Galunisertib

在抗逆转录病毒治疗期间，HIV-1的持续存在或许是由于其在静止的免疫细胞中建立了长寿的病毒库。近日，一篇发表在国际杂志Nature Communications上题为“TGF-β blockade drives a transitional effector phenotype in T cells reversing SIV latency and decreasing SIV reservoirs in vivo”的研究报告中，来自美国西北大学等机构的科学家们通过HIV-1的感染模型，探索抑制免疫细胞的信号通路与抗逆转录病毒疗法结合时会如何促进机体的免疫反应并帮助降低病毒的持久性。相关研究结果或有望改善科学家们对HIV-1躲避并攻击宿主机体的免疫系统背后机制的理解，同时也有望开发抵御这种毁灭性疾病的新型疗法策略。据美国CDC数据显示，目前美国大约有120万人感染了HIV，其中男性和黑人个体的感染率尤其高。尽管目前科学家们无法治愈HIV感染，但抗逆转录病毒疗法（ART）能帮助抑制病毒复制和受感染的免疫细胞，从而就能削弱患者机体的免疫系统功能并帮助改善其生活质量并延长其寿命。尽管疗法取得了一定的成功，但这种疗法必须让患者终生服用，HIV感染能通过“病毒库”（viral reservoirs）来持续存在并躲避机体的免疫反应，而在治疗期间，当病毒在免疫细胞中持续存在并处于潜伏期时就会出现这种状况。此前研究中，研究人员调查了细胞因子TGF-β对HIV-1持久性的影响，TGF-β能在HIV-1患者中高水平释放，2022年发表在JCI Insight杂志上的一项研究表明，TGF-β能抑制潜伏感染免疫细胞中的HIV的再度激活，而且阻断TGF-β信号或能促进逆转录病毒的再激活并增强机体的免疫反应。当前研究中，研究人员旨在阐明促进HIV-1病毒库背后的机制，并更好地理解TGF-β抑制剂药物对于HIV感染的免疫细胞所产生的影响。Martinelli说道，我们正在努力开发的策略就是利用这些药物让病毒重现，文章中，我们利用单细胞RNA测序和转录组学技术来研究猿类免疫缺陷病毒（SIV，simian immunodeficiency virus）感染的非人类灵长类动物模型机体的免疫细胞，SIV是一种能在非灵长类动物中引起持久性感染的逆转录病毒，这类模型能利用抗逆转录病毒疗法和随后一定剂量的galunisertib（TGF-β抑制剂）来治疗。特殊抑制性通路的释放或能促进机体抵御HIV感染的免疫反应图片来源：Nature Communications (2024). DOI:10.1038/s41467-024-45555-x研究人员发现，这种疗法策略能促进HIV-1病毒的再激活并能逆转病毒的潜伏，而且这种方法还能增强CD4 T细胞和其它免疫细胞及淋巴结中的免疫反应。这或许就是这种策略的美妙之处，其不仅能允许病毒暴露自身，还能增强宿主机体的免疫反应，因此免疫细胞就能杀死被病毒所感染的细胞，这就是从本质上减少病毒库的原因。研究人员希望TGF-β抑制剂与抗逆转录病毒疗法结合时能帮助控制HIV-1的病毒载量，从而最终允许患者停止进行抗逆转录病毒疗法，而且还不会增加患病风险。然而后期研究人员还需要进行更多的研究来理解这对于HIV持久性存在的影响。目前研究人员正在努力更好地理解其中的机制，尤其关注患者机体组织中发生的事件，在寻找HIV治愈策略的方法上，研究人员进行了大量工作，但他们的重点一直关注血液中发生了什么，因为对血液进行研究相对容易一些。然而目前有了这些新技术的加持，研究人员就能真正观察到组织中发生的事件并开展更大规模的对照研究。综上，本文研究结果表明，一种临床研究阶段的TGF-β抑制剂—galunisertib或能通过驱动T细胞向效应表型转变，从而逆转猿类免疫缺陷病毒的潜伏期并减少其病毒库的存在，同时还能在不产生毒性的情况下增强宿主机体的免疫反应。参考文献：Kim, J., Bose, D., Araínga, M. et al. TGF-β blockade drives a transitional effector phenotype in T cells reversing SIV latency and decreasing SIV reservoirs in vivo. Nat Commun 15, 1348 (2024). doi：10.1038/s41467-024-45555-x本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！

AMSTERDAM and GENEVA, Oct. 19, 2023 /PRNewswire/ -- iOnctura, a clinical-stage biotech developing selective cancer therapies against targets that play critical roles in multiple tumor survival pathways, today announces publication of new research data in the peer-reviewed journal Cancer Research, that supports a strategy of combining autotaxin inhibitor IOA-289 with TGF-β pathway inhibitor IOA-359. The research, generated in collaboration with the lab of Professor Davide Melisi, Associate Professor of Medical Oncology at the Department of Medicine, University of Verona, uncovers a central role for autotaxin in resistance to TGF–β pathway inhibition. The TGF-β pathway plays a critical role in promoting tumor aggressiveness, immune escape and resistance to therapy, which has made it an attractive target for cancer therapy. Previous attempts to interrupt TGF-β pathway signaling in cancer have been thwarted by activation of alternative resistance pathways by the tumor. By characterising these resistance mechanisms, iOnctura is designing novel, safe combination treatments that promise to override resistance. Professor Davide Melisi said: "We have uncovered a new mechanism of action for autotaxin in resistance to TGF–β pathway inhibition. Data generated by our laboratory across in vitro and in vivo models and from human clinical samples support this important finding. These findings pave the way for clinical studies combining autotaxin inhibitors with TGF-β pathway inhibitors, addressing the fibrotic barrier that protects tumors and reversing immunosuppressive mechanisms encouraging the immune system to mount an attack against cancer cells." Catherine Pickering, Chief Executive Officer of iOnctura, said: "These data support the clinical