It is hypothesized that OGF biotherapy may be safely administered in combination with gemcitabine to individuals with unresectable pancreatic cancer. The study includes two aims, the first is to evaluate the safety and toxicity of the combination of OGF and gemcitabine chemotherapy. The second aim of the trial is to study the efficacy of OGF and gemcitabine when used in combination.

开始日期2009-01-01

申办/合作机构

Hershey Medical Center

[+2]

NCT00706576 / Completed临床1期IIT

Treatment of Unresectable Hepatocellular Cancer With Opioid Growth Factor: a Phase I Study

Hepatocellular cancer, one of the world's most deadly tumors, is associated with chronic liver injury and cirrhosis. With the increasing occurrence of viral hepatitis, the incidence of this cancer in the United States continues to rise. Surgical resection offers the only hope for cure; but sadly, few patients are candidates for surgery due to their liver disease. Liver transplant can be an effective treatment, but due to a scarcity of organs, most patients do not qualify for this therapy either. Patients who are not candidates for these procedures have very few therapeutic options as chemotherapy and radiation have little efficacy. New therapies are desperately needed.
Opioid Growth Factor (OGF) inhibits the growth of a number of cancer lines in vitro by a receptor-mediated mechanism. In pancreatic cancer this phenomenon has been well defined not only in vitro but in animal models. Based upon these findings, a phase I trial has been conducted demonstrating that OGF can be administered safely to patients with pancreatic cancer. The investigators hypothesize that administration of OGF will inhibit the course of cancer progression in human subjects with unresectable hepatocellular cancer and cirrhosis. As a first step in testing this hypothesis, the investigators propose a phase I trial to study the toxicity and pharmacokinetics of this therapy in patients suffering from inoperable hepatocellular cancer and cirrhosis.

开始日期2008-06-01

申办/合作机构

University of Missouri

[+1]

NCT00982696 / Terminated临床2期IIT

Treatment of Advanced Head and Neck Cancer With Opioid Growth Factors: Phase II

This study will investigate the efficacy of opioid growth factor (OGF) on tumor size and survival in patients with head and neck cancer who have failed standard therapy.

开始日期2008-02-01

申办/合作机构

Hershey Medical Center

100 项与甲硫氨酸脑啡肽相关的临床结果

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100 项与甲硫氨酸脑啡肽相关的转化医学

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100 项与甲硫氨酸脑啡肽相关的专利（医药）

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2,913

项与甲硫氨酸脑啡肽相关的文献（医药）

2024-11-01·MOLECULAR PHARMACOLOGY

Ketamine and Major Ketamine Metabolites Function as Allosteric Modulators of Opioid Receptors

Article

作者: Devi, Lakshmi A ; Margolis, Elyssa B ; Fricker, Lloyd D ; Gomes, Ivone ; Gupta, Achla

Ketamine is a glutamate receptor antagonist that was developed over 50 years ago as an anesthetic agent. At subanesthetic doses, ketamine and some metabolites are analgesics and fast-acting antidepressants, presumably through targets other than glutamate receptors. We tested ketamine and its metabolites for activity as allosteric modulators of opioid receptors expressed as recombinant receptors in heterologous systems and with native receptors in rodent brain; signaling was examined by measuring GTP binding, β-arrestin recruitment, MAPK activation, and neurotransmitter release. Although micromolar concentrations of ketamine alone had weak agonist activity at μ opioid receptors, the combination of submicromolar concentrations of ketamine with endogenous opioid peptides produced robust synergistic responses with statistically significant increases in efficacies. All three opioid receptors (μ, δ, and κ) showed synergism with submicromolar concentrations of ketamine and either methionine-enkephalin (Met-enk), leucine-enkephalin (Leu-enk), and/or dynorphin A17 (Dyn A17), albeit the extent of synergy was variable between receptors and peptides. S-ketamine exhibited higher modulatory effects compared with R-ketamine or racemic ketamine, with ∼100% increase in efficacy. Importantly, the ketamine metabolite 6-hydroxynorketamine showed robust allosteric modulatory activity at μ opioid receptors; this metabolite is known to have analgesic and antidepressant activity but does not bind to glutamate receptors. Ketamine enhanced potency and efficacy of Met-enkephalin signaling both in mouse midbrain membranes and in rat ventral tegmental area neurons as determined by electrophysiology recordings in brain slices. Taken together, these findings support the hypothesis that some of the therapeutic effects of ketamine and its metabolites are mediated by directly engaging the endogenous opioid system. SIGNIFICANCE STATEMENT: This study found that ketamine and its major biologically active metabolites function as potent allosteric modulators of μ, δ, and κ opioid receptors, with submicromolar concentrations of these compounds synergizing with endogenous opioid peptides, such as enkephalin and dynorphin. This allosteric activity may contribute to ketamine's therapeutic effectiveness for treating acute and chronic pain and as a fast-acting antidepressant drug.

