Rindopepimut

癌症是一种由肿瘤细胞不受控制，异常生长造成的疾病，其核心在于肿瘤细胞逃避了人体的免疫系统，从而无限增殖造成的。近百年来，科学家们都在研究如何通过激活免疫系统，达到治疗肿瘤的目的，从而让患者获益。大多数癌症免疫疗法主要依靠T细胞来抑制肿瘤。但在两项新的研究中，丹娜-法伯癌症研究所（Dana-Farber）和斯坦福大学的科学家发现了新的免疫肿瘤学方法，表明利用免疫系统的其他组成部分可以达到更好的抗肿瘤效果。2022年5月25日，发表在《Nature》杂志的一项研究中，由Dana-Farber领导的团队开发了一种癌症疫苗，该疫苗靶向T细胞和自然杀伤（NK）细胞，采取双管齐下的攻击方式，防止肿瘤细胞逃避免疫系统的攻击。此外，近期发表于《Science Immunology》上的另一项研究中，斯坦福大学的一个团队发现，将Dynavax的疫苗佐剂加入Dragonfly Therapeutics研发的白细胞介素-12 （IL-12）药物中，并将其直接注射到肿瘤中，由于B细胞和T细胞之间存在的密切联系，该方法可以激活B细胞并诱导全身抗肿瘤反应。两个团队都表示，他们的方法是具有潜力的癌症治疗方法，可以增强抗肿瘤反应并防止患者癌症复发。什么是癌症疫苗？1890年，科学家发现可以通过外源刺激免疫反应，使肿瘤消退，这也成为了癌症治疗疫苗的理论基石。但由于缺乏对肿瘤抗原的深入了解，癌症疫苗发展缓慢。肿瘤细胞具有极强的反击能力，它们在肿瘤边缘形成了强大的保护层，使很多肿瘤疫苗或转输到体内的T细胞不能发挥抑制肿瘤的功能。医学界对癌症疫苗的研究从未中断，但效果都不理想，Celldex的Rintega、Argos的rocapuldencel-T、和Agenus的Prophage G-200均先后在临床试验中以失败告终。除了HPV疫苗是知名的预防性癌症疫苗外，2010年，FDA批准了全球首个也是目前唯一一款癌症治疗疫苗Provenge（sipuleucel-T），用于治疗晚期前列腺癌。这种疫苗第一次实现了利用患者自身的免疫系统攻击癌细胞的设想。但由于Provenge效果一般，价格却不便宜，其研发公司Dendreon最终也以破产告终。目前，癌症疫苗中疗效及预防复发效果较为突出的是树突状细胞疫苗和个性化新抗原疫苗等，树突状细胞（DCs）能提呈肿瘤蛋白给适应性免疫细胞（如T细胞），帮助激活T细胞免疫反应进而攻击肿瘤细胞。DC疫苗的主要优势之一是，其不存在HLA不匹配的风险。在德国、日本也有树突状细胞疫苗用于临床辅助治疗多种癌症，如肺癌、肝癌、肾癌、乳腺癌、皮肤癌等，这是癌症患者治疗的新希望。肿瘤免疫治疗的机理是什么？肿瘤免疫治疗通过调控免疫系统来达到控制肿瘤的目的，所以肿瘤免疫治疗的直接作用目标是免疫细胞而不是肿瘤细胞。肿瘤免疫治疗的目的是恢复或增强免疫细胞识别和清除肿瘤细胞的能力，其治疗效果取决于诱导出的免疫细胞清除肿瘤细胞的能力。免疫反应有两种类型：固有免疫反应和适应性免疫反应。前者反应快，不具有抗原特异性；后者反应较慢，对抗原具有特异性，并具有记忆功能，是保护性免疫疫苗的理论基础。巨噬细胞和自然杀伤细胞（NK细胞）是两种主要的能杀伤肿瘤的固有免疫细胞。适应性免疫细胞主要包括T细胞和B细胞。肿瘤细胞与正常细胞不同，它们表达独特的肿瘤抗原，这些肿瘤抗原能被T细胞识别而引发免疫反应。肿瘤抗原是包埋在MHC分子内的，而不是直接表达在肿瘤细胞表面。MHC提呈的抗原被T细胞表达的T细胞受体识别。一个T细胞只能表达一种T细胞受体并且只能识别一种抗原。与T细胞不同，B细胞不直接杀死肿瘤细胞，而是产生攻击分子（又叫抗体）。这些抗体能够捕捉目标抗原，一种抗体只能和一种抗原结合。一旦抗体与抗原结合，它们要么阻断这个靶分子的功能，要么引导其他免疫细胞（如巨噬细胞和自然杀伤细胞）杀死表达抗原的靶细胞，这一过程称为抗体依赖的细胞介导的细胞毒性作用（ADCC）。在肿瘤治疗中，特别是血液肿瘤中，ADCC起着关键作用。1T细胞+NK细胞，通用型疫苗癌症疫苗的工作原理是诱导T细胞对肿瘤细胞表面的特定抗原产生反应。但肿瘤细胞可以发展出各种各样的机制来干扰抗原向T细胞呈递，从而隐藏自己不被免疫系统识别。更重要的是，每个个体的肿瘤抗原可能是不同的，因此很难设计出一款可以同时治疗很多患者的通用型癌症疫苗。Dana-Farber的科学家们在Kai Wucherpfennig医学博士的带领下，针对两种表面蛋白：MICA和MICB进行了疫苗的研发。主要组织相容性复合体（MHC）相关蛋白A和B（MICA/MICB）属于应激蛋白。MHC的主要功能是将抗原“呈现”在细胞表面，供合适的T细胞识别。MHC可测量细胞内是否有肿瘤抗原，因此该指标在许多实体瘤上高水平表达。在DNA损伤等应激条件下，这些蛋白质的表达可能会增加。然后它们结合并激活T细胞和NK细胞，从而清除异常细胞。但是肿瘤细胞可以通过切断MICA和MICB，使其脱落，从而逃脱这种免疫反应。新的疫苗诱导抗体抑制肿瘤细胞MICA/MICB脱落到无法检测到的水平，并将不同群体的T细胞和NK细胞招募到小鼠的肿瘤中。此种疫苗可同时调动T细胞和NK细胞，从而对肿瘤细胞起到杀伤作用，还能避开肿瘤细胞的免疫逃逸机制。该疫苗进入了临床试验的哪个阶段？在此项临床研究中，研究人员在小鼠中进行体内试验来检验疫苗的作用。这款抗癌疫苗MICB-vax（针对MICB α3结构域设计的疫苗）在控制表达MICB/MICA的黑色素瘤细胞和淋巴瘤细胞方面显示出显著功效。更为惊喜的是，MICB-vax疫苗还可有效抑制肿瘤转移、预防肿瘤复发。在侵袭性黑色素瘤的小鼠模型中，MICB疫苗显著缩小了肿瘤，在某些情况下甚至根除了肿瘤，而对照组小鼠则出现了主要肿瘤的生长。该团队还在患有黑色素瘤的小鼠身上测试了这种疫苗，这些小鼠对目前的免疫疗法具有耐药性，但在接受该疫苗治疗后效果良好。50%至75%的小鼠在疫苗治疗后100天以上保持无瘤状态。进一步的分析表明，为有效控制肿瘤，T细胞和NK细胞都是不可或缺的。基于在小鼠体内试验的积极疗效以及在猴子体内试验的一些免疫原性和安全性结果，Dana-Farber的科学家们表示，他们目前正计划对这种疫苗进行首次人体试验。研究人员在《Nature》杂志的研究中写道，这种疫苗“也可能与局部放疗相结合，因为DNA损伤会增强癌细胞的MICA/MICB表达”。值得一提的是，由于表达MICA/MICB是肿瘤普遍的特点，因此针对此靶点的疫苗具有通用型，不用针对每位患者进行个性化定制，此研究使通用型抗癌疫苗的研发迈出了重要一步。2B细胞的意外发现，局部+远端同时治疗从传统的细胞毒化疗药物、小分子抑制剂、到免疫检查点抑制剂治疗，肿瘤治疗的方法呈爆发式发展。这些进展同时也伴随着新的毒性和疾病。免疫相关不良事件最常累及的器官是胃肠道、皮肤和内分泌系统。与传统的化疗相比，肿瘤免疫治疗有着特殊的不良反应谱。免疫治疗相关不良反应的早期识别和治疗是患者管理的重要环节。白细胞介素12（IL-12）是由P35和P40亚基组成的异源二聚体，是诱导细胞免疫的主要细胞因子之一。