天士力 簽下 日本AJT240 (EA Pharma)大中華權益: 透析Secondary hyperparathyroidism (SHPT)

天士力與日本EA製藥株式會社簽署藥物引進授權合約 7月18日，天士力醫藥集團股份有限公司（以下簡稱"天士力"）與日本EA製藥株式會社（以下簡稱"EA製藥"）在天士力國際交流展示中心簽署授權合約。天士力將引進EA製藥研發的一款針對晚期腎功能損害及血液透析所導致的繼發性甲狀旁腺功能亢進症（SHPT）患者的治療藥品——鈣感應受體的變構調節劑（簡稱"AJT240"）。該藥目前正在進行全球多中心臨床II期試驗。未來，天士力將擁有其大中華地區的開發、生產和商業化權益。天士力控股集團董事局執行主席閆凱境、EA製藥董事長&CEO Yuji Matsue分別代表雙方企業簽署協定，天士力研究院執行院長周水準、天士力醫藥集團股份有限公司常務副總經理劉金平，EA製藥執行副總裁Akira Shinji、EA製藥BD總經理Takashi Shibano等共同見證了簽約儀式。 AJT240由EA製藥研發並擁有全球智慧財產權，是一款針對晚期腎功能損害及血液透析所導致的繼發性甲狀旁腺功能亢進症(SHPT)患者的靜脈注射藥物，具有持久穩定降低甲狀旁腺激素(PTH)的作用，有利於提高透析患者的藥物依從性,減少現有口服SHPT藥物治療中觀察到的如噁心、嘔吐等胃腸副作用。該藥物臨床II期試驗研究預計2018年在日本完成，爭取儘早在華上市。EA製藥是衛材和味之素兩家大型日本公司的合資企業，兩家企業在生物藥領域均已積累深厚基礎。通過此次與EA製藥合作、引進創新藥物，可與天士力現有產品管線形成戰略協同，豐富公司現有心腦血管及消化代謝相關治療領域產品組合，進一步拓寬整個慢病市場的產品管線，同時將世界最前沿領域藥品引入中國，為中國患者提供更多世界水準的創新藥物。此次合作也將成為天士力實施國際化戰略的重要里程碑。此前天士力國際化聚焦美國市場，此次與日本藥企合作是天士力全面國際化戰略特別是開拓亞洲市場的重要一環，將持續擴大天士力國際化品牌影響力，助力國際藥企更好地瞭解天士力的創新藥合作開發能力和在華市場開拓能力，為未來引入更多世界前沿產品奠定良好基礎。

Secondary hyperparathyroidism (SHPT) is one of the complications that occurs with progression of chronic renal disease (chronic renal failure). In SHPT, the parathyroid glands excessively secrete parathyroid hormone (PTH). Excessive PTH promotes efflux of phosphorus and calcium from bone into the blood. This increases the risk of bone fracture or causes deposition of phosphorus and calcium salts in non-bone tissues, i.e., ectopic calcification, which leads to bone pain, joint pain and other symptoms. Particularly, there has been reported that, when the deposition occurs in the cardiovascular system, the risk of cardiovascular diseases including arteriosclerosis increases and even can affect prognosis.

AJT240 directly acts on the calcium-sensing receptor expressed on the cell membrane of parathyroid glands and suppresses the excessive secretion of parathyroid hormone. AJT240 is an intravenous injection that can be administered through the dialysis circuit intravenously after a dialysis session. This is expected improve medication adherence of patients receiving maintenance dialysis and reduce the gastrointestinal side effects such as nausea, vomiting and the like that are observed in treatment with existing oral SHPT drugs.

On April 1, 2016, the Eisai Group's gastrointestinal disease business built up over 60 years and the Ajinomoto Group's gastrointestinal disease business with amino acid technologies at its core will be integrated to establish EA Pharma, a gastrointestinal specialty pharma with a full value chain including research and development, production and logistics, sales and marketing. EA Pharma will strive toward realizing an Enterprise Architecture that will create new innovation from the two companies' combined knowledge.

October 31, 2017, EA Pharma Co., Ltd. (President, Yuji Matsue; Headquarters, Tokyo, Japan) (hereinafter "EA Pharma"), the gastrointestinal disease area subsidiary of Eisai Co., Ltd.,. announced today that EA Pharma signed yesterday a license agreement with JW Pharmaceutical CORPORATION (Representative Directors, Kyung Ha Lee, Sung Kwon Han; Headquarters, Seoul, Korea) (hereinafter "JWP") to grant JWP the rights to develop and market a secondary hyperparathyroidism treatment agent (Code: AJT240) in Korea for patients receiving hemodialysis.

Anti-addiction market potential betel quid users and smokers: pilocarpine + nicotine gum

Scientists develop nicotine gum for 'betel quid' addiction By Allen Cone| July 19, 2018 at 3:10 PM By combining nicotine gum with an existing medication used to treat dry mouth, two researchers found it curbs the addition to the mixture of areca nut (pictured), spices, slaked lime and, sometimes, tobacco. Photo by Thamizhpparithi Maari/Wikimedia Commons July 19 (UPI) -- Researchers are developing a way for users to kick an addiction to betel quid -- a cheap stimulant that can lead to oral disease and cancer.By combining nicotine gum with an existing medication used to treat dry mouth, two University of Florida Health researchers found it curbs the addition to the mixture of the areca nut, spices, slaked lime and, sometimes, tobacco. Betel nut is considered the world's fourth most-used stimulant after caffeine, alcohol and tobacco."This deals with the nicotine dependence but also gives them the chewing experience they crave without consuming the caustic lime that is found in betel quid," Dr. Roger Papke, a UF College of Medicine pharmacology professor, said in a press release.Papke sees the nicotine and pilocarpine gum as a way to break the addiction to betel quid. It is grown and used throughout much of Southeast Asia. As a cultural tradition, in small doses, it creates a sense of euphoria and alertness. But prolonged use can create addiction and lead to oral cancer. "The idea is to use nicotine replacement therapies the same way they do for smokers," he said. "The obvious choice is to use a gum because betel nut users are already used to chewing something. "He said the nicotine gum works because the areca nut's active ingredient, arecoline, works the same receptor proteins in the brain as nicotine.But users crave the quid's other effects, including the intense salivation caused by the lime, in the multisensory experience, Papke said. He came up with the idea of employing the drug, pilocarpine, which is used to improve salivary function in people with dry mouth. Papke and a Singapore-based company are seeking grants and in-kind support to bring the gum, known as Quid X, to the estimated 22 million betel quid users in Myanmar and hundreds of millions of others in India and southeast Asia. Dr. Indraneel Bhattacharyya, an oral pathology researcher in the UF College of Dentistry, is collaborating with Papke on the application, including developing surveys for U.S. cities with large populations of people from India and South Asia to gauge interest in the product. "It's culturally embedded in a large part of the world, but I also understand its biology," he said. In the United States, the drug has already been approved for other uses and a U.S. patent application is pending. The product builds on Papke's 2015 findings, which showed nicotine dependence and betel nut addiction are linked to the same site of action in the brain. In 2017, Papke and other researchers identified compounds derived from the areca nut that could help smokers and betel quid users break their addictions. They started testing different compounds. "We can see that there are common anti-addiction needs with betel quid users and smokers," Papke said at the time. "We're hoping to take what we have learned from betel quid research and create a drug that will help both groups."