2024-09-01·EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Modulation of endogenous opioid signaling by inhibitors of puromycin-sensitive aminopeptidase

Article

作者: Vince, Robert ; Singh, Rohit ; More, Swati S ; Dobariya, Prakashkumar ; Xie, Jiashu ; Williams, Jessica ; Rothwell, Patrick E ; Jiang, Rongrong ; Hanak, Filip

The endogenous opioid system regulates pain through local release of neuropeptides and modulation of their action on opioid receptors. However, the effect of opioid peptides, the enkephalins, is short-lived due to their rapid hydrolysis by enkephalin-degrading enzymes. In turn, an innovative approach to the management of pain would be to increase the local concentration and prolong the stability of enkephalins by preventing their inactivation by neural enkephalinases such as puromycin-sensitive aminopeptidase (PSA). Our previous structure-activity relationship studies offered the S-diphenylmethyl cysteinyl derivative of puromycin (20) as a nanomolar inhibitor of PSA. This chemical class, however, suffered from undesirable metabolism to nephrotoxic puromycin aminonucleoside (PAN). To prevent such toxicity, we designed and synthesized 5'-chloro substituted derivatives. The compounds retained the PSA inhibitory potency of the corresponding 5'-hydroxy analogs and had improved selectivity toward PSA. In vivo treatment with the lead compound 19 caused significantly reduced pain response in antinociception assays, alone and in combination with Met-enkephalin. The analgesic effect was reversed by the opioid antagonist naloxone, suggesting the involvement of opioid receptors. Further, PSA inhibition by compound 19 in brain slices caused local increase in endogenous enkephalin levels, corroborating our rationale. Pharmacokinetic assessment of compound 19 showed desirable plasma stability and identified the cysteinyl sulfur as the principal site of metabolic liability. We gained additional insight into inhibitor-PSA interactions by molecular modeling, which underscored the importance of bulky aromatic amino acid in puromycin scaffold. The results of this study strongly support our rationale for the development of PSA inhibitors for effective pain management.

2024-09-01·JOURNAL OF CONTROLLED RELEASE

A nanomedicine approach for the treatment of long-lasting pain

Article

作者: Benhamou, Dan ; Sitbon, Philippe ; Mougin, Julie ; Cailleau, Catherine ; Prades, Lucas ; Gobeaux, Frédéric ; Feng, Jiao ; Couvreur, Patrick ; Hazam, Hadjer ; Lepetre-Mouelhi, Sinda ; Hamdi, Leïla

This study explores the potential of a nanomedicine approach, using Leu-enkephalin-squalene nanoparticles (LENK-SQ NPs) for managing long-lasting pain. It was observed that the nanomedicine significantly improved the pharmacological efficacy of the Leu-enkephalin, a fast metabolized neuropeptide, in a rat model of acute inflammatory pain, providing local analgesic effect, while minimizing potential systemic side effects by circumventing central nervous system. The LENK-SQ NPs were tested in a rat model of postoperative pain (Brennan's rodent plantar incision model) using continuous infusion via Alzet® pump, with an additional bolus injection. The analgesic activity was assessed through stimulus-evoked methods, such as the von Frey and Hargreaves tests. Both mechanical and thermal hyperalgesia were significantly reduced at days 2 and 3 post-incision. An additional pharmacokinetic study was conducted, showing that LENK-SQ NPs allowed a sustained circulation of the neuropeptide under its prodrug form. On the other hand, the biodistribution of fluorescently labelled LENK-SQ NPs revealed their selective accumulation in the incised paw within the first hour post administration, followed by a disassembly of the NPs, starting 24 h later. The study proposes the following multi-step mechanism for the anti-nociceptive pharmacological activity of LENK-SQ NPs: (i) protection of the neuropeptide from metabolization into the bloodstream, (ii) targeted accumulation of the nanoparticles within the incised painful tissue and (iii) gradual release of LENK at the onset of the inflammatory process, leading to the observed analgesic activity.