在肿瘤微环境中，IL-12刺激活化的T细胞和自然杀伤细胞（NK）释放毒杀性的酶类或分泌效应细胞因子如IFNγ，这些效应分子对于肿瘤的清除至关重要。IL-12可以激活免疫细胞的细胞因子，被认为是一种有效的抗肿瘤药物，但毒性一直是限制IL-12临床应用的主要原因。斯坦福大学的研究团队尝试将Dragonfly Therapeutics改良的IL-12药物以低剂量方案注射到肿瘤局部，同时利用其治疗潜力以降低毒性。根据2020年签署的一项协议，百时美施贵宝（Bristol Myers Squibb）已经授权Dragonfly公司的IL-12候选药物（编号为DF6002或BMS-9896415）用于癌症治疗。研发团队有什么新发现？在他们的研究中，由医学博士Ronald Levy领导的斯坦福团队意外发现，在接受局部免疫治疗后，B细胞竟然还能有助于远处肿瘤的缩小。斯坦福大学的科学家进一步添加了Dynavax公司的疫苗佐剂CpG SD-101作为刺激，以实现更有效的T细胞免疫反应。在淋巴瘤、结肠癌、三阴性乳腺癌和黑素瘤的多个小鼠模型中，联合治疗实现了局部和远处肿瘤控制，并显著提高了动物的生存率。虽然这种治疗是为了增强T细胞介导的反应，但科学家们惊奇地发现，B细胞在这种全身反应中也是必不可少的。研究小组发现，在联合治疗之前和治疗期间，用抗CD20抗体清除B细胞可以消除全身效应。在进一步研究了B细胞的行为后，研究小组发现B细胞产生了肿瘤特异性抗体。在第一个肿瘤附近的淋巴结中，它们将肿瘤抗原呈递给T细胞。这些处理过的T细胞随后移动到远处的肿瘤并杀死它们。斯坦福大学团队在研究中写道，“我们的数据表明，在未来， B细胞在其他形式的肿瘤免疫治疗中的作用应该被研究。提供B细胞刺激的药物可以加入到T细胞刺激的方法中，以增强免疫治疗方案的效力和特异性。”3结语了解免疫系统及其肿瘤治疗中的作用有助于开发早期抗肿瘤疫苗。疫苗能够刺激宿主产生免疫力对抗肿瘤，而且方便在门诊使用且毒性更小。但是，缺乏理想的抗原以及疗效较差是目前抗肿瘤疫苗研发的主要瓶颈。理想的抗肿瘤疫苗必须克服肿瘤细胞产生的免疫耐受。随着人类对免疫系统作用机制的进一步了解，对癌症疫苗的研发也会取得更多的突破，相信不远的将来，癌症或许不再是人类无法攻克的疾病。参考资料：https://www.fiercebiotech.com/research/novel-cancer-vaccines-dana-farber-and-stanford-look-beyond-t-cells-better-fight-tumors《通用型癌症疫苗获重大突破！同时激活T细胞和NK细胞，有望治疗多种癌症！》《癌症疫苗30年，为什么就是研发不出来？》其他公开资料。版权声明/免责声明本文为原创文章，版权归拥有者。仅供感兴趣的个人谨慎参考，非商用，非医用、非投资用。欢迎朋友们批评指正！衷心感谢！文中图片、视频为授权正版作品，或来自微信公共图片库，或取自网络根据CC0协议使用，版权归拥有者。任何问题，请与我们联系（电话：13651980212。微信：27674131。邮箱：contact@drugtimes.cn）。衷心感谢！推荐阅读寒冬之下，逆势前行！2021年度中国最佳「生物医药领域投资案例」TOP10出炉，这些公司有何特别之处？生物经济来临，如何应对挑战，穿越AI制药产业新周期？受美国预摘牌影响的14家中国药企之股价、市值分析 | 药时代出海系列中国新药出海，传奇再现！全球新，中国创！本维莫德终获FDA批准！恒瑞喜讯频传！。。。| 药时代出海系列2022 ASCO 各领域口头报告一览（附：731页ASCO 会议摘要）【诚聘付费专家】电话咨询主题：抑郁症、肺鳞癌、黑色素瘤、糖尿病、肥胖新药研发之竞争格局与潜在机遇Fierce Biotech裁员盘点：生物技术行业正向着“小而精”的趋势发展药时代BD项目 | 高亲和力、高效能CD24靶向单克隆抗体斑秃患者的福音！JAK抑制剂CTP-543的III期临床试验取得阳性结果！维昇药业首个关键3期临床试验达到主要终点点击这里，帮您找到理想的合作伙伴！

December 14, 2016 By Karl Thiel for BioSpace.com Many of us will be glad to see the end of 2016, a year that was marked by terrorism both domestic and international, a string of celebrity deaths, a new disease scourge (Zika became the new Ebola), and a whole lot of political turmoil that made for some tense Thanksgiving table conversations. Here in our little corner of the world, there was plenty of volatility too. So without further delay, let’s count down this year’s wholly subjective list of the year’s top 10 biotech trends and events. #10: Brexit. The U.K.'s decision to exit the European Union will likely have some broad-reaching and long-lasting effects, most of which are yet to be felt. In the short term, the move has been on balance positive for U.K.'s pharma sector—for a simple reason. A historically weak pound sterling is helping companies like GlaxoSmithKline and AstraZeneca boost dollar-denominated profits. Rumors initially swirled that both these pharma giants would pull up roots and leave the U.K., but that doesn’t appear to be the case, at least for now. Longer term, it remains to be seen if some of the bigger fears—failure to attract or retain top talent, securing investment, and keeping favorable trade deals—come