Neil Kevin, Génier Samuel, Poisson Marie-Ève, Douchin Julie, Giguère Hugo, Daniel Lauren, Gonzalez Melisa Farias, Huang Sally, Trinh Vincent Quoc-Huy, Tai Lee-Hwa, Rodrigue Sébastien, Millau Jean-François
TATUM bioscience, Sherbrooke, Quebec, Canada
TATUM bioscience, Sherbrooke, Quebec, Canada.
J Immunother Cancer. 2025 Aug 31;13(8):e011331. doi: 10.1136/jitc-2024-011331.
Checkpoint inhibitors revolutionized cancer treatment by potentiating antitumor immune responses. However, many patients do not respond to these therapies, often due to the lack of a pre-existing immune response against cancer cells. Developing immunotherapies that promote cancer-cell antigen recognition, and the initiation of antitumor immune responses could thus improve response rates.
We established multimodal nanofilament immunotherapy as an antigen-agnostic in situ cancer vaccine modality. Through genetic engineering of the M13 bacteriophage, nanofilaments displaying combinations of therapeutic agents were generated to guide immune recognition and response against cancer cells. TAT003 is a multimodal nanofilament combining the natural adjuvant properties of M13 with the display of both anti-PD-L1 single-chain antibody fragments (scFvs) and interleukin-2 (IL-2) molecules. It was developed to bind to the surface of cancer cells and transform them into immunological targets. After validation of TAT003's biological activities in vitro and assessment of its biodistribution, its potency was evaluated after intratumoral administration in murine syngeneic tumor models, both as a single agent and in combination with Programmed Death protein 1 (PD-1) blockade therapy. In addition, the mechanism of action of TAT003 was characterized using cytokine and immune profiling and T-cell activation assays.
TAT003 nanofilaments displayed several copies of biologically active anti-Programmed Death ligand 1 (PD-L1) and IL-2 molecules. On intratumoral injection, TAT003 attached durably to the tumor, thus limiting systemic exposure to the drug. TAT003 profoundly remodeled the tumor microenvironment of injected lesions, where it initiated a robust myeloid-cell infiltrate, and promoted the invasion of non-injected, contralateral lesions by T cells. This translated into potent regression of both injected and non-injected tumors in several cancer models, and potentiated PD-1 blockade therapy. TAT003 treatment induced the expansion of cancer-cell specific effector T cells systemically, providing a long-lasting antitumor vaccine response.
Multimodal nanofilament immunotherapy is a novel approach to mounting systemic antitumor immune responses in situ by physically attaching large immunostimulatory molecules to cancer cells. TAT003 induced marked tumor regression by leveraging synergies between therapeutic agents displayed on its surface while offering a favorable tolerability profile. The results presented here establish multimodal nanofilaments as an innovative and versatile immunotherapy platform for developing in situ cancer vaccines.
检查点抑制剂通过增强抗肿瘤免疫反应彻底改变了癌症治疗方式。然而，许多患者对这些疗法没有反应，这通常是由于缺乏针对癌细胞的预先存在的免疫反应。因此，开发能够促进癌细胞抗原识别并启动抗肿瘤免疫反应的免疫疗法可能会提高反应率。
我们建立了多模态纳米丝免疫疗法，作为一种与抗原无关的原位癌症疫苗模式。通过对M13噬菌体进行基因工程改造，生成了展示治疗剂组合的纳米丝，以引导对癌细胞的免疫识别和反应。TAT003是一种多模态纳米丝，它将M13的天然佐剂特性与抗程序性死亡配体1（PD-L1）单链抗体片段（scFvs）和白细胞介素-2（IL-2）分子的展示相结合。它的开发目的是与癌细胞表面结合并将其转化为免疫靶点。在体外验证TAT003的生物学活性并评估其生物分布后，在小鼠同基因肿瘤模型中瘤内给药后评估其效力，既作为单一药物，也与程序性死亡蛋白1（PD-1）阻断疗法联合使用。此外，使用细胞因子和免疫谱分析以及T细胞激活试验对TAT003的作用机制进行了表征。
TAT003纳米丝展示了多个具有生物活性的抗程序性死亡配体1（PD-L1）和IL-2分子拷贝。瘤内注射后，TAT003持久地附着在肿瘤上，从而限制了药物的全身暴露。TAT003深刻重塑了注射病灶的肿瘤微环境，在那里它引发了强大的髓样细胞浸润，并促进T细胞对未注射的对侧病灶的侵袭。这在多个癌症模型中转化为注射和未注射肿瘤的有效消退，并增强了PD-1阻断疗法。TAT003治疗系统性地诱导了癌细胞特异性效应T细胞的扩增，提供了持久的抗肿瘤疫苗反应。
多模态纳米丝免疫疗法是一种通过将大型免疫刺激分子物理附着于癌细胞来原位引发全身抗肿瘤免疫反应的新方法。TAT003通过利用其表面展示的治疗剂之间的协同作用诱导了显著的肿瘤消退，同时具有良好的耐受性。此处呈现的结果确立了多模态纳米丝作为开发原位癌症疫苗的创新且通用的免疫疗法平台。