项与甲硫氨酸脑啡肽相关的新闻（医药）

2024-09-02

·生物探索

Sci Trans Med丨李珂团队合作揭示葡萄糖转运体GLUT10在CD8+ T细胞抗肿瘤免疫中的关键作用

引言 CD8+ T细胞在接受抗原信号刺激后可快速增殖活化为效应T细胞来发挥抗肿瘤免疫功能【1, 2】。研究表明，CD8+ T细胞在活化初期会经历代谢重编程，增强细胞内产能和生物合成来维持CD8+ T细胞快速增殖和抗肿瘤功能【2, 3】，而糖酵解在CD8+ T细胞活化中发挥重要作用【4】。葡萄糖摄取是细胞糖代谢的第一步，体细胞的糖摄取主要由葡萄糖转运体家族——GLUT家族（glucose transport family）所介导。既往研究发现，葡萄糖转运体1（glucose transport 1, GLUT1）主要介导CD4+ T细胞的糖摄取和糖代谢，对CD4+ T细胞活化、增殖和抗炎反应至关重要，而GLUT1在CD8+ T细胞中缺失并不影响CD8+ T细胞的活化和效应功能【5】。因此，长期以来CD8+ T细胞活化过程中介导葡萄糖摄取的转运体并不清楚，探究CD8+ T细胞活化及抗肿瘤免疫过程中介导其糖摄取的关键转运体及机制对提高CD8+ T细胞介导的抗肿瘤免疫十分重要。 2024年8月28日，中国医学科学院、北京协和医学院医药生物技术研究所李珂团队在Science Translational Medicine杂志上发表题为Activation and antitumor immunity of CD8+ T cells are supported by the glucose transporter GLUT10 and disrupted by lactic acid的研究论文。研究发现GLUT10（glucose transport 10）是CD8+ T细胞活化及发挥抗肿瘤免疫功能所依赖的主要葡萄糖转运体，而肿瘤微环境中堆积的乳酸能够抑制GLUT10功能，妨碍CD8+ T细胞糖摄取，从而抑制CD8+ T细胞的抗肿瘤活性。为寻找CD8+ T细胞活化及抗肿瘤过程中介导葡萄糖摄取的关键转运体，作者首先检测静息状态下CD8+ T细胞、活化的CD8+ T细胞以及肿瘤微环境中CD8+ T细胞中GLUT家族的表达水平，发现与静息状态下CD8+ T细胞相比，活化的CD8+ T细胞及肿瘤微环境中CD8+ T细胞中GLUT10 表达水平明显升高。通过对消化道癌患者多色免疫荧光染色，作者发现GLUT10主要表达在CD8+ T细胞，而GLUT1主要表达在肿瘤细胞（图1）。图1. 多色免疫荧光检测GLUT1和GLUT10在肿瘤细胞和CD8+ T细胞的表达（Credit: Science Translational Medicine）为阐明GLUT10在CD8+ T细胞中的作用，作者构建了T细胞上特异性敲除GLUT10的转基因小鼠（CD4CreGlut10fl/fl），发现T细胞上特异性敲除Glut10明显抑制CD8+ T细胞糖摄取能力、活化及抗肿瘤活性。RNA-seq结果显示，T细胞上特异性敲除GLUT10能够明显抑制CD8+ T细胞中糖酵解信号通路、PI3K/mTOR增殖信号通路的富集。接下来作者探究增加肿瘤微环境中糖含量对于CD8+ T细胞的活性和功能影响，发现使用GLUT1抑制剂、敲除肿瘤细胞上GLUT1的表达来抑制肿瘤细胞的糖摄取或外源补充葡萄糖均不能恢复CD8+ T细胞抗肿瘤活性。因此，作者猜测可能是肿瘤微环境存在某种代谢物影响CD8+ T细胞糖摄取和杀伤活性。通过对血清和肿瘤间质液的代谢组学分析，研究发现，乳酸在肿瘤间质液中的水平明显升高。体内外实验证实抑制肿瘤细胞乳酸的分泌能够恢复CD8+ T细胞糖摄取及肿瘤杀伤活性，而乳酸主要是与通过CD8+ T细胞上GLUT10结合来抑制GLUT10的糖摄取功能，降低CD8+ T细胞的抗肿瘤活性。作者进一步解析了乳酸与GLUT10结合的主要区域为GLUT10的第六段胞内域（IR6），针对GLUT10与乳酸相互作用的结构域，研究团队设计了模拟肽来打断GLUT10与乳酸相互作用。