to fruition. #9: Sharply declining approvals. Both 2014 and 2015 were tough acts to follow. There were 45 novel drugs approved last year; 41 the year before. As I write, there have only been 19 novel drugs approved in 2016—putting this on track to be the worst year since 2007. This isn’t necessarily the FDA’s fault—they can only approve the applications these receive…and some would argue that the agency has, if anything, been overly lenient in granting approvals this year. #8: Lots of big clinical failures. While 2016 has certainly had its bright spots, the year has been more notable for high-pro failures than for its successes. There’s BioMarin’s drisapersen, Celldex Therapeutics’ Rintega, Eli Lilly’s solenuzumab, Alnylam’s Revusiran, Clovis Oncology’s rociletinib, and Bristol Myers-Squibb’s Opdivo in lung cancer. Juno Therapeutics has run into some serious, perhaps program-ending difficulties with JCAR-015. Gilead has had a bad run of luck with almost everything it touched this year, from GS-5745 (in ulcerative colitis) to simtuzumab to eleclazine to Zydelig (in first-line cancer applications). Bluebird Bio went from hot to not after turning out disappointing early results in its sickle cell programs. There have been some great achievements (see below)—but it’s hard to counter-balance this depressing list. #7: The drug price debate continues, then stops, then starts up again. Drug companies always make juicy political targets, so it’s no surprise that the heat stayed high all during this election year. It’s been a debate long on rhetoric and short on substance, with the main result being that companies grew more eager to get in price increases before the music stopped. Some, of course, were a little more ham-fisted about than others (cough, Mylan ). Pharma investors breathed a sigh of relief after the election of Donald Trump (see point #1 below), but that sense of resolution may have come too early. Also, don’t forget about some of the most visible faces of price-gouging— Valeant subsidiary Philidor and its CEO have had criminal charges filed against them, and there may be more to come. Martin Shkreli is guaranteed to be back in the news in 2017, since that’s when his criminal fraud trial is likely to take place. #6: M&A slowed to a comparative crawl. 2015 was a record-breaking year for biopharma M&A, with some $330 billion in deals, even after you factor out the $183 billion Pfizer - Allergan link-up that never happened. Few expected this year to match that sum, but fewer still expected the totals to drop so sharply. The final tallies won’t be in until the New Year, but 2016 was recently running under $100 billion in pharma and biotech M&A. Will a flood of repatriated cash, courtesy of a new Trump tax policy, change the calculus in 2017? I have my doubts (and not only because it will take a while to change the tax code, even with a willing Congress). But it wouldn’t be surprising to see the pace pick up