AT-108

*仅供医学专业人士阅读参考 不知道为啥，癌细胞在我心里总有一种彻底疯了十头牛也拉不回来的劲头。但就是这样的坏角色，也有方法教它们重新做胞、立地成佛。 近期，Asgard Therapeutics和隆德大学科研团队在《科学》杂志发文，研究者们开发了一种通过复制缺陷的腺病毒载体递送特定转录因子、将癌细胞原地改造为具有1型常规树突状细胞（cDC1）表型的抗原递呈细胞的方法。这不仅直接消灭了肿瘤的有生力量，还能有效改善实体瘤的抑制性微环境、募集免疫细胞，进一步加速肿瘤的灭亡并建立长期的免疫效果。 这项技术实际上就是Asgard Therapeutics的看板项目AT-108，此前在《科学·免疫学》发表的论文显示，PU.1、IRF8、BATF3（PIB）三种转录因子的组合能够在36种不同癌细胞系中诱导癌细胞转变为cDC1表型，此次发表在《科学》杂志上的成果则证实了AT-108在实验动物体内的直接效果。 癌细胞，改恶向善还不够，你也来给我打工吧！ 论文题图 自诱导性多能干细胞诞生，细胞分化就不再是单行道了。我们能够将体细胞逆转回到干细胞状态，自然也能完成不同体细胞之间的转换。 在这方面，科学家们已经成功将胰腺外分泌细胞转化成了胰岛β细胞，将心脏成纤维细胞变成心肌细胞。只要找到合适的转录因子组合，让坏细胞改邪归正，也不是梦话。 几年前，我们报道过《细胞研究》发表的一项成果，第二军医大学东方肝胆外科医院团队成功将肝癌细胞逆转为肝细胞样细胞，逆转了细胞过度增殖等恶性表型，还能协助重建肝脏、恢复肝功能。 今天说的这项研究则更进一步，直接让癌细胞转职学习免疫细胞cDC1，调头枪指旧日队友。 cDC1是树突状细胞的一个罕见亚群，表达高水平的MHC和共刺激因子CD40，主要参与抗原递呈，在维持免疫反应中有重要作用。在肿瘤中，cDC1参与T细胞的募集和激活，对抗肿瘤免疫有至关重要的作用。 此前研究者们就发现，PIB这三种转录因子的组合可以将癌细胞重编程为cDC1样抗原递呈细胞，本次实验则进一步测试了这一策略在体内直接应用的可行性。 研究者分别尝试了给小鼠移植转导了PIB的癌细胞，和给小鼠瘤内注射病毒载体递送的PIB。 实验思路 研究者测试了B16、B2905、YUMM1.7等不同免疫原性的黑色素瘤细胞系，均观察到了小鼠肿瘤消退和中位生存期的显著延长。 AT-108与免疫治疗的联用效果也非常好，特别是对免疫治疗耐药的YUMM1.7小鼠，完全缓解（CR）比例达到了100%。 AT-108可解除免疫治疗耐药 检查小鼠可见，AT-108治疗9天后，即可大幅度改善抑制性肿瘤微环境。研究者观察到了免疫细胞募集、细胞毒性T细胞群体的扩增、调节和衰竭T细胞减少。 研究者还在肿瘤微环境中观察到了三级淋巴结构（TLS）的形成，无疑是意外之喜。此前也有研究发现，三级淋巴结构与免疫治疗预后较好有关。 可见三级淋巴结构形成 AT-108实现了持久的免疫记忆，给小鼠再移植肿瘤，也能够有效避免复发。此外，AT-108还实现了显著的远隔效应，为小鼠建立了全身性的抗肿瘤免疫。 AT-108建立了持久的免疫记忆和远隔效应 目前，Asgard Therapeutics已准备提交临床试验申请，以期测试其在人体中的安全性和有效性。希望我们能早日见证结果。 奇点糕近期推出了《2024ASCO年会深度盘点》课程，为大家系统盘点了2024ASCO年会上实体瘤领域的重磅进展，让您在100分钟内迅速深入把握前沿。长按识别下图中的二维码即可购买，购买后您可以在「奇点网小程序」收听，或下载奇点网「医学奇点」苹果客户端收听。如果遇到任何技术问题大家可以戳我们下图中的客服小伙伴来解决~~ 参考资料： [1]https://www-science-org.libproxy1.nus.edu.sg/doi/10.1126/sciimmunol.add4817 本文作者丨代丝雨

Study of Asgard's new cancer immunotherapy modality demonstrates potent anti-tumor effects by turning tumor cells against themselves New data "paves the way for first-in-human trials" of lead program AT-108, which is undergoing CMC development for GMP manufacturing AT-108 is an off-the-shelf gene therapy that induces an immune response tailored against each unique patient's cancer LUND, Sweden, Sept. 5, 2024 /PRNewswire/ -- Asgard Therapeutics, a privately held biotech company pioneering in vivo direct cell reprogramming for cancer immunotherapy, today announces the publication of key proof-of-concept data supporting its lead program, AT-108, in the high-impact, peer-reviewed journal, Science[1]. Novel data shows that AT-108 reprograms tumor cells, directly within the immunosuppressed tumor microenvironment, into an immunogenic cell fate, which mounts strong anti-tumor, antigen-specific responses and durable tumor shrinkage even upon metastatic rechallenge. The study, co-led by Asgard Therapeutics and the Pereira Lab at Lund University, demonstrated efficient dendritic cell reprogramming in mouse models resistant to checkpoint blockade treatment and patient-derived tumor samples. The data provides preclinical proof-of-concept for an off-the-shelf, yet tumor-specific, first-in-class cancer immunotherapy, paving the way for first-in-human trials of AT-108. Reprogramming tumor cells so that they are converted into antigen-presenting dendritic cells "elicits systemic and long-term antitumor immunity," stated the authors of the study. The study entitled, In vivo dendritic cell reprogramming for cancer immunotherapy, also shows the systematic selection of an optimal delivery system for expression of key reprogramming factors in the tumor, which led to the nomination of Asgard's lead program. Publication of the study follows Asgard's €30 million Series A financing to advance its cell reprogramming platform, as the Company continues to make significant progress in preparing AT-108 for clinical development. Asgard recently commenced activities to establish CMC process for scale-up manufacturing of GMP-grade AT-108 for Phase I/II trials. Cristiana