细胞間質蛋白保护心脏降低老化心衰竭: Vinculin

Age-related heart failure could be prevented in the future by taking a pill that fills the body with a protein that strengthens the organ, scientists claim PUBLISHED: 18:27 BST, 17 July 2018 | UPDATED: 20:50 BST, 17 July 2018Researchers hope vinculin – a protein that strengthens the organ – could eventually be dished out as a medication. Experiments on fruit flies bred to make more of the protein had healthier hearts and lived for a third longer. Levels of vinculin are known to fall in humans as they grow older, causing the heart to gradually become less efficient. Over time, this can lead to irreversible heart failure - which progressively worsens until it proves fatal. The new study, by researchers at the University of California, San Diego, pinpoints vinculin as a potential treatment. Vinculin has been touted as a promising therapy for people at risk of age-related heart failure over the past two years. Studies have shown boosting levels of the protein can also stave off the demise of the heart muscle in rats and monkeys. The latest trial was conducted on fruit flies, considered one of the most valuable organisms for biological research of ageing. Fruit flies that made more of the chemical survived up to nine weeks, instead of the usual six. They were also more active and able to climb the walls of their enclosures, a test of the humble insect's athletic ability.IS HEART FAILURE MORE LIKELY TO KILL WOMEN? Women are more likely to die from heart failure, research found earlier this week. Their chances of dying from the condition within a year of being diagnosed are 14 per cent higher than men. The Canadian study also found that women were more likely than men to be admitted to hospital with the condition. And while hospital admissions had fallen for men due to better care, they were continuing to rise in women. The researchers could not say why the death rates and hospital admissions for heart failure are so much higher for women. Professor Adam Engler, author of the study, said: 'Their quality of life is a lot better.' But he added that it can be 'hard to measure'. His team were surprised by how much improving heart function also helped the flies maintain a healthier metabolism. To measure this, they fed the flies a special form of glucose and detected how they modified and used the sugar.Flies with more vinculin broke down more glucose than their counterparts, according to the study published in APL Bioengineering. This showed higher levels in the heart enabled other organs to efficiently get the nutrients they needed in the breakdown process. Specific muscle cells in the heart, called cardiomyocytes, produce vinculin, which glues them together. But over time, cardiomyocytes struggle to produce the same amounts – causing heartbeats to become less efficient. Heart failure affects around 900,000 adults in the UK and 5.7 million in the US, but the incidence is rising as the population is aging. The condition occurs when the heart muscle is too weak to pump blood round the body and it gradually worsens. Patients commonly develop the condition after a heart attack or due to another problem such as an irregular heart rhythm or high blood pressure. Heart failure patients often take several medications, including beta-blockers and ACE inhibitors, to control their symptoms. Vinculin is a cytoplasmic actin-binding protein enriched in focal adhesions and adherens junctions that is essential for embryonic development.

糖尿病治疗药物GLP-1 medication恶心呕吐解药: vitamin B-12 !!!

Common type 2 diabetes drug could be mixed with vitamin B to stop medication causing nausea and vomiting, finds study By SAM BLANCHARD FOR MAILONLINEPUBLISHED: 18:10 BST, 17 July 2018 | UPDATED: 21:30 BST, 17 July 2018 People with Type 2 diabetes cannot properly regulate the levels of sugar in their blood because their body does not use the hormone insulin normally. GLP-1 medications mimic the hormones in a non-diabetic person's body to prevent patients' blood sugar getting too high. Up to 50 per cent of people on medication get nausea They are widely prescribed but cause nausea and vomiting in as many as half of people who take them. The condition means the body does not react properly to insulin – the hormone which controls absorption of sugar into the blood – and cannot properly regulate blood glucose levels. Excess fat in the liver increases the risk of developing type 2 diabetes as the buildup makes it harder to control glucose levels, and also makes the body more resistant to insulin. This, the researchers say, is a reason many people stop taking medications, which can increase their risk of deadly complications from the condition. 'Drug regimens often have long lists of side effects which negatively impact treatment,' said Bart De  Jonghe of University of Pennsylvania School. Side effects stop people from taking their medicine' In Type 2 diabetes, nausea and vomiting top that list. It's the main reason people stop taking their diabetes medications, and diminishes quality of life for millions who do take them. 'In the study the scientists found attaching vitamin B-12 stopped the drug triggering the part of the brain which causes vomiting. Some 90 per cent of shrews which took the unmodified drug were sick, but only 12 per cent of those that were given the vitamin-combined drug vomited. Shrews were used for the study because mice and lab rats are unable to throw up. Dr De Jonghe added: 'The vomiting results are striking and very encouraging. 'It's rare to see such positive results with a new drug compared to the standard. It's hard to not be optimistic.' Type 2 diabetes is closely associated with obesity and other risk factors include genetics, being over 40 years old, or being of of south Asian, Chinese, African Caribbean or black African origin.

(糖尿病藥or癌藥 ??) Metformin二甲雙胍: 延緩肺癌患者靶向藥耐藥時間&逆轉肺纖維化 !!!!!

一片不到一塊錢的糖尿病藥物，竟把肺癌總生存期延長了10個月！ 原創： 覓健肺癌康復圈"聽說二甲雙胍能延緩肺癌患者靶向藥耐藥時間？請問這是真的嗎？"這是一位患者在"肺凡力量"講座上對上海長征醫院腫瘤科臧遠勝教授提出的疑惑。臧遠勝教授："二甲雙胍確實是個'神藥'，最近兩年的學術報告上都有相關的研究，大家可以關注一下。"臧遠勝教授並沒有具體回答，但卻肯定了二甲雙胍的神奇。那麼這個價格很便宜、應用很廣泛的糖尿病傳統用藥究竟能不能延緩靶向藥耐藥時間呢？它在治療肺癌過程中還有哪些神奇的作用呢？小編深度解析了關於二甲雙胍在今年美國臨床腫瘤學會議（ASCO）上的報告以及近日在《Nature Medicine》上發表的一項科學研究，得出了結論——它可以輔助治療肺癌，不僅能提高患者使用靶向藥的時間及療效，還可以逆轉肺纖維化。

二甲雙胍有抗癌作用，還可提高患者對靶向藥的敏感度 二甲雙胍，是世界上使用最廣泛的糖尿病治療藥物，至今已經有50多年的歷史了。意外的是，在最近的研究中，這個用於治療糖尿病患者的藥物搖身一變變成了抗癌新藥。在上個月的ASCO大會上，醫學家Oscar Arrieta發佈了一項研究：對於擁有EGFR突變的非小細胞肺癌患者，二甲雙胍聯合一代、二代的EGFR-TKI能顯著提高EGFR-TKI單獨使用的療效。

研究資料解析：在非小細胞肺癌患者中，LKB1是一種抑癌基因，它的失活常常是癌症發生的原因之一；並且這類腫瘤侵襲性還比較高。而二甲雙胍正是可以通過各種機制來影響抑癌基因LBK1，以達到抗癌的作用。對於肺癌患者，二甲雙胍還可以增加非小細胞肺癌對於TKI的敏感度。

什麼是EGFR-TKI ？很多覓友可能會疑惑，到底什麼是EGFR-TKI呢？EGFR-TKI是一種表皮長因數受體酪氨酸激酶抑制劑的統稱（epidermal growth factor receptor-tyrosine kinase inhibitor, EGFR-TKI）。也就是大家常說的針對EGFR位點突變的靶向藥物。一代的TKI藥物主要有厄洛替尼、埃克替尼、吉非替尼，它們在臨床上有效率能達到70%以上。第二代靶向藥主要有阿法替尼，是靶向EGFR（HER1）及HER2的雙靶點抑制劑。其中，超過一半的患者是因為發生了T790M（就是第790氨基酸由"T"蘇氨酸變成了"M"甲硫氨酸）的二次突變，而發生一代TKI藥物耐藥，針對於此的第三代EGFR-TKI抑制劑奧希替尼也因此誕生。奧希替尼不僅對T790M突變有良好的應對之策，還能透過血腦屏障，可以一定程度上緩解患者腦轉移的症狀。但是在此次的研究中，研究人員只是採取二甲雙胍和一代或者二代的EGFR-TKI聯合來對比研究的，對三代TKI聯合二甲雙胍的研究還沒有展開。這是一項雙盲、隨機且對照安慰劑的二期臨床試驗（NCT03071705），試驗納入了1116名有EGFR突變的晚期非小細胞肺癌患者。他們被分成兩組，一組只接受EGFR-TKI治療，另一組患者接受二甲雙胍+EGFR-TKI的治療。