at least a little next year. #5: Market meltdown. The “Trump bump” to the stock market—and the biotech market in particular—was nice for investors while it lasted. Even at its best, it did little to erase what happened in the opening weeks of 2016. As we stand now, the Nasdaq Biotech Index, up less than 2 percent since the election. It is down over 20 percent year-to-date. A number of other points in this list help explain why. #4: The (controversial) rise of antisense. Antisense has been kicking around since the 1980s without much commercial success. While that technically continued to be true this year, it’s about to change. Spinraza, the antisense drug for spinal muscular atrophy developed by Ionis Pharma and Biogen , produced strong enough results in a study of infantile onset spinal muscular atrophy that the trial was stopped early. Since then, robust signals have been seen in patients with later-onset disease. And the drug reportedly has a reasonably clean safety pro since side effects and safety concerns have dogged some other antisense drugs. Then there’s Sarepta’s eteplirsen, trade-named Exondys 51, approved to treat Duchenne muscular dystrophy is a specific subset of patients. The decision to approve was controversial and, according to some, undermined the credibility of the FDA. Certainly it remains unclear whether the drug’s miniscule effect on dystrophin production will create a meaningful change in the course of the disease. But that probably won’t stop it from racking up hundreds of millions of dollars in sales. #3: CAR-T meltdown? Cancer immunotherapy has been so hot over the past few years that some pundits have bemoaned a lack of research dollars going elsewhere. CAR-T seems like an obvious next step—a way to program T-cells to attack specific cancers. And early clinical results have shown astounding success, producing apparent cures in leukemia. But the therapy has turned out to be quite dangerous in some situations, dousing another fire that burned so bright for biotech in 2015. That’s been particularly true for Juno Therapeutics , which has put its pivotal trial of JCAR-015 on clinical hold twice. Novartis , once arguably the leader in the area, seemingly stepped back from CAR-T this past summer, dissolving its dedicated unit, bringing programs back into the larger organization and perhaps putting less emphasis on the technology (though they continue to push forward). Kite Pharma is the beneficiary of these developments, yet investors are regarding the company warily. The stock is down sharply for the year and well off its 52-week high even as it files for its first approval. Call it another case of hype waking up to reality: CAR-T remains a very promising technology, but it’s still unclear how effective it will be outside of blood cancers, and how it will be used even in leukemias, where oncologists will have to weigh up robust results against serious potential risks. #2: CRISPR goes public. At