研究发现，模拟肽不仅可以打断GLUT10与乳酸结合，而且能够恢复CD8+ T细胞糖摄取及杀伤肿瘤活性。最终作者在动物模型上评价GLUT1抑制剂WZB117或PD-1单抗与模拟肽PG10.3联用均有较好的抗肿瘤效果。综上所述，该研究揭示了CD8+ T细胞抗肿瘤免疫过程中主要依赖的葡萄糖转运体为GLUT10，通过靶向乳酸与GLUT10相互作用，解除乳酸对GLUT10功能抑制可以恢复CD8+ T细胞抗肿瘤活性，具有较好的抗肿瘤免疫治疗前景。参考文献 1. A. V. Menk, N. E. Scharping, R. S. Moreci, X. Zeng, C. Guy, S. Salvatore, H. Bae, J. Xie, H. A. Young, S. G. Wendell, G. M. Delgoffe, Early TCR Signaling Induces Rapid Aerobic Glycolysis Enabling Distinct Acute T Cell Effector Functions. Cell Rep 22, 1509-1521 (2018). 2. I. Hamaidi, L. Zhang, N. Kim, M. H. Wang, C. Iclozan, B. Fang, M. Liu, J. M. Koomen, A. E. Berglund, S. J. Yoder, J. Yao, R. W. Engelman, B. C. Creelan, J. R. Conejo-Garcia, S. J. Antonia, J. J. Mule, S. Kim, Sirt2 Inhibition Enhances Metabolic Fitness and Effector Functions of Tumor-Reactive T Cells. Cell Metab 32, 420-436 e412 (2020). 3. E. H. Ma, M. J. Verway, R. M. Johnson, D. G. Roy, M. Steadman, S. Hayes, K. S. Williams, R. D. Sheldon, B. Samborska, P. A. Kosinski, H. Kim, T. Griss, B. Faubert, S. A. Condotta, C. M. Krawczyk, R. J. DeBerardinis, K. M. Stewart, M. J. Richer, V. Chubukov, T. P. Roddy, R. G. Jones, Metabolic Profiling Using Stable Isotope Tracing Reveals Distinct Patterns of Glucose Utilization by Physiologically Activated CD8(+) T Cells. Immunity 51, 856-870 e855 (2019). 4. M. Z. Madden, J. C. Rathmell, The Complex Integration of T-cell Metabolism and Immunotherapy. Cancer Discov 11, 1636-1643 (2021). 5. A. N. Macintyre, V. A. Gerriets, A. G. Nichols, R. D. Michalek, M. C. Rudolph, D. Deoliveira, S. M. Anderson, E. D. Abel, B. J. Chen, L. P. Hale, J. C. Rathmell, The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab 20, 61-72 (2014). http://doi.org/10.1126/scitranslmed.adk7399 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