結果振奮人心——接受二甲雙胍聯合治療的患者較單藥治療的患者中位無進展生存期超出了4個月（14.0月vs 10.0月）！不僅如此，總生存週期延長了接近10個月！對於腫瘤的緩解程度也大大提高，客觀緩解率達到67.4% vs. 47.5%。與單獨使用EGFR-TKI的總反應率為54.3%相比，二甲雙胍和EGFR-TKI聯合使用的總反應率顯著較高，達到了71%。這些資料非常明顯地告訴我們，二甲雙胍是具有一定的抗癌作用的。因為對於有EGFR突變的非小細胞肺癌患者，在使用EGFR靶向藥物中加入二甲雙胍可以明顯提高患者的PFS（無進展生存期）、OS（總生存期）和ORR（客觀緩解率）。雖然，一代TKI聯合使用二甲雙胍的研究資料優勝于單藥，但是使用同時要密切觀察藥物的安全性。還要特別注意的是，研究中未納入第三代EGFR-TKI藥奧希替尼。2

二甲雙胍可逆轉肺纖維化 二甲雙胍不僅僅是在抗癌的方面有一定的作用，經過科學家的研究，它還有助於逆轉已經形成的肺纖維化。肺癌患者的肺部本就脆弱，尤其是經過放療的患者，很可能會發生肺纖維化，也就是說大量的成纖維細胞增殖聚集在肺部，這樣可能造成原有的肺泡組織損傷或者在肺部形成疤痕。就像我們皮膚表皮被割傷後，再怎麼癒合都難以和以前一模一樣了，這些難看的疤痕在我們的手上胳膊上可能只是看起來難看，並不影響功能。但是在肺部，如果肺纖維化範圍較大，會影響人體呼吸功能，表現為乾咳、進行性呼吸困難（自覺氣不夠用）等症狀，這對於肺癌患者簡直就是雪上加霜。近日在《Nature Medicine》上發表了一項科學研究：美國阿拉巴馬大學伯明罕分校(University of Alabama at Birmingham， UAB)的研究人員發現二甲雙胍居然可以逆轉已經產生的肺纖維化(pulmonary fibrosis)。研究中，研究人員先使用化療藥物讓小鼠產生肺纖維化，在服用化療藥物三周之後小鼠肺部已經產生了嚴重的纖維化。這時，研究人員讓小鼠服用二甲雙胍。奇跡出現在服用二甲雙胍 5周之後，研究者們發現二甲雙胍竟然可以加快已經產生的纖維化組織的消融速度。經過這個研究，在概念上已經證明了使用二甲雙胍或其它藥物啟動AMPK能夠啟動促進纖維化組織消融的信號通路，從而最終加快肺纖維化部分的消融速度。二甲雙胍也可能因此成為治療進行性纖維化疾病的新秀！但目前，這項研究僅停留在動物試驗階段，到真正的人體臨床使用還有一段距離。但無論如何，對於肺癌的患者，可能在將來，會不用太再懼怕放化療引起的肺纖維化和由此造成的肺部損傷了！

編後：二甲雙胍確實是神藥，在內分泌領域既便宜又好用，目前在腫瘤領域它也顯示了神奇的功效。但大家一定不要盲從，因為這兩項臨床試驗只是在一定程度上探索了二甲雙胍的藥理作用，且不說是否覆蓋了亞洲人群，只是肺纖維化的試驗還尚且停留在動物試驗階段。廣大的覓友興奮之余一定要保持理智，因為所有腫瘤用藥都要在醫生的指導下使用，切不可擅自購買二甲雙胍聯合使用。在不遠的未來，相信醫學家會把二甲雙胍研究得更加透徹，在保證了安全性和有效性的基礎下應用，才是我們應對肺癌的正確選擇。

オリザ油化ではツバメの巣エキスについて、タイトジャンクション形成促進作用を有する旨の特許を取得したことを発表した（特許番号6358692号）

( エーブィエ バイオファーム)2018/7/13タイトジャンクション（TJ）とは、隣り合う細胞同士の隙間を接着させ、細胞と細胞の隙間を水やイオンが自由に行き来しないようにする役割を持つ構造のこと。表皮TJ は体内の水分が過剰に漏れださないよう、また体外からの異物を入り込ませないようバリア機能を果たしている。TJ 構成タンパクであるクローディンやオクルディンは細胞膜上に存在し、隣り合う細胞と細胞の間をジッパーで閉じ合わせるように細胞間の隙間をシールしている。そのため、TJの形成を促進することにより、皮膚の弾力等の改善効果が期待できる。同社では、ツバメの巣エキスを使ってタイトジャンクション形成促進作用を調べた。正常ケラチノサイトを培養し、TJ構成タンパクのなかでも特に皮膚バリア機能に関与すると考えられるクローディン１・クローディン４の遺伝子・タンパク発現を見たところ、ツバメの巣エキス0.1％以上の添加で各遺伝子・タンパクともに発現を増強させることを確認した。また正常ケラチノサイトのクローディン4 タンパクを蛍光色素で染色し、ツバメの巣エキスによる影響を蛍光顕微鏡で観察した結果、無添加と比較して0.1％添加では細胞間をシールするようにクローディン4 の発現が確認された。以上の結果により同社はツバメの巣エキスにおけるタイトジャンクション形成促進作用を有することを見出し、特許取得に至った。ツバメの巣エキスは主として美肌向上素材として上市されたもの。広範な細胞の分化や増殖に影響を与える上皮細胞増殖因子（Epidermal Growth Factor；EGF）を含有し、美肌作りに欠かせない皮膚細胞（ケラチノサイト、線維芽細胞）の増殖効果を有し、創傷治癒効果を有することを自社データで見出している。これにより、日本のみならず世界で数々の採用実績を持っている。今回のタイトジャンクション形成促進作用における特許の取得により、皮膚バリア機能を有する素材として期待することができ、国内外の更なるグローバルな拡販も期待されている。

有利生小孩時間: 精子活動力最強時間與月份 (7.30am, March~May)

Scientists discover the best time and months to have sex if you're trying for a baby: 7.30am during March, April and May By STEPHEN MATTHEWS FOR MAILONLINE PUBLISHED: 16:50 BST, 13 July 2018 | UPDATED: 17:05 BST, 13 July 2018  Scientists in Switzerland claim sperm have their own 24-hour internal clock They found sperm are the most potent in the early hours of the morning  Scientists claim the findings could 'be used to improve natural fertility' Sperm are also in the healthiest shape and size during the spring months Couples trying for a baby should have sex before 7.30am on spring mornings if they want to become pregnant, research suggests. Scientists claim sperm have their own 24-hour internal clock - and they are most potent in the early hours of the morning. The samples were cross-checked for sperm concentration, total sperm count, progressive motility and normal morphology. Lead author Dr Brigitte Leeners said: 'Male semen quality varies with both circadian and circannual rhythms. 'Collection of semen in the early morning, where semen quality was highest, can be used to improve natural fertility. 'However, she added that the findings could also be used to boost the chances of conceiving through fertility treatments. Semen collected in the spring months of March, April and May had the greatest concentration of sperm. Significant decreases were noted in the summer.