the start of the year, there were zero pure-play companies in the CRISPR space. Now there are three— Editas Medicine , Intellia Therapeutics , and CRISPR Therapeutics —not to mention a bunch more companies dabbling in the space. But these companies—which have had a mixed-at-best reception with investors—are only the tip of the iceberg, held back in part by complex and acrimonious intellectual property disputes. CRISPR has exploded around the world, with the University of Pennsylvania planning a seeming Hail Mary pass into clinical trials thanks to funding from the Parker Institute, only to be beaten to the punch by Sichuan University in China. Even without clinical trials, the technology is making all sorts of experiments possible—even if some raise safety or ethical issues. By this time next year, perhaps we’ll all have access to giant CRISPR beagles . #1: Trump elected president. This election upset takes the number one spot. But what it means for the biotech sector (or anything else) remains unclear. Trump has certainly been known to spout anti-science rhetoric and anti-vaxxer drivel. He’s said he wants to cut drug prices, using mechanisms like reimportation and direct Medicare negotiation. But then he went mum on those topics. And then he started up again, so who knows? He has said he wants to streamline FDA and get medicines to people more quickly, pushing a popular political hot button. But does that mean a bigger FDA budget, laxer standards, or something else? It seems likely, based on both his rhetoric and his choice of Rep. Tom Price (R-Ga.) as Secretary of Health and Human Services , that he plans to make good on his promise to repeal and replace Obamacare. Yet how will that play out? The Affordable Care Act has generally been popular with drug companies, because it has given them millions of new customers. But it has also come with new regulatory burdens, like requirements to compile and submit data to Patient Centered Outcomes Research Institutes. What is simply repealed and what is replaced will have a big impact on companies. Here’s another irony: One interesting impact of Obamacare is that it gives the president fairly broad authority to enact price controls when Medicare grows at a certain level beyond inflation—as it is expected to do in 2017 for the first time since the law was passed. So biopharma companies who’ve thus far seen the most favorable side of the law may be saved from its restrictions just before the hammer comes down—if Trump and Congress do indeed repeal. But maybe Trump will decide he likes the authority in the current law. However it goes down, it’s going to be an interesting 2017. - Karl Thiel Read the BioPharm Executive online newsletter December 14, 2016. Sign-up for the free monthly subscription to the BioPharm Executive Related Jobs VP, Clinical Development Director, Genomics VP, Clinical Development Director of Operations VP, Sales Director, Biostatistics View More Jobs