Aldesleukin

正文共2146字 共2图预计阅读时间：7分钟资本寒冬之际，Xilio Therapeutics Ink却迎来了命运高光时刻，先是公布了总额最高超6亿美元的合作，后又迎来了1130万美元的融资。两笔巨额资金无疑是雪中送炭，让Xilio“起死回生”。2023年时，Xilio曾宣布其现有资金只够维持到2024年年中。但如今来看，Xilio维持到2025年应该不成问题。而Xilio的好运气大部分来自一个已经过气的靶点“IL-12”，关系到一个陷入困局的研发方向“细胞因子疗法”。引言1909年，奥地利科学家Paul Ehrlich首次提出了“免疫监视”（Immune Surveillance）的概念，Paul推测免疫系统具有识别并清除体内异常细胞（包括潜在癌变细胞）的能力。这一理论为后来肿瘤免疫（IO，Immunooncology）治疗的研究奠定了理论基础。历经数十年的实验与临床探索，一个又一个突破性的发现接连出世，肿瘤免疫治疗逐渐形成了包括免疫检查点抑制剂、过继性细胞疗法、免疫激动剂（包括细胞因子疗法）、免疫调节细胞疗法、肿瘤疫苗等多个研究方向。其中风头最盛的是以PD-1/PD-L1抑制剂为代表的免疫检查点抑制剂，新任药王K药就是其中的代表产品。同属于IO治疗，细胞因子疗法也被予以厚望，业界期待在这个领域有朝一日可以诞生如K药一样百万级别的重磅产品。细胞因子于20世纪七八十年代被发现，在肿瘤领域的应用已得到临床验证。1981年，FDA批准了首个细胞因子药物——干扰素α（IFNα），用于治疗慢性乙型肝炎和毛细胞白血病。1992年，FDA又批准Chiron Corporationde 的aldesleukin（重组IL-2）用于转移性肾癌的治疗。白细胞介素-12（IL-12）则是继IL-2之后又一个被看好的方向。IL-12是怎么在肿瘤治疗领域起作用的？介绍IL-12在肿瘤治疗中的作用机理之前，先要了解一个有趣的概念，即“热”肿瘤和“冷”肿瘤。所谓“热”和“冷”实际上描述的是肿瘤内免疫细胞的活性程度。其中，“热”肿瘤内部富含CD8+T细胞和NK细胞，这两种细胞均是对抗肿瘤细胞的关键效应细胞，可直接识别并杀伤肿瘤细胞。而冷肿瘤的情况与之截然相反，不仅缺乏CD8+T细胞和NK细胞，内部还存在一些抑制免疫反应的细胞。因此，相比之下热肿瘤往往更容易对肿瘤免疫治疗更敏感。此外，丰富的CD8+ T细胞和NK细胞往往伴随着局部的炎症反应和相关的促炎细胞因子（如IFN-γ、TNF-α等）的产生。这种炎症微环境虽然可能导致一定程度的肿瘤相关炎症，但也可能有利于吸引和激活更多的免疫细胞，形成对肿瘤的持续压力。了解了以上内容，让我们回到IL-12本身。IL-12由先天免疫细胞和抗原递呈细胞产生，可激活T细胞、NK细胞和巨噬细胞，并且将进一步诱导产生IFN-γ等细胞因子，这些细胞因子可增强CD8+T细胞、NK细胞的抗肿瘤活性，抑制肿瘤血管生成。最重要的是，IL-12能通过重塑肿瘤微环境，将将原本对免疫“冷”的肿瘤转化为“热，增加对现有免疫疗法的敏感性。图片来源：Xilio官网作为免疫治疗组合的一部分，IL-12还可与免疫检查点抑制剂、其他细胞因子疗法、肿瘤疫苗、放化疗等联用，可能产生协同效应，进一步增强免疫反应，提高治疗响应率。尤其是在对单一疗法响应不足的患者群体中，IL-12作为联合治疗的组成部分，可能提供新的治疗机会。表现出的巨大潜力让业界看到了新机遇，于是一众MNC纷纷合作入局，却又都草草收场。往事不可追忆纵览IL-12在肿瘤治疗方面的研究，OncoSec的TAVO（IL-12的质粒DNA药物）进度最快，其关于黑色素瘤的研究目前已进入III期临床阶段。除此之外，大部分研究还处在I期临床。这其中有不少MNC的影子，但均为与第三方合作/授权的项目，结果也未见突破性进展。翻来翻去，一半是“失败”，另一半是“进行中”。2018年，远大医药联营公司OncoSec Medical Incorporated（OncoSec）与默沙东合作，启动了TAVO（IL-12的质粒DNA药物）和K药（PD-1）联用治疗晚期三阴性乳腺癌的II期临床研究（KEYNOTE-890）。2020年时，KEYNOTE-890研究得出积极结果，OncoSec宣布计划将此试验提升至一线治疗三阴性乳腺癌。两年后，两家公司又启动了另一项III期KEYNOTE-C87研究，旨在研究TAVO与K药联用对难以通过免疫检查点治疗方案获益的晚期黑色素瘤患者总生存期方面的影响。2020年8月，BMS花费4.75亿美元获得了Dragonfly Therapeutics开发的IL-12在研免疫疗法DF6002的全球独家许可。DF6002是一种单价IL-12细胞因子与Fc融合形成的融合蛋白，具有延长的半衰期。不到三年（2023年2月），BMS宣布退回了DF6002。理由是：DF6002的临床表现未达预期。目前，被退回的DF6002由Dragonfly继续开发。就在一年前，阿斯利康陆续停止了两项IL-12疗法与PD-L1联用治疗实体瘤的I期临床试验。2022年11月，因治疗效果有效，阿斯利康宣布停止MEDI9253项目。2023年2月，阿斯利康宣布管线优化计划，项目MEDI1191赫然在列。试验数据不如意，MNC又接连退出。再加上全球资本寒冬，不少公司管线缩紧，IL-12的头顶一片阴霾。MNC的又一次押注IL-12最近又被提起，是因为吉利德的一项合作。几天前，吉利德与Xilio达成独家许可协议，用4350万美元的预付款拿下了Xilio的一款处于I期临床的IL-12项目：XTX301。据悉，通过这项合作，Xilio将有机会拿到最高6亿美元的收益。在先行者接连挑战失败的情况下，吉利德却大手笔入场，是在XTX301身上看到了成功的希望吗？从理论上讲，XTX301的确有其独特之处。由于引入掩蔽结构和半衰期延长结构，XTX301可以实现在肿瘤局部高效释放活性IL-12，达到减少毒性、扩大治疗窗的作用，这恰好解决了IL-12全身给药会导致严重系统性毒性这一难题。图片来源：Xilio官网这一点也得了其I期爬坡试验数据的支持。试验结果显示，在高剂量下，受试者耐受性良好，且未观察到剂量限制性毒性。但这并不能保证之后的试验也一样顺利，掩蔽结构的临床有效性也还需要更多试验去验证，XTX301的成功目前还无法保证。或许，这仅仅只是吉利德一次普普通通的押注，成功固然是好，失败也可以承受。但对于仅有技术傍身的Xilio来讲，这次合作却直接影响了今后的命运。参考资料1.各公司官网2.其他公开资料封面图来源：PIXABAY版权声明/免责声明本文为团队原创文章。本文仅作信息交流之目的，不提供任何商用、医用、投资用建议。文中图片、视频、字体、音乐等素材或为药时代购买的授权正版作品，或来自微信公共图片库，或取自公司官网/网络，部分素材根据CC0协议使用，版权归拥有者，药时代尽力注明来源。如有任何问题，请与我们联系。衷心感谢!药时代官方网站:www.drugtimes.cn联系方式:电话:13651980212微信:27674131邮箱:contact@drugtimes.cn点击阅读原文，了解更多！

SAN CARLOS, Calif., March 22, 2024 (GLOBE NEWSWIRE) -- Iovance Biotherapeutics, Inc. (NASDAQ: IOVA) ("Iovance" or the “Company”), a biotechnology company focused on innovating, developing, and delivering novel polyclonal tumor infiltrating lymphocyte (TIL) therapies for patients with cancer, today announced that on March 22, 2024 (the “Date of Grant”), the Company approved the grant of inducement stock options covering an aggregate of 97,700 shares of Iovance’s common stock to twenty new, non-executive employees. The awards were granted under Iovance’s 2021 Inducement Plan, which was adopted on September 22, 2021 and amended on January 12, 2022 and May 10, 2023, and provides for the granting of equity awards to new employees of Iovance by the Company’s compensation committee in accordance with Nasdaq Listing