DOES INFERTILITY RAISE YOUR RISK OF AN EARLY DEATH? Infertility increases a woman's chance of dying early by 10 per cent compared to women who have had children, a University of Pennsylvania study found in October. Having fertility problems also raised the chance of getting breast cancer by 43 per cent – and increased the chances of dying from diabetes. But having children protects women from dying prematurely, research presented at the Annual Congress of the American Society for Reproductive Medicine in San Antonio, showed, suggesting giving birth has a 'rejuvenating effect' on a woman's body. Whether having children prolongs or shortens a woman's life has long been debated. One school of thought holds that being pregnant and giving birth to a child takes its toll on a woman. An opposing view is that being infertile may be a sign of underlying health problems, which may worsen overall health.While samples collected in the early morning, before 7.30am, showed the highest levels of concentration and normal morphology. The study, published in the scientific journal Chronobiology International, comes amid a rise of infertility. As many as one in seven couples has difficulty conceiving, according to the NHS. And studies suggest poor semen quality is a factor in up to half of cases. Fertility experts across the world today welcomed the study of sperm samples, but warned its findings should be treated with caution. Dr Hana Visnova, medical director of the IVF Cube fertility clinic in Prague, told MailOnline: 'Sperm collection is clearly a vital aspect of any IVF procedure.'So if we can maximise the potency of a sample then that's to be encouraged. 'Yet the evidence relating to the best times of the day, or the year, for that to take place is conflicting and controversial. 'She added men with a low sperm count should not bank on having morning sex, and may still need medical help to achieve their dreams of having kids. World health officials class low sperm count to be anything fewer than 15 million sperm per millilitre of semen. It comes as recent reports have revealed sperm counts in men worldwide have declined by half over the past 50 years.

(臨床研究) 年長者提升免疫力&抗衰老: TORC1 inhibitor therapy (mTOR)

Drug boosts immune system in elderly people by 40% and it also has antiaging effect in fruit flies brian  wang | July 13, 2018Drugs were created to block a protein called the mammalian target of rapamycin (mTOR) and it boosted the immune system by about 40% in elderly people. They safely reducing infections in elderly volunteers around 40% by enhancing the immune system. In 2004, tests that blocked a similar enzyme in fruit flies gave them a longer lifespan. Science – TORC1 inhibition enhances immune function and reduces infections in the elderly Aging may be regulated by a discrete set of intracellular proteins including the mechanistic target of rapamycin (mTOR) kinase. mTOR functions within two multiprotein complexes called TORC1 and TORC2. Inhibition of TORC1 has extended life span in every species studied to date and ameliorated multiple aging-related pathologies including declining immune function. Mannick et al. now show that low-dose TORC1 inhibitor therapy in elderly humans decreased the incidence of all infections, improved influenza vaccination responses, and up-regulated antiviral immunity. Thus, targeting the TORC1 pathway that regulates aging may have clinical benefits for elderly humans including improvement in immune function and decreased infection rates.

Abstract – TORC1 inhibition enhances immune function and reduces infections in the elderly Inhibition of the mechanistic target of rapamycin (mTOR) protein kinase extends life span and ameliorates aging-related pathologies including declining immune function in model organisms. The objective of this phase 2a randomized, placebo-controlled clinical trial was to determine whether low-dose mTOR inhibitor therapy enhanced immune function and decreased infection rates in 264 elderly subjects given the study drugs for 6 weeks. A low-dose combination of a catalytic (BEZ235) plus an allosteric (RAD001) mTOR inhibitor that selectively inhibits target of rapamycin complex 1 (TORC1) downstream of mTOR was safe and was associated with a significant (P = 0.001) decrease in the rate of infections reported by elderly subjects for a year after study drug initiation. In addition, we observed an up-regulation of antiviral gene expression and an improvement in the response to influenza vaccination in this treatment group. Thus, selective TORC1 inhibition has the potential to improve immune function and reduce infections in the elderly.

(從演化 學 癌生機) 黑色素 與 造血幹細胞

黑色素隨演化轉移位置保護血幹細胞，相關研究可為相關移植鋪路 作者 Chen Jeffery | 發布日期 2018 年 07 月 15 日 1970 年代末，生物學家理解造血幹細胞在體內需要專一的微環境，這種環境被科學家稱為造血區位（haematopoietic niche）。而他們好奇的是，為何具有相同功能的區位在不同生物體內的位置會有差別，比如說包括人類的成年哺乳類動物位於骨髓，而非哺乳類的脊椎動物卻位在腎臟。40 多年後，由哈佛大學幹細胞與再生醫學系、波士頓兒童醫院幹細胞計畫、哈佛大學幹細胞研究機構合作的一項研究刊登在《自然》期刊，論文提到一項意義重大的線索：他們認為腎臟上方的黑色素（他們的研究對象為斑馬魚，這種魚的造血區位位於腎臟）就是解開這項謎團的關鍵。黑色素細胞會製造決定膚色的色素，而原先是佛里德里希‧卡普（Friedrich Kapp）醫學博士在用顯微鏡觀測造血幹細胞時，發現腎臟上的黑色素細胞擋住了他的視野。「位於腎臟上方的黑色素細胞讓我想到陽傘，所以我猜想，它們是要保護造血幹細胞免於紫外線的照射嗎？」他說。為了證實這段假說，研究團隊將斑馬魚的幼蟲突變使牠們失去黑色素，再將牠們和正常組別一起照射紫外光，結果顯示突變組別中造血幹細胞的數量明顯減少，不僅如此，只要將正常的斑馬魚上下倒置並對牠照射紫外光，一樣會有類似的結果。

從水面下到陸地的演化 下一步研究團隊順著這項發現的軌跡回溯生命演化樹來找尋相似性，他們發現早在 500 萬年前從脊椎動物獨立出來的魚類，黑色素細胞就已經圍繞造血區位。除了斑馬魚，他們還研究箭毒蛙，並發現在蝌蚪長出腳時幹細胞會從覆滿黑色素的腎臟轉移到骨髓，在整個發育過程，造血區位一樣會被保護不受紫外光照射。也就是說紫外線可能是造成區位位置出現差異的天擇壓力。研究的第一作者、哈佛大學幹細胞與再生醫學教授李奧納‧松（Leonard Zon）醫學博士還特別提到這項研究對幹細胞移植的重要性。「身為一位要治療癌症及血液疾病的血液學家及腫瘤學家，一旦我們更了解區位的特性，我們就能更安全地進行造血幹細胞移植。」他如此說。

(Cell Reports) 癌細胞逃脫PD-L1/PD-1 治療 新發現: 自我中和PD-L1/PD-1 (無靶)

Biologists discover process that neutralizes tumors July 10, 2018, University of California - San Diego The molecular "brake" known as PD-1 can bind and neutralize the same tumor cell, instead of an opposing tumor cell. Credit: Hui Lab, UC San Diego Researchers from the University of California San Diego have identified an unexpected mechanism that could help determine whether a cancer patient will respond to immunotherapy. Ideally, the immune system identifies tumors as threatening elements and deploys immune cells (T cells) to find and kill them. However, tumor cells have evolved to employ a protein called PD-L1 to blind T cells from carrying out their functions and evade immune defenses. PD-L1 protects tumor cells by activating a "molecular brake" known as PD-1 to stop T cells. In important therapeutic progress, antibodies developed to block PD-L1/PD-1 have been clinically proven to benefit certain cancer patients. Yet why some patients don't respond to such therapy has remained a mystery. Now, UC San Diego's Yunlong Zhao, Enfu Hui and their colleagues at the University of Chicago and the Nanjing Medical School in China have uncovered some clues. As described July 10 in the journal Cell Reports, the researchers discovered an unexpected twist in the tumor versus T cell battle. Some tumor cells display not only their PD-L1 weapon, but also the PD-1 "brake." This simultaneous expression leads PD-1 to bind and neutralize PD-L1 on the same tumor cell. Thus, the PD-L1 on these tumor cells can no longer engage the PD-1 brake on T cells."It's a very exciting finding," said Hui. "Our study uncovered an unexpected role of PD-1 and another dimension of PD-1 regulation with important therapeutic implications."This study suggests that patients with high levels of PD-1 on tumor cells may not respond well to the blocking antibodies because the PD-1 pathway is self-canceled. In these patients, mechanisms other than PD-L1/PD-1 are likely employed by the tumors to escape from immune destruction. Looking to extend the immunotherapy potential of the finding, Hui and his colleagues are now seeking to determine additional mechanisms of "self-cancellation" at the interface of the tumor and immune cells."We think that our finding is the tip of the iceberg," said Hui, recently named a Pew Biomedical Scholar and Searle Scholar. "We speculate that self-cancellation is a general mechanism to regulate immune cell function. Understanding these processes more clearly will help develop better immunotherapy strategies and more reliably predict whether a patient will respond or not."