免疫疗法

2024-07-21

·生物探索

Nat Neurosci | 从分子到行为：创新基因编码荧光探针技术解密阿片类神经肽动态

引言阿片类神经肽在调节疼痛、奖赏和厌恶等生理过程中发挥着关键作用，具有重要的临床相关性。这类神经肽包括强啡肽、脑啡肽和β-内啡肽等，它们通过激活κ、δ和μ阿片受体来发挥作用。然而，由于缺乏能够精确解析阿片类神经肽复杂动态特征的实验工具，相关研究长期受到限制。传统的检测方法如微透析和免疫组织化学等存在时空分辨率低、无法实时检测等缺点。因此，开发具有高时空分辨率的阿片类神经肽检测技术对于深入了解其在生理和病理条件下的功能至关重要。 2024年7月15日，加州大学戴维斯分校Lin Tian实验室与华盛顿大学Michael R. Bruchas实验室和加州大学圣地亚哥分校Matthew R. Banghart实验室在Nature Neuroscience杂志在线发表了题为"Unlocking opioid neuropeptide dynamics with genetically encoded biosensors"的研究论文，报道了一种基于基因编码的荧光探针技术，可用于实时监测内源性阿片类神经肽的动态变化。该研究团队开发了一系列基于κ、δ和μ阿片受体的基因编码荧光探针，分别命名为κLight、δLight和μLight。这些探针的设计原理是将环形置换绿色荧光蛋白(cpGFP)插入到相应阿片受体的第三胞内环中。当阿片类神经肽与受体结合时，会引起受体构象变化，进而导致荧光强度的改变。研究人员首先对这些探针在哺乳动物HEK293T细胞和离体神经元中的药理学特性进行了表征。结果显示，这些探针对相应的内源性阿片类肽具有高度的选择性和灵敏度。例如，κLight对强啡肽A1-13的半数有效浓度(EC50)达到了89.8 pM，而δLight对甲硫氨酸脑啡肽的EC50为6.5 nM。（Credit: Nature Neuroscience）随后，研究人员利用κLight成功识别了在脑切片中触发内源性阿片类肽释放的电刺激参数。他们发现，在海马CA3区域，15次1秒50Hz的电刺激可以诱发显著的κLight荧光信号增强，这一反应可以被κ受体拮抗剂nor-BNI所抑制。更令人兴奋的是，研究人员利用光遗传学技术结合κLight，实现了在活体小鼠中对特定神经环路阿片类肽释放的检测。他们在基底外侧杏仁核(BLA)表达光敏通道蛋白ChRimson，同时在伏隔核壳部(NAcSh)表达κLight。通过光刺激BLA神经元的轴突终末，成功诱发和检测到了NAcSh中的强啡肽释放, 该释放并没有在强啡肽敲除的动物里检测到，进一步证明了在体内κLight对于强啡肽的特异性。此外，研究人员还观察到在恐惧和奖赏条件下，不同脑区阿片类肽的释放动态存在差异。例如，在恐惧条件学习过程中，κLight在背侧和腹侧伏隔核壳部均检测到了强啡肽的释放，但背侧区域的信号更强。而在奖赏相关的巴甫洛夫条件学习中，κLight检测到伏隔核中强啡肽的释放随着学习进程逐渐增强。这项研究的主要发现包括: 1. 成功开发了基于κ、δ和μ阿片受体的高灵敏度荧光探针，实现了对内源性阿片类肽的亚纳摩尔级别检测； 2. 揭示了脑切片中内源性阿片类肽的释放和扩散特征，测定了强啡肽在纹状体中的有效扩散系数为1.4 μm2/s； 3. 在活体动物中实现了光遗传刺激诱发的阿片类肽释放的实时检测，展示了特定神经环路中的肽能信号传递； 4. 观察到恐惧和奖赏条件下不同脑区阿片类肽释放的动态变化，为理解这些神经肽在情绪和动机行为中的作用提供了新的见解。综上所述，这项研究提供了一套强大的工具，可用于实时监测内源性阿片类神经肽的动态变化。这些新型探针为深入研究阿片类神经肽在各种生理和病理条件下的功能开辟了新的途径。它们有望帮助科研人员更好地理解阿片类神经肽在疼痛、应激、奖赏和药物成瘾等过程中的作用机制。该研究成果为阿片类神经肽的研究领域带来了突破性进展。这些高时空分辨率的荧光探针不仅可以用于基础研究，还可能为开发新的疼痛治疗策略和解决阿片类药物滥用问题提供新的思路。例如，通过实时监测内源性阿片类肽的释放，可以更精确地评估不同疼痛治疗方法的效果，或者研究药物成瘾过程中大脑奖赏系统的变化。未来，研究人员计划进一步优化这些探针，提高其灵敏度和动态范围。他们还希望将这种技术扩展到其他类型的神经肽，如催产素和血管加压素等。此外，结合光遗传学和基因编辑技术，这些探针有望用于构建复杂的神经环路图谱，揭示不同神经肽系统之间的相互作用。这项技术的发展为神经科学研究提供了一个强大的新工具，有望推动阿片类神经肽相关疾病的诊断和治疗取得重大进展，并深化我们对大脑功能的理解。参考文献 https://www.nature.com/articles/s41593-024-01697-1 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