development of autotaxin inhibitors in combination with TGF-β inhibitors and standard of care for the treatment of pancreatic cancer. This validates our strategy of combining IOA-289, iOnctura's clinical stage autotaxin inhibitor, with IOA-359, our TGF–β inhibitor that we are preparing for clinical development." The published research showed that blocking the TGF–β pathway in vivo or in in vitro co-culture models increased the number of autotaxin-producing inflammatory cancer associated fibroblasts (iCAFs). The autotaxin enzyme in turn increased lysophosphatidic acid (LPA) NF- κB signaling in tumor cells which triggered treatment resistance. Specifically, NF-kB promoted CXCL1 expression and recruitment of myeloid suppressive cells (MDSCs), that limited CD8 T-cell infiltration. Adding the autotaxin inhibitor IOA-289 to TGF-β pathway inhibitor galunisertib and standard of care in PDAC-bearing mice, suppressed NF-κB signaling, reduced MDSC and increased CD8 T-cell infiltration, resulting in prolonged overall survival and curing 40% of the mice. Most importantly, pancreatic ductal adenocarcinoma (PDAC) patients treated with galunisertib from the H9H-MC-JBAJ trial, had significantly elevated levels of autotaxin compared to patients in the control arm. Median progression free survival was shorter for those with higher autotaxin levels compared to those with lower. About iOnctura iOnctura is a clinical-stage biotech developing selective cancer therapies against targets that play critical roles in multiple tumor survival pathways such as cellular proliferation; escape from immune detection; and drug resistance. iOnctura's pioneering approach to drug development is expected to offer significant clinical benefits over the traditional approach of targeting a single pathway alone. iOnctura has progressed two therapeutic candidates into mid-stage clinical development: Roginolisib (IOA-244), a first-in-class allosteric modulator of PI3Kδ; and IOA-289, a highly-selective, non-competitive autotaxin (ATX) inhibitor. IOA-359, a TGF–β pathway inhibitor is also undergoing an extensive pre-clinical program in preparation for first-in-human studies. iOnctura is backed by specialist institutional investors including M Ventures, Inkef Capital, VI Partners, Schroders Capital, and 3B Future Health Fund. iOnctura BV is headquartered in Amsterdam, The Netherlands with its wholly owned Swiss subsidiary, iOnctura SA, located in Geneva, Switzerland. About IOA-289 IOA-289 is an orally dosed molecule that has shown preclinically to inhibit the growth and proliferation of cancer cells, stimulate immune cell infiltration into tumours and inhibit the development of fibrosis. IOA-289 is being developed as a first-in-class therapy for highly fibrotic cancer indications that overexpress ATX including pancreatic, liver, colorectal, ovarian and breast cancers. A Phase 1b study of IOA-289 in combination with chemotherapy in metastatic pancreatic cancer started in Q4 2022 (NCT05586516). About IOA-359 IOA–359 is a novel oral TGF–β pathway inhibitor that will be evaluated in solid tumors. Activation of the TGF-β signaling pathway in tumors correlates with tumor aggressiveness, immune escape and resistance to therapy, making it an attractive target for cancer therapy. The inhibition of TGF-β signaling with IOA-359 is expected to attenuate cancer progression through direct effects on cancer, immune and stromal cells. By characterising the resistance mechanisms that typically arise when targeting the TGF-β pathway alone, iOnctura's data-driven precision oncology methods are being used to design novel combination treatments that promise to override tumor survival pathways. SOURCE iOnctura