Rule 5635(c)(4). Each of the stock options granted as referenced in this press release has an exercise price of $15.02, the closing price of Iovance’s common stock on the Date of Grant. Each stock option vests over a three-year period, with one-third of the shares vesting on the first anniversary of the employee’s start date (the “First Vesting Date”), and the remaining shares vesting in eight quarterly installments over the next two years, commencing with the first quarter following the First Vesting Date, subject to continued employment with the Company through the applicable vesting dates. About Iovance Biotherapeutics, Inc. Iovance Biotherapeutics, Inc. aims to be the global leader in innovating, developing, and delivering tumor infiltrating lymphocyte (TIL) therapies for patients with cancer. We are pioneering a transformational approach to cure cancer by harnessing the human immune system’s ability to recognize and destroy diverse cancer cells in each patient. The Iovance TIL platform has demonstrated promising clinical data across multiple solid tumors. Iovance’s Amtagvi™ is the first FDA-approved T cell therapy for a solid tumor indication. We are committed to continuous innovation in cell therapy, including gene-edited cell therapy, that may extend and improve life for patients with cancer. For more information, please visit www.iovance.com. Amtagvi™ and its accompanying design marks, Proleukin®, Iovance®, and IovanceCares™ are trademarks and registered trademarks of Iovance Biotherapeutics, Inc. or its subsidiaries. All other trademarks and registered trademarks are the property of their respective owners. Forward-Looking Statements Certain matters discussed in this press release are “forward-looking statements” of Iovance Biotherapeutics, Inc. (hereinafter referred to as the “Company,” “we,” “us,” or “our”) within the meaning of the Private Securities Litigation Reform Act of 1995 (the “PSLRA”). Without limiting the foregoing, we may, in some cases, use terms such as “predicts,” “believes,” “potential,” “continue,” “estimates,” “anticipates,” “expects,” “plans,” “intends,” “forecast,” “guidance,” “outlook,” “may,” “could,” “might,” “will,” “should,” or other words that convey uncertainty of future events or outcomes and are intended to identify forward-looking statements. Forward-looking statements are based on assumptions and assessments made in light of management’s experience and perception of historical trends, current conditions, expected future developments, and other factors believed to be appropriate. Forward-looking statements in this press release are made as of the date of this press release, and we undertake no duty to update or revise any such statements, whether as a result of new information, future events or otherwise. Forward-looking statements are not guarantees of future performance and are subject to risks, uncertainties, and other factors, many of which are outside of our control, that may cause actual results, levels of activity, performance, achievements, and developments to be materially different from those expressed in or implied by these forward-looking statements. Important factors that could cause actual results, developments, and business decisions to differ materially from forward-looking statements are described in the sections titled "Risk Factors" in our filings with the U.S. Securities and Exchange Commission, including our most recent Annual Report on Form 10-K and Quarterly Reports on Form 10-Q, and include, but are not limited to, the following substantial known and unknown risks and uncertainties inherent in our business: the risks related to our ability to successfully commercialize our products, including Amtagvi and Proleukin, for which we obtain U.S. Food and Drug Administration (“FDA”), European