打造 人魚線、馬甲線 & 治療 男性女乳症: 超音波溶脂手術

超音波溶脂細緻雕塑 低溫減脂塑身免留傷口 2018年07月13日【記者徐乃義／桃園報導】患有「男性女乳症」的劉姓男子從事房屋仲介，拜訪客戶或與人近距離互動時，因為自己身材而缺乏自信，經與醫師診斷評估後，接受超音波溶脂手術治療。醫學美容科醫師吳宗軒表示，比起傳統抽脂手術，超音波溶脂手術過程的出血較小，對神經血管的傷害較低，溶脂抽取較均勻，術後的瘀青降低，外觀較平整，也可以做出人魚線、馬甲線等更細緻的身材雕塑。吳宗軒說，超音波溶脂手術是將探針伸入皮下脂肪部位，以超音波將脂肪震碎成細小脂肪，再利用負壓原理，將乳糜化的脂肪吸出。手術後持續溶解的油脂，亦會經由身體的自然代謝及淋巴系統排出。超音波溶脂手術恢復期較短，再加上適用於腹部、腰部、大腿、小腿、手臂部位，以及男性女乳、狐臭等症狀，因此有不少人指定做超音波溶脂手術。吳宗軒醫師表示，傳統抽脂及超音波溶脂都是侵入性手術，需要麻醉，目前有較新技術「冷凍低溫減脂塑身」非侵入性治療，不會有傷口，價位又有競爭力，適用於腹部、腰部、臀部、手臂、大腿、背部、副乳等部位，民眾接受度頗高。「冷凍低溫減脂塑身」是利用脂肪細胞不耐冷的特性，只要將儀器接口放在皮膚表面，讓攝氏零下9度左右的低溫能量，直接作用於皮下的脂肪層，脂肪細胞就自然凋亡而不會傷害周圍組織。脂肪細胞經過分解，將透過人體自然代謝出體外，療程結束即可回復日常生活作息，無須恢復期。單次治療需時約1小時左右，依減脂部位面積而定。吳宗軒說，有民眾為了讓婚禮和蜜月的拍照都能留下美好影像，因此特別選擇不留傷口的「冷凍低溫減脂塑身」。壢新醫院指出，任何抽脂減重的手術或治療，都應找專科醫師親自診察，並與醫師詳細討論及評估。手術麻醉應由麻醉專科醫師執行，雷射及超音波等醫療儀器需由醫事人員操作，如此才有安全保障。未滿20歲，或是罹患心臟疾病、凝血障礙、懷孕或哺乳中，以及特殊病史者，都應該避免這方面的治療。

大鵬薬品3億美金 拿下AB928亞洲權力 (中國除外): Antagonist adenosine 2a and 2b receptors 瞄準免疫抗體藥合併使用 !!!

大鵬薬品　新たながん免疫療法の開発に参入 Arcus Bioscience社のアデノシン受容体阻害剤をアジアで独占的に開

Arcus Biosciences Announces That Taiho Pharmaceutical Has Exercised Its Option to Develop and Commercialize AB928 in Its Territories July 12, 2018  HAYWARD, Calif.--(BUSINESS WIRE)--Arcus Biosciences, Inc. (NYSE:RCUS), a clinical-stage biopharmaceutical company focused on creating innovative cancer immunotherapies, today announced that Taiho Pharmaceutical Co., Ltd. (Taiho) exercised its option under the Option and License Agreement entered into in September 2017 (Taiho Agreement) to obtain an exclusive development and commercialization license to the Company's adenosine receptor antagonist program, which includes AB928 and back-up compounds, in Japan and certain other territories in Asia (excluding China). In addition to an option exercise payment, Arcus is eligible to receive clinical and regulatory milestones totaling up to $130 million as well as commercialization milestones and royalties on net sales for this program."Our collaboration with Arcus is an important relationship for Taiho, as we expand our oncology franchise in Japan and other important territories in Asia" "We are pleased that Taiho has decided to exercise their option just as we are initiating our Phase 1/1b program for AB928 in the U.S. and Australia," said Terry Rosen, Ph.D., CEO at Arcus. "We believe that Taiho's decision to exercise their option to this program at this early stage reflects their recognition that AB928, the first adenosine 2 receptor antagonist in clinical development to be specifically designed for the oncology setting, has significant potential to treat a broad array of tumor types. We are confident that Taiho's expertise and capabilities in oncology, as well as their experience co-promoting Keytruda® in Japan, make them the ideal partner to bring AB928 to cancer patients as quickly as possible in their territories.""Our collaboration with Arcus is an important relationship for Taiho, as we expand our oncology franchise in Japan and other important territories in Asia," said Masayuki Kobayashi, President and Representative Director at Taiho. "We have been impressed by Arcus's small molecule drug discovery capabilities, the quality of their clinical candidates and the scientific rigor of their candidate selection process. AB928 appears to have the ideal properties to block the immuno-suppressive effects of adenosine in the tumor microenvironment. We look forward to working with Arcus on the development of this important new immuno-oncology mechanism for the treatment of multiple tumor types."

About the Taiho Agreement Arcus and Taiho entered into an option and license agreement in September 2017. Taiho will provide $35.0 million of cash payments to Arcus during the first three years of the agreement in exchange for an exclusive option, over a five-year period, to in-license the development and commercialization rights to clinical stage product candidates from Arcus's portfolio for Japan and certain other territories in Asia (excluding China). Taiho is obligated to pay an option exercise payment for each option exercise of between $3.0 million to $15.0 million, with the amount dependent on the development stage of the applicable Arcus program for which the option is exercised. In addition, Taiho is obligated to pay to Arcus clinical, regulatory and commercialization milestones up to $275.0 million per program as well as royalties ranging from high single digits to mid-teens on net sales in Taiho's territories.

About AB928 AB928 is an orally bioavailable, highly potent antagonist of the adenosine 2a and 2b receptors. The activation of these receptors by adenosine interferes with the activity of key populations of immune cells and inhibits an optimal anti-tumor immune response. By blocking these receptors, AB928 has the potential to reverse adenosine-induced immune suppression within the tumor microenvironment. AB928 was designed specifically for the oncology setting, with a profile that includes potent activity in the presence of high concentrations of adenosine and a minimal shift in potency due to non-specific protein binding, both essential properties for efficacy in the tumor microenvironment. AB928 has other attractive features, including high penetration of tumor tissue and low penetration through the healthy blood-brain barrier. In a Phase 1 trial in healthy volunteers, AB928 has been shown to be safe and well tolerated and to have pharmacokinetic and pharmacodynamic profiles consistent with a once-daily dosing regimen.

About Arcus Biosciences Arcus Biosciences is a clinical-stage biopharmaceutical company focused on creating innovative cancer immunotherapies. Arcus has several programs targeting important immuno-oncology pathways, including a dual adenosine receptor antagonist AB928, which will be evaluated in combination with other agents in multiple tumor types in a Phase 1/1b program, and an anti-PD-1 antibody, which is being evaluated in a Phase 1 trial and will be tested in combination with Arcus's other product candidates. Arcus's other programs include a small molecule inhibitor of CD73 and an anti-TIGIT antibody, both of which are in IND-enabling studies. Arcus has extensive in-house expertise in medicinal chemistry, immunology, biochemistry, pharmacology and structural biology. For more information about Arcus Biosciences, please visit www.arcusbio.com.