2023-01-17

·生物谷

《自然·免疫学》：找到“反卷”T细胞！缺氧可让耗竭T细胞产生免疫抑制效果

这项研究发现肿瘤中终末耗竭的T细胞不仅表现出功能障碍，还会表现出免疫抑制的作用。肿瘤的缺氧环境可以诱导tTex细胞上CD39的表达，进而参与腺苷代谢来制造免疫抑制微环境。当T细胞加班加点地对抗肿瘤时，它们会进入一种精疲力竭的状态（T细胞耗竭），不再正常工作。在之前的认知中，大家大多觉得T细胞只是自身“躺平”了而已，而最近的这项研究发现，在肿瘤缺氧的环境中，终末耗竭的T细胞还会“化身叛徒”，阻止其他的T细胞“卷”。来自美国匹兹堡大学免疫学系的Greg M. Delgoffe团队在《自然·免疫学》期刊发表重要研究成果，他们发现缺氧可以增强终末耗竭T细胞上CD39的表达，从而制造出一种免疫抑制微环境，来抑制其他T细胞的功能[1]。这一发现拓展了我们对耗竭性T细胞的认知，并可能为肿瘤免疫治疗带来新的思路。论文首页截图在肿瘤中，T细胞会表现出一种“耗竭”的异常功能状态。先前的研究已经知道，CD8 T细胞的耗竭不是一个单一的状态，其中表达转录因子TCF-1的耗竭前体T细胞（pTex）具有自我更新能力，并可以进一步变为不表达TCF-1的终末耗竭T细胞（tTex）[2]。肿瘤中tTex细胞的富集往往和较差的免疫检查点抑制剂治疗反应相关[3,4]。之前的研究大多认为这是T细胞功能丧失的结果，而Greg M. Delgoffe团队却猜测，会不会不仅是T细胞本身耗竭了，它们还促进了免疫抑制性肿瘤微环境的形成呢？大家知道，Treg细胞发挥着免疫抑制功能。Greg M. Delgoffe团队发现，随着CD8 T细胞走向终末耗竭，tTex细胞会倾向于上调Treg细胞相关的基因。为了确定肿瘤中的tTex细胞是否确实具有抑制功能，研究人员将B16-F10黑色素瘤小鼠的Treg细胞以及耗竭性T细胞分选出来，与其他T细胞进行共培养。结果发现，tTex和Treg细胞对共同培养的T细胞有着类似的抑制作用，而pTex细胞则没有表现出抑制能力。终末耗竭T细胞（Tex）和Treg细胞对共培养的T细胞有着类似的抑制作用，而耗竭前体T细胞（pTex）没有表现出抑制能力。此外，研究人员还在其他免疫治疗不敏感的肿瘤模型（例如Clone24，MEER模型）中验证了这一发现。然而有趣的是，从免疫检查点抑制剂治疗敏感的MC38结肠癌小鼠肿瘤中分离的tTex并没有表现出抑制功能。这些数据提示，tTex细胞所处的环境可能对它的抑制功能有着关键作用。那么，tTex细胞是如何发挥抑制功能的呢？ Treg细胞可以通过分泌IL-10来发挥抑制作用，先前也有研究发现了一群分泌IL-10的CD8 T细胞[5]。然而Il10敲除的tTex细胞与野生型tTex细胞有着相似的抑制功能，说明tTex细胞并非通过IL-10发挥抑制功能。先前的研究还表明，Treg细胞上高表达的CD39和CD73可以将凋亡细胞释放的ATP水解为腺苷，从而发挥抑制功能[6]。在人和小鼠的肿瘤中，CD39可以作为终末耗竭CD8 T细胞的标志分子[7, 8]。Greg M. Delgoffe团队发现，tTex细胞上CD39的表达水平与其抑制功能表现出正相关。 tTex细胞上CD39的表达水平与抑制能力正相关。但是与Treg细胞不同的是，CD8 tTex细胞虽然会高表达CD39，但并不会同时高表达CD73。因此，研究人员推测tTex细胞上表达的CD39，可能和周围其他细胞上表达的CD73一起产生腺苷，从而制造免疫抑制的微环境。为了证明这一猜测，研究人员从CD73敲除小鼠中分离出T细胞和抗原呈递细胞，并与野生型tTex细胞共培养，结果发现tTex细胞的抑制能力显著降低。此外，敲除T细胞的CD39可以使tTex细胞的抑制功能完全丧失，并可以减缓肿瘤生长。在效应T细胞中过表达CD39可以抑制自身和邻近T细胞的功能。敲除T细胞上的CD39（Entpd基因）可以使tTex细胞的抑制功能完全丧失。基于这些发现，研究人员又进一步探究了靶向CD39在肿瘤治疗中的作用。他们发现，CD8 T细胞中CD39的缺失本身可以在一定程度上减缓肿瘤进展。更有意思的是，在CD39缺失的情况下，免疫检查点抑制剂的治疗效果得到显著增强，肿瘤浸润T细胞的效应功能也得到显著提高。这提示靶向抑制CD39介导的免疫抑制通路可以重新激活抗肿瘤免疫反应，并可增强肿瘤免疫治疗的效果。敲除CD39可以增强免疫检查点抑制剂的治疗效果。先前的研究表明，缺氧、氧化应激和促炎介质均可诱导CD39的表达[9]。Greg M. Delgoffe团队发现，相比于pTex细胞，tTex细胞经历了明显的缺氧，且缺氧程度与细胞表面CD39的表达正相关。体外培养也发现，在缺氧条件下培养的CD8 T细胞表达更高水平的CD39，而敲除缺氧诱导因子-1（Hif1α）可以阻止CD39的升高。 CD39的表达与缺氧程度正相关。前面我们提到MC38肿瘤浸润的tTex细胞大多是非抑制性的，而这些tTex细胞大多也低表达CD39，且与B16-F10等其他肿瘤相比，这些tTex细胞所处环境的缺氧程度也更低。此外，敲除肿瘤细胞的线粒体复合体I亚基Ndufs4可以显著降低肿瘤缺氧程度，在Ndufs4敲除的B16-F10肿瘤中浸润的tTex细胞也表现出较低的CD39表达。 Greg M. Delgoffe团队之前的研究发现，阿昔替尼和二甲双胍可以使缺氧肿瘤对免疫检查点抑制剂变得敏感。在本研究中，他们进一步发现阿昔替尼和二甲双胍可以降低肿瘤缺氧程度，并可降低tTex细胞上CD39的表达水平，进而降低tTex细胞的免疫抑制功能。这些结果提示，改善肿瘤的缺氧环境，也可能成为增强肿瘤免疫反应的潜在新策略。总的来说，这项研究发现肿瘤中终末耗竭的T细胞不仅表现出功能障碍，还会表现出免疫抑制的作用。肿瘤的缺氧环境可以诱导tTex细胞上CD39的表达，进而参与腺苷代谢来制造免疫抑制微环境。通过靶向肿瘤缺氧或CD39的活性，可以减弱tTex细胞的抑制功能，这一发现可能为肿瘤免疫治疗带来新的思路。