Pires, Co-founder and Chief Executive Officer of Asgard Therapeutics, said: "This study demonstrates that Asgard's platform converts tumor cells into dendritic cells within living organisms – and not just in vitro. This publication in such a high-impact journal as Science demonstrates the enormous potential of our cell reprogramming approach and the quality of our scientific methodology. Together with ongoing work to establish manufacturing process for lead program, AT-108, we are focused on completing IND-enabling studies, including pharmacokinetic and GLP toxicology studies, in advance of our near-term objective of filing a clinical trial application for testing of AT-108 in patients." Co-Lead author Fábio Rosa, PhD, Co-founder and Head of Research of Asgard Therapeutics, commented: "We are very pleased with the publication of this joint effort with Filipe Pereira and his team at Lund University, as it represents a significant milestone for the company ahead of clinical development. The new findings support the selection of a replication-deficient adenoviral vector for AT-108, demonstrating its proof-of-concept and prompting the start of advanced preclinical development. We were very excited to see that AT-108 induces complete tumor regressions and protects mice from tumor re-challenge – even in the metastatic setting." The reprogramming of tumor cells to cDC1-like cells restores tumor antigen presentation and remodels the tumor microenvironment, reducing exhausted and regulatory populations, and promoting infiltration and activation of cytotoxic T cells. Importantly, in vivo dendritic cell reprogramming induces complete responses as a monotherapy and synergizes with immune checkpoint blockade in aggressive immune-deserted tumor models. The finding of an abscopal effect on distant non-treated tumors highlights that benefits extend beyond the primary tumor. Alongside the Pereira Lab from where the technology spun-out, Asgard collaborated with additional researchers at Lund University, Inge Marie Svane and Özcan Met from CCIT-DK, Denmark, and Irina Agarkova and team from InSphero, Switzerland to complete the study. The Company's research has received support from Eurostars-2 Joint Program with co-funding from the European Union's Horizon 2020 research and innovation program, Sweden's Innovation Agency, E!115376 REPRINT Grant 2021-03371, and the Strategic innovation programs, Swelife. Notes to Editors About Asgard Therapeutics Asgard Therapeutics is a privately held preclinical stage biotech company pioneering in vivo direct cell reprogramming for cancer immunotherapy. The company builds on ground-breaking and proprietary reprogramming technologies to develop gene therapy products designed to set in motion efficient and personalized immune responses. Backed by Johnson & Johnson Innovation – JJDC, Inc., RV Invest, Novo Holdings, Boehringer Ingelheim Venture Fund, and Industrifonden, Asgard Therapeutics aims to establish a pipeline of off-the shelf cancer immunotherapies that trigger personalized anti-cancer immune responses for the benefit of cancer patients in need. For more information, please visit: . About AT-108 AT-108 is a first-in-class, off-the-shelf gene therapy that directly reprograms tumor cells into a rare subset of dendritic cells critical for mounting efficient cytotoxic T cell responses, cDC1 cells (conventional dendritic cells type 1), which forces the tumor cells to present their tumor antigens, ultimately leading to a personalized anti-tumor immune response. It is based on a replication-deficient adenoviral vector that delivers three proprietary reprogramming factors into tumor cells, rewiring their gene expression signatures and thus "programming" them to become antigen-presenting cDC1-like cells. 1. SOURCE Asgard Therapeutics