 ( エーブィエ バイオファーム)・販売する権利を取得 大鵬薬品工業株式会社 (本社：東京都千代田区、代表取締役社長：小林将之、以下「大鵬薬品」)は、革新的ながん免疫療法の創薬・開発に注力している米国のArcus Biosciences社 (以下、｢Arcus社｣) が開発中のアデノシン受容体阻害剤AB928とそのバックアップ化合物を、アジア (中国除く) で独占的に開発・販売する権利を取得したことをお知らせいたします。これは、2017年9月に両社が締結したオプション契約に基づき、大鵬薬品がオプション権を行使したものです。AB928は、がん微小環境における免疫抑制メカニズムに関与すると考えられているアデノシン受容体のサブタイプA2aおよびA2bを選択的に阻害する低分子化合物です。アデノシン受容体阻害剤がさまざまな疾患で開発されている中で、AB928はがんをターゲットに設計されたアデノシン受容体阻害剤であり、経口剤としてArcus社が開発を進めています。アデノシン受容体阻害剤は、今後がん免疫療法における新たな治療法になる可能性があるとして期待されています。Arcus社はAB928に関して、健常人における第I相臨床試験を既に実施しており、AB928の安全性、忍容性および薬物動態が確認されています。また、AB928と化学療法やPD-1抗体などさまざまな併用療法を複数のがん種において検討する第I相臨床試験を本年開始しました。Arcus社は本試験を通して、AB928の安全性等をさらに検討する予定です。大鵬薬品は今後Arcus社とともに最適な治療法をできるだけ早期に確立、提供することを目指しています。大鵬薬品は、今後もがん治療において、患者さんや医療関係者により一層貢献できるよう努めてまいります。

Arcus receives FDA approval for Phase l/lb trial of AB928 combination，12 JUNE 2018  Arcus Biosciences has received approval from the US Food and Drug Administration (FDA) validating its two new product candidates, AB928 and AB122. The approval is based on the investigational new drug (IND) applications submitted by Arcus and has enabled the company to conduct its proposed Phase l/lb trial of AB928 in combination with other agents, including AB122 and chemotherapy. The trial aims to examine the safety, tolerability and preliminary efficacy of the AB928 combination for the treatment of patients with breast and gynaecologic malignancies. It will include a dose-escalation phase to determine the optimal dose of AB928 to be combined with fixed doses of AB122 and with each of the three different immunogenic cell death (ICD) inducing chemotherapy regimens. After selecting the recommended dose of AB928 for each combination, the trial will enrol expansion cohorts to investigate AB928 in combination with AB122 or chemotherapy to begin three tumour-specific trials for breast, gynaecologic and gastrointestinal malignancies, as well as lung cancer and renal cell carcinoma (RCC). “If approved, the company will start trials of AB928 combinations in gastrointestinal malignancies, non-small cell lung cancer (NSCLC) and RCC.” Each of the trials will allow Arcus to add new AB928 combination arms in the future. In the dose-escalation portion of the trials, the company will evaluate the evidence of immune engagement to enable a mechanistic understanding of early clinical responses and others. Results from the dose-escalation portion of the Phase l/lb trial are scheduled to be available in the first half of next year. In addition, Arcus plans to submit two additional IND applications this month. If approved, the company will start trials of AB928 combinations in gastrointestinal malignancies, non-small cell lung cancer (NSCLC) and RCC.Arcus has also been completing the regulatory process to investigate the combination of AB928 and AB122 in patients in Australia and expects to dose its first patient with this combination soon.

(Orion Pharma) 挺進 三期運用: 肌萎縮 脊髓側索硬化症（Amyotrophic lateral sclerosis，縮寫為ALS）呼吸治療臨床: Simdax (levosimendan心衰竭藥)

Orion takes repurposed heart failure drug into phase 3 for ALS by Phil Taylor | Jul 6, 2018 Finnish drugmaker Orion Pharma is pressing ahead with a pivotal trial for its amyotrophic lateral sclerosis drug ODM-109, despite mixed results in a phase 2 trial. The first patients have now been recruited into its phase 3 trial of ODM-109—an oral formulation of Orion's heart failure drug Simdax (levosimendan)—in the hope of showing that it can help support breathing function in patients with the devastating neurodegenerative disease. Orion said it plans to enroll 450 subjects in the placebo-controlled trial at sites in Europe, North America and Australia, with patients taking the drug for a year to see if it can slow down the respiratory difficulties that are the usual cause of death in ALS. In a phase 2 trial involving 66 ALS patients, ODM-109 missed its primary endpoint of an improvement in sitting slow vital capacity (SVC)—a measure of lung function—but was able to improve SVC when patients were lying on their backs."If the results of the [phase 3] trial are positive, the aim is to file for marketing authorization in the U.S. and Europe," according to Orion. Results from the study are due in 2020.For years, ALS only had one FDA-approved therapy—Sanofi's Rilutek (riluzole)—which has limited efficacy, with most patients still dying three to five years after diagnosis. In 2017, Mitsubishi Tanabe got FDA approval for free radical scavenger Radicava (edaravone), after filing the drug at the agency's request, based on a six-month study that showed a slower decline in physical function compared to placebo. Not all are convinced by the data for Radicava just yet, however, and it's widely recognized that other new therapies are desperately needed that can definitively slow down the loss of function in ALS. Prospects for a new therapy for ALS took a big knock last year after the high-profile failure in phase 3 of Cytokinetics' tirasemtiv, despite major tweaks to the trial protocol, but the company is hoping a clutch of new drugs, along with ODM-019, could end the drought. Another European biotech, France's AB Science, had a marketing application for its masitinib drug for ALS provisionally turned down in Europe in April, with regulators saying a phase 2/3 trial that showed efficacy at the highest dose used wasn't sufficient to support approval. The company has filed additional information to the EMA and is planning a confirmatory trial that it hopes will also support a U.S. filing. Meanwhile, some of the other players in the field include Biogen and Ionis, which have a SOD1-targeting antisense drug called BIIB067 in phase 1/2 trials, Amylyx with AMX0035 (sodium phenylbutyrate and tauroursodeoxycholic acid) in phase 2 with results due later this year, and new startup QurAlis.

Levosimendan(治療慢性心衰竭) 藉由增加細胞內鈣離子與心肌的troponin C結合之敏感度而導致心臟收縮，因此，不會損害心室放鬆。此外，Levosimendan 打開位於血管平滑肌上對ATP敏感的鉀離子管道，藉此誘導全身、冠狀動脈及全身靜脈血管的擴張。體外試驗證實 Levosimendan為具選擇性的 phosphodiesterase III 抑制劑，但並不清楚其在治療濃度下的相關性。對於患有心衰竭的患者，Levosimendan之心收縮力增強及血管放鬆作用，可導致收縮力的增加，並且降低前負荷與後負荷，而不會對舒張期功能有不良的效應。在PTCA或血栓溶解之後，Levosimendan會活化患者之心肌。 Simdax輸注可增加心臟手術後病人的冠狀動脈血流量和改善心衰竭病人的心肌灌注量，但不會增加心肌的氧氣消耗量。使用Simdax輸注治療，會明顯的降低鬱血性心衰竭病人循環系統中之 endothelin-1濃度。在建議的輸注速率下，則不會增加血漿中catecholamine的濃度。

肺癌 免疫治療如何精準治療: PD-L1 高低不重要？！癌突變壓力(Tumor mutation burden) 成關鍵？

CheckMate 227 trial in advanced lung cancer by Dr. Borghaei.

Tumor mutation burden matters than PD-L1: 

1, regardless of the level of PD-L1 expression or histology, patients who had this biomarker of a high tumor mutational burden above a certain threshold had a better outcome compared to patients with a relatively low tumor mutational burden, in terms of PFS and response rate, with the combination of ipilimumab plus nivolumab compared to chemotherapy alone.