参考文献 [1] P.D.A. Vignali, K. DePeaux, M.J. Watson, C. Ye, B.R. Ford, K. Lontos, N.K. McGaa, N.E. Scharping, A.V. Menk, S.C. Robson, A.C. Poholek, D.B. Rivadeneira, G.M. Delgoffe, Hypoxia drives CD39-dependent suppressor function in exhausted T cells to limit antitumor immunity, Nat Immunol, (2022). [2] I. Siddiqui, K. Schaeuble, V. Chennupati, S.A. Fuertes Marraco, S. Calderon-Copete, D. Pais Ferreira, S.J. Carmona, L. Scarpellino, D. Gfeller, S. Pradervand, S.A. Luther, D.E. Speiser, W. Held, Intratumoral Tcf1(+)PD-1(+)CD8(+) T Cells with Stem-like Properties Promote Tumor Control in Response to Vaccination and Checkpoint Blockade Immunotherapy, Immunity, 50 (2019) 195-211.e110. [3] B.C. Miller, D.R. Sen, R. Al Abosy, K. Bi, Y.V. Virkud, M.W. LaFleur, K.B. Yates, A. Lako, K. Felt, G.S. Naik, M. Manos, E. Gjini, J.R. Kuchroo, J.J. Ishizuka, J.L. Collier, G.K. Griffin, S. Maleri, D.E. Comstock, S.A. Weiss, F.D. Brown, A. Panda, M.D. Zimmer, R.T. Manguso, F.S. Hodi, S.J. Rodig, A.H. Sharpe, W.N. Haining, Subsets of exhausted CD8(+) T cells differentially mediate tumor control and respond to checkpoint blockade, Nat Immunol, 20 (2019) 326-336. [4] M. Sade-Feldman, K. Yizhak, S.L. Bjorgaard, J.P. Ray, C.G. de Boer, R.W. Jenkins, D.J. Lieb, J.H. Chen, D.T. Frederick, M. Barzily-Rokni, S.S. Freeman, A. Reuben, P.J. Hoover, A.C. Villani, E. Ivanova, A. Portell, P.H. Lizotte, A.R. Aref, J.P. Eliane, M.R. Hammond, H. Vitzthum, S.M. Blackmon, B. Li, V. Gopalakrishnan, S.M. Reddy, Z.A. Cooper, C.P. Paweletz, D.A. Barbie, A. Stemmer-Rachamimov, K.T. Flaherty, J.A. Wargo, G.M. Boland, R.J. Sullivan, G. Getz, N. Hacohen, Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma, Cell, 175 (2018) 998-1013.e1020. [5] Y. Zhao, H. Zhao, Y. Sun, J. Hao, X. Qi, X. Zhou, Z. Wu, P. Wang, S.M. Kaech, C.T. Weaver, R.A. Flavell, L. Zhao, Z. Yao, Z. Yin, IL-4 induces a suppressive IL-10-producing CD8+ T cell population via a Cdkn2a-dependent mechanism, J Leukoc Biol, 94 (2013) 1103-1112. [6] S. Deaglio, K.M. Dwyer, W. Gao, D. Friedman, A. Usheva, A. Erat, J.F. Chen, K. Enjyoji, J. Linden, M. Oukka, V.K. Kuchroo, T.B. Strom, S.C. Robson, Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression, J Exp Med, 204 (2007) 1257-1265. [7] P.K. Gupta, J. Godec, D. Wolski, E. Adland, K. Yates, K.E. Pauken, C. Cosgrove, C. Ledderose, W.G. Junger, S.C. Robson, E.J. Wherry, G. Alter, P.J. Goulder, P. Klenerman, A.H. Sharpe, G.M. Lauer, W.N. Haining, CD39 Expression Identifies Terminally Exhausted CD8+ T Cells, PLoS Pathog, 11 (2015) e1005177. [8] F.P. Canale, M.C. Ramello, N. Nunez, C.L. Araujo Furlan, S.N. Bossio, M. Gorosito Serran, J. Tosello Boari, A. Del Castillo, M. Ledesma, C. Sedlik, E. Piaggio, A. Gruppi, E.A. Acosta Rodriguez, C.L. Montes, CD39 Expression Defines Cell Exhaustion in Tumor-Infiltrating CD8(+) T Cells, Cancer Res, 78 (2018) 115-128. [9] P. Jayaprakash, P.D.A. Vignali, G.M. Delgoffe, M.A. Curran, Hypoxia Reduction Sensitizes Refractory Cancers to Immunotherapy, Annu Rev Med, 73 (2022) 251-265.

