方案，其中将肿瘤疫苗递送系统与 aPD-L1 或 PI3Kγ 抑制剂联合使用，以提高肿瘤免疫治疗效果。