2, even in this population of PD-L1–negative patients, a high tumor mutational burden was associated with better PFS and better duration of response with ipilimumab plus nivolumab than either chemotherapy alone or nivolumab plus chemotherapy.

3, patients have PD-L1–negative tumors and a low tumor mutational burden, the addition of nivolumab to chemo or ipilimumab to nivolumab didn’t really provide additional benefit over chemotherapy alone.

Side effects: add nivolumab to chemotherapy there are more side effects compared to chemotherapy alone. But interestingly, in this analysis, the group of patients that got ipilimumab plus nivolumab had a lower percentage of the grade 3 and 4 severe side effects. In the chemotherapy-plus-nivolumab group, the grade 3 and 4 toxicities were close to 50%—but only 25% and 35% of patients in the ipilimumab-plus-nivolumab group and chemotherapy-alone group experienced these toxicities.

*Ipilimumab is a monoclonal antibody that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.

* Nivolumab binds to and blocks the activation of PD-1, an Ig superfamily transmembrane protein, by its ligands programmed cell death ligand 1 (PD-L1), overexpressed on certain cancer cells, and programmed cell death ligand 2 (PD-L2), which is primarily expressed on APCs. This results in the activation of T-cells and cell-mediated immune responses against tumor cells or pathogens. Activated PD-1 negatively regulates T-cell activation and and plays a key role in in tumor evasion from host immunity. 

(臨床III期失敗) DNA疫苗ASP0113 用於CMV (Cytomegalovirus) reactivation

安斯泰來與Vical開發巨細胞病毒疫苗臨床III期遇挫 MedMed醫學傳播時訊 文章來源：新浪醫藥新聞編譯：Bernardo安斯泰來製藥和Vical1月23日宣佈，作為一種針對巨細胞病毒（CMV）陽性的造血幹細胞移植（HSCT）接受者而開發的研究性DNA疫苗ASP0113，在III期HELIOS臨床試驗中未達到其主要或次要終點。該疫苗耐受性好，且注射部位的反應是通常所報導的不良事件。安斯泰來的開發總裁Bernhardt G. Zeiher表示："對於CMV終末器官疾病的整體生存率下降在研究中沒有顯示出顯著改善，我們感到失望。但要感謝參與這個重要試驗的病人和臨床醫生。"該臨床III期試驗設計旨在評價ASP0113，對比安慰劑，在接受異基因HSCT的CMV血清陽性受者中的有效性。在移植後的第一年，使用總死亡率和CMV末端器官疾病的主要複合終點來評估效力，而該終點未被達到。第一個方案限定的CMV病毒血症時間的次要終點和第一次使用判定的CMV特異性抗病毒療法的時間也未被達到。Vical公司的首席執行官Vijay Samant表示："臨床III期的結果令人失望。安斯泰來和Vical的員工們、研究者和研究現場的人員在這項研究中做的相當出色，但不幸的是，這種疫苗無法為這個難治的患者群體提供全因死亡率的保護。"該臨床III期試驗是一項1：1隨機、雙盲、安慰劑對照的研究，共招募了514名接受造血幹細胞移植的CMV血清陽性受試者。通過供受體的相關性和供體CMV血清狀態進行隨機化分層。受試者移植後隨訪1年。CMV是一種皰疹病毒，在美國估計有一半以上的成年人到50歲時會被感染，在發展中國家更為普遍。健康的免疫系統通常保護感染者免受CMV疾病侵擾，但不能預防或清除潛伏感染。免疫系統功能不全的個體伴有CMV重新啟動的高風險，可能會導致嚴重的疾病或死亡。這些處於高風險的群體包括HCT和實體器官移植受者，以及母親在懷孕期間首先感染的嬰兒。ASP0113是一種被設計用於預防CMV-血清陽性HCT受者的CMV疾病和相關併發症的研究性候選疫苗，是一種編碼CMV磷蛋白65和誘導細胞和體液免疫應答的糖蛋白B抗原的二價體DNA疫苗，由專有的基於泊洛沙姆的載體系統配製而成。ASP0113最初由Vical開發，與Astellas合作進行進一步的開發和商業化。該藥物在美國和歐洲被認定為孤兒藥物。

About Cytomegalovirus  CMV is a herpes virus that is estimated to infect more than half of all adults in the United States by age 50, and is even more widespread in developing countries. A healthy immune system typically protects an infected person against CMV disease, but does not prevent or clear latent infection. Individuals whose immune systems are not fully functional are at high risk of CMV reactivation, potentially leading to severe illness or death. Those at greatest risk include HCT and solid-organ transplant recipients, as well as infants born to mothers who first become infected during pregnancy.

About ASP0113 ASP0113 is an investigational vaccine candidate designed to prevent CMV disease and associated complications in CMV-seropositive HCT recipients. ASP0113 is a bivalent DNA vaccine encoding CMV phosphoprotein 65 and glycoprotein B antigens for induction of both cellular and humoral immune responses, formulated with a proprietary poloxamer-based delivery system. ASP0113 was initially developed by Vical which partnered with Astellas for further development and commercialization. ASP0113 received Orphan Drug Designation in the United States and Europe.

(NEJM) 27 種腫瘤TMB對 PD-1 Inhibition療效/ (Cancer Cell) nivolumab+ipilimumab 適用 SCLC小細胞肺癌 TMB腫瘤突變負荷高/

TMB標誌物顯神威！可增加小細胞肺癌I-O治療有效性 腫瘤資訊2018-05-15 編譯：月下荷花 來源：腫瘤資訊 CheckMate032研究表明，小細胞肺癌（SCLC）可獲益於免疫檢查點抑制治療，但哪些患者在免疫治療中獲益更多並不清楚。近日美國Hellmann教授在Cancer Cell雜誌發表了CheckMate032的回顧性研究，結果表明高腫瘤突變負荷(TMB)SCLC患者從納武利尤單抗（nivolumab）聯合伊匹木單抗（ipilimumab）治療中獲益最大。

研究背景 小細胞肺癌占所有肺癌10%–15%，大約75%患者為廣泛期。標準一線治療為含鉑化療，一旦疾病進展則缺少有效治療，預後極差。納武利尤單抗為免疫檢查點抑制劑，無論是單藥還是與伊匹木單抗聯合治療既往接受過治療的SCLC，均可獲得持續治療反應，延長生存。CheckMate 032研究中，納武利尤單抗單藥治療進展期SCLC的2年生存率14%，與伊匹木單抗聯合為26%，因此NCCN指南推薦納武利尤單抗±伊匹木單抗作為SCLC的二線或二線以上治療。然而一直缺少有效預測SCLC免疫檢查點抑制治療有效性的標誌。與其它腫瘤不同，SCLC較少表達程式化死亡配體1（PD-L1），而且無論有無PD-L1表達，納武利尤單抗±伊匹木單抗治療均可能有效。多數SCLC與吸煙有關，因此SCLC特徵之一是高體突變負荷。其它實體腫瘤中已顯示高TMB與免疫檢查點抑制治療有效性相關，但在SCLC中是否也存在這種關係並不清楚。

研究方法CheckMate032研究中接受納武利尤單抗單藥（3mg/kg，每2週一次）或納武利尤單抗+伊匹木單抗（1mg/kg+3mg/kg，每3週一次，共4週期，然後納武利尤單抗3mg/kg，每2週一次）聯合治療的SCLC患者進行全外顯子測序。TMB定義為錯義體突變總和，採用三分位法將TMB分為低負荷＜143突變，中等負荷143-247突變，高負荷≥248突變。