Medicines Agency (“EMA”), or other regulatory authority approval; the risk that the EMA or other regulatory authorities may not approve or may delay approval for our biologics license application (“BLA”) submission for lifileucel in metastatic melanoma; the acceptance by the market of our products, including Amtagvi and Proleukin, and their potential pricing and/or reimbursement by payors, if approved (in the case of our product candidates), in the U.S. and other international markets and whether such acceptance is sufficient to support continued commercialization or development of our products, including Amtagvi and Proleukin, or product candidates, respectively; our ability or inability to manufacture our therapies using third party manufacturers or at our own facility may adversely affect our commercial launch; the results of clinical trials with collaborators using different manufacturing processes may not be reflected in our sponsored trials; the risk regarding the successful integration of the recent Proleukin acquisition; the risk that the successful development or commercialization of our products, including Amtagvi and Proleukin, may not generate sufficient revenue from product sales, and we may not become profitable in the near term, or at all; the risk that future competitive or other market factors may adversely affect the commercial potential for Amtagvi or Proleukin; the risks related to the timing of and our ability to successfully develop, submit, obtain, or maintain FDA, EMA, or other regulatory authority approval of, or other action with respect to, our product candidates; whether clinical trial results from our pivotal studies and cohorts, and meetings with the FDA, EMA, or other regulatory authorities may support registrational studies and subsequent approvals by the FDA, EMA, or other regulatory authorities, including the risk that the planned single arm Phase 2 IOV-LUN-202 trial may not support registration; preliminary and interim clinical results, which may include efficacy and safety results, from ongoing clinical trials or cohorts may not be reflected in the final analyses of our ongoing clinical trials or subgroups within these trials or in other prior trials or cohorts; the risk that enrollment may need to be adjusted for our trials and cohorts within those trials based on FDA and other regulatory agency input; the risk that the changing landscape of care for cervical cancer patients may impact our clinical trials in this indication; the risk that we may be required to conduct additional clinical trials or modify ongoing or future clinical trials based on feedback from the FDA, EMA, or other regulatory authorities; the risk that our interpretation of the results of our clinical trials or communications with the FDA, EMA, or other regulatory authorities may differ from the interpretation of such results or communications by such regulatory authorities (including from our prior meetings with the FDA regarding our non-small cell lung cancer clinical trials); the risk that clinical data from ongoing clinical trials of Amtagvi will not continue or be repeated in ongoing or planned clinical trials or may not support regulatory approval or renewal of authorization; the risk that unanticipated expenses may decrease our estimated cash balances and forecasts and increase our estimated capital requirements; the effects of the COVID-19 pandemic; and other factors, including general economic conditions and regulatory developments, not within our control. CONTACTS Iovance Biotherapeutics, Inc:Sara Pellegrino, IRCSenior Vice President, Investor Relations & Corporate Communications650-260-7120 ext. 264Sara.Pellegrino@iovance.com Jen SaundersSenior Director, Investor Relations & Corporate Communications267-485-3119Jen.Saunders@iovance.com