免疫疗法临床研究

100 项与甲硫氨酸脑啡肽相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	甲硫氨酸脑啡肽	-	DB12668

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
胰腺癌	临床2期	美国	Biostax Corp.	2014-03-25
卵巢癌	临床2期	美国	Biostax Corp.	2012-01-23
肝细胞癌	临床2期	-	LadRx Corp.	-
肝细胞癌	临床2期	-	Immune Pharmaceuticals, Inc.	-
肝细胞癌	临床2期	-	TNI BioTech Ltd.	-
HIV感染	临床2期	-	Immune Pharmaceuticals, Inc.	-
HIV感染	临床2期	-	TNI BioTech Ltd.	-
HIV感染	临床2期	-	LadRx Corp.	-
晚期恶性实体瘤	临床1期	美国	Innovive Pharmaceuticals, Inc.	2005-11-01
流感病毒感染	临床前	美国	-	-

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT00109941 (Pubmed)	临床2期	晚期胰腺腺癌	24	OGF 250 µg/kg	築鹹遞壓淵鏇繭鹹夢艱(鏇艱築醖壓顧鑰積獵醖) = No adverse effects on hematologic or chemistry parameters were noted 窪艱製製簾艱鹹壓夢選 (窪壓壓網淵選齋觸夢簾 ) 更多	积极	2010-03-01
SFN2005	N/A	-	-	Met-enkephalin	製鹹鹹願鏇簾壓遞顧醖(簾膚壓網構鬱鹹簾鑰醖) = 齋顧範範鹽鏇壓築獵廠襯艱餘鹽襯憲襯遞鹹範 (築選艱鑰繭窪衊獵鏇壓 ) 更多	-	2005-11-15
SFN2000	N/A	肿瘤	-	Excess OGF exposure	齋廠膚膚壓襯襯鑰齋壓(鏇淵夢觸鏇襯艱衊鑰衊) = 壓窪壓壓鬱願遞築鬱齋廠觸衊艱蓋夢鑰窪積夢 (廠齋齋鬱襯鹹範觸夢窪 ) 更多	-	2000-11-05
SFN2000	N/A	肿瘤	-	Naltrexone (NTX)	齋廠膚膚壓襯襯鑰齋壓(鏇淵夢觸鏇襯艱衊鑰衊) = 獵繭鹹簾顧觸膚膚窪顧廠觸衊艱蓋夢鑰窪積夢 (廠齋齋鬱襯鹹範觸夢窪 ) 更多	-	2000-11-05