研究結果 結果表明納武利尤單抗單藥和納武利尤單抗+伊匹木單抗聯合治療，高TMB患者的客觀反應率（21.3%和46.2%）高於低（4.8%和22.2%）和中（6.8%和16.0%）TMB患者，所有患者納武利尤單抗+伊匹木單抗聯合治療的客觀反應率高於納武利尤單抗單藥治療。無論是聯合還是單藥治療，獲得完全或部分反應患者的TMB高於疾病穩定或疾病進展的患者。納武利尤單抗單藥和納武利尤單抗+伊匹木單抗聯合治療，高TMB患者的1年無進展生存率（21.2%和30.0%）高於低（不能計算和6.2%）中（3.1%和8.0%）腫瘤突變患者，高TMB患者聯合治療的1年無進展生存率優於單藥治療，低中TMB患者聯合治療與單藥治療無差異，總生存結果與之相似。總之，高TMB增迦納武利尤單抗和納武利尤單抗+伊匹木單抗有效性，納武利尤單抗+伊匹木單抗的臨床獲益超過納武利尤單抗單藥。

結果討論與展望這項研究評估了SCLC的TMB與免疫檢查點抑制治療有效性的關係，結果表明高TMB 患者較低中TMB患者從納武利尤單抗和納武利尤單抗+伊匹木單抗治療中獲益更多，這與納武利尤單抗治療非小細胞肺癌（NSCLC）和尿路上皮癌、伊匹木單抗治療黑色素瘤的結果相似，因此TMB可能也是SCLC免疫檢查點治療反應的預測標誌。初始觀察發現雖然納武利尤單抗+伊匹木單抗聯合治療SCLC能增加獲益，但較納武利尤單抗單藥治療的毒性更大，因此確定單藥或聯合治療的不同預測標誌十分必要。這項研究發現，SCLC患者伴高TMB時，納武利尤單抗+伊匹木單抗聯合治療的生存遠超過歷史對照，中低TMB患者聯合治療的客觀反應率雖較單藥改善，但無進展生存和總生存並無差別。結果提示高TMB患者，聯合治療獲益優於單藥治療，而中低TMB患者單藥治療也許是最佳選擇。這項研究表明，TMB對SCLC免疫治療反應有預測作用，但尚不清楚其分子多樣性是否足以區分免疫治療反應不同的臨床亞組，目前只能得出負荷最高者免疫治療獲益最多。有人認為突變負荷分析並不可行，因為SCLC標本取材多為小標本且存在較多壞死組織。但這項研究顯示，61%患者的活檢組織足以用於全外顯子檢測，因為是回顧性研究，活檢取材時並未預先計畫全外顯子檢測，若事先計畫全外顯子檢查則取材合乎標準的患者比例可能更高。總之這項研究證實，SCLCTMB檢測可行，如若為前瞻性研究則可獲更高的成功率。目前不清楚TMB和納武利尤單抗+伊匹木單抗治療結果之間究竟如何產生聯繫。有假說認為，加入伊匹木單抗增加抗腫瘤T細胞克隆儲備，同時也降低TMB的預測相關性。但這個假說似乎與SCLC無關，因為TMB在SCLC中是納武利尤單抗+伊匹木單抗治療反應增加的預測標誌。與之相似，有研究顯示NSCLC採用納武利尤單抗+伊匹木單抗聯合治療的反應進一步改善。需要更多研究明確二者協同作用的潛在免疫學機制。研究還發現，不論是均分法、三分法還是四分法，皆顯示高TMB與結果改善相關，說明SCLC的TMB與免疫治療獲益的關係很穩定，同時也提示多個閾值均可富集獲益人群，需要進一步優化，也要更好地理解增加免疫原性的體突變分子特徵。目前另有二個評估納武利尤單抗±伊匹木單抗治療SCLC有效性的III期研究（CheckMate331和CheckMate451），這二項研究會有更多資料明確TMB與治療結果間的關係。總之，SCLC患者採用納武利尤單抗單藥或納武利尤單抗+伊匹木單抗聯合治療時，高TMB能增加治療有效性，其中以聯合治療的臨床獲益更多，聯合治療的1年生存率幾乎是單藥治療的2倍。高TMBSCLC患者接受免疫聯合治療時，無進展生存和總生存改善尤其顯著，這與NSCLC的資料相似，提示TMB可能是所有肺癌免疫治療的潛在生物學標誌。

參考文獻 連結：https://www.ncbi.nlm.nih.gov/pubmed/?term=Tumor+Mutational+Burden+and+Efficacy+of+Nivolumab+Monotherapy+and+in+Combination+with+Ipilimumab+in+Small-Cell+Lung+Cancer

Tumor Mutational Burden and Response Rate to PD-1 Inhibition

December 21, 2017 N Engl J Med 2017; 377:2500-2501

TO THE EDITOR: Inhibitors of programmed death 1 (PD-1) protein or its ligand (PD-L1) have shown remarkable clinical benefit in many cancers.1 One emerging biomarker of response to anti–PD-1 therapy is the tumor mutational burden (i.e., the total number of mutations per coding area of a tumor genome). This finding is supported by the clinical activity of anti–PD-1 therapy in colorectal cancer with mismatch repair deficiency, a tumor subtype with a high tumor mutational burden, as compared with the colorectal cancer subtype with mismatch repair proficiency, which has a significantly lower tumor mutational burden and a poor response to these agents.2,3

To evaluate the relationship between the tumor mutational burden and the objective response rate, we plotted the objective response rate for anti–PD-1 or anti–PD-L1 therapy against the corresponding median tumor mutational burden across multiple cancer types (Figure 1). Through an extensive literature search, we identified 27 tumor types or subtypes for which data regarding the objective response rate are available. For each tumor type, we pooled the response data from the largest published studies that evaluated the objective response rate. We included only studies of anti–PD-1 or anti–PD-L1 monotherapy that enrolled at least 10 patients who were not selected for PD-L1 tumor expression. (Details about the methods are provided in the Supplementary Appendix, available with the full text of this letter at NEJM.org.) The median tumor mutational burden for each tumor type was obtained from a validated comprehensive genomic profiling assay performed and provided by Foundation Medicine.4 We observed a significant correlation between the tumor mutational burden and the objective response rate (P<0.001). The correlation coefficient of 0.74 suggests that 55% of the differences in the objective response rate across cancer types may be explained by the tumor mutational burden. Some cancer subtypes have a response to therapy that is better than would be predicted by the tumor mutational burden (e.g., Merkel-cell carcinoma), and some have a response that is worse than would be predicted (e.g., colorectal cancer with mismatch repair proficiency). The higher-than-anticipated objective response rates for Merkel-cell carcinoma and some other cancers that have been associated with viruses suggest that the presentation of viral antigens on certain tumor types may confer an increased response rate to anti–PD-1 therapy.5

Our linear correlation formula — objective response rate=10.8×loge(X)−0.7, where "X" is the number of coding somatic mutations per megabase of DNA — can be used to make hypotheses with respect to the objective response rate in tumor types for which anti–PD-1 therapy has not been explored. For example, we anticipate a clinically meaningful objective response rate of 40.1% (95% confidence interval [CI], 31.2 to 50.6) for basal-cell carcinoma of the skin and of 20.6% (95% CI, 16.7 to 24.5) for sarcomatoid carcinoma of the lung on the basis of a median tumor mutational burden of 47.3 and 7.2, respectively.4 We anticipate a low objective response rate (<5%) for several other cancers (e.g., pilocytic astrocytoma and small-intestine carcinoid).4 A limitation of our analysis is that the sequenced tumor specimens were probably not the same ones for which clinical responses were assessed. Many different factors modulate the clinical response to an immune checkpoint inhibitor, but our findings highlight the strong relationship between the tumor mutational burden and the activity of anti–PD-1 therapies across multiple cancers.Mark Yarchoan, M.D. Alexander Hopkins, Ph.D. Elizabeth M. Jaffee, M.D. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD ejaffee@jhmi.edu

Correlation between Tumor Mutational Burden and Objective Response Rate with Anti–PD-1 or Anti–PD-L1 Therapy in 27 Tumor Types.