FDA全票通過 Novartis基因治療 (CAR-T : CTL019 for pediatric, young adult r/r B-cell ALL)

FDA委员会建议批准白血病的基因疗法本周三美国食药监(FDA)的一个委员会打开了医药领域的新纪元，全体委员一致建议FDA批准一项先锋疗法，该疗法可以从基因水平改变病人的细胞，使之成为一种"活体药物"，通过强力增进患者的免疫功能来对抗癌症。FDA很有可能接受这项建议——一旦批准，该疗法将成为首个上市的基因疗法。诸多的研究者和药企为达到这一里程碑，彼此间业已激烈竞争了几十年，他们都对此充满期待。Novartis公司已经蓄势待发。该药物主要用于治疗某一类型的白血病，不过在数百名另一型白血病的病人身上也有作用，还可用于治疗多发性骨髓瘤和侵袭性脑肿瘤等。为了运用这项技术，每位患者需接受单独定制的疗法——将他们的细胞在有资质的医疗机构进行分离、冻存、递送至Novartis的工厂进行复苏和处理、再次冻存并寄回原址。数十名参与此项研究的患者已经用尽了所有其他疗法而不见起色，时刻面临死亡，但在接收了此疗法的单次治疗后便获得了较长的缓解期，甚至有治愈的可能。委员会推荐将这项疗法用于年龄在3至25岁、患有难治性或复发性急性B淋巴细胞白血病的患者。今年12岁的Emily Whitehead是第一个接受了转化细胞的儿童。在父母的陪伴下，她来到委员会的面前支持批准这一救命神药。2012年，时年6岁的她在费城儿童医院参与到这项研究中。骤升的体温、急降的血压、肺血管的栓塞——种种不良反应几乎要了她的命。但是她的癌症消失了，并且一直保持到了今天。Emily的父亲Tom Whitehead告诉委员会："我们相信这项疗法一旦通过，将拯救全世界数以千计的孩子们的生命。我希望有朝一日坐在对面的各位委员可以告诉你们的后代，你们也曾致力于终止将有害的放化疗作为标准疗法、将血液肿瘤变成一种可治愈的疾病，使得大多数患者即使复发也能活下来。"Novartis展现在FDA面前的主要证据来自一项在2015年4月-2016年8月开展的、包括了63名患者的研究。其中52人(占82.5%)进入缓解期——对此种严重的疾病来说算是很高了。11人死亡。Dr. Gwen Nichols说："这是一个全新的世界，一项激动人心的疗法。"她是"白血病与淋巴瘤协会"的首席医学官，该协会为部分相关研究提供了资金支持。她表示，下一步就是"找一找可与之联用的疗法，或是看看能否将此种疗法用于轻症患者，他们的免疫系统功能更好，更能抗病"。她补充说："这是宏大蓝图的开端。"会上，委员会的各位专家并未质疑此种疗法在绝症患者身上救命的能力。不过他们很关心潜在的致命副作用——短期的担忧集中在Emily经历过的急性期反应上，长期的忧虑则是关于融合细胞是否会在数年之后引起继发肿瘤等多种问题。肿瘤学家已经学会如何应对急性期反应，而时至今日尚未侦测到长期的问题，但排除这些问题所需的时间还不够长。接受这项疗法的患者需进行登记，并持续随访15年。治疗中用到的活细胞属于"生物制剂"，比一般的药物更难制造，委员们也担心Novartis在扩大生产规模后能否保持高品质，发挥持续的疗效。会上的另一位家长Don McMahon讲述了他的儿子Connor自3岁患上重型复发型白血病以来，总计12年的痛苦病史。在McMahon先生展示的照片上，Connor插着气管导管，头上没有一根头发。他说化疗让他的儿子失去了生育能力。一年前，当Connor的家人在为骨髓移植做准备时听说了这个细胞疗法，随后便送他去杜克大学加入进去。当他回家的时候都能打冰球了。McMahon先生表示，标准的治疗要求数不清的脊椎穿刺和痛苦的骨髓检测，相比之下T细胞疗法更容易承受；他敦促委员会投下赞成的一票。第3位家长Amy Kappen也建议通过，尽管她5岁的女儿Sophia死在细胞治疗的过程中。不过治疗确实减轻了她的症状，多给了她几个月时间。Sophia的病情太过严重，Kappen女士认为如果能早一点接受治疗的话，Sophia或许能活下来。她说："我们希望更多的与病魔多斗争的家庭和他们的孩子能多一些时间，孩子们理应得到这样的机会。"这项疗法由宾夕法尼亚大学的研究者开发，属Novartis公司所有。这种疾病并不常见，因此新疗法一开始并不会广泛应用。每年患病的人数只有5000人左右，其中60%是儿童和青少年。多数儿童可经标准疗法治愈，但大约15%的患者——比如Emily和Connor这种——对治疗没有反应，或者疾病会复发。分析人士预计这种私人定制疗法的花费可能在30万美元以上，但Novartis的新闻发言人Julie Masow拒绝给出明确的报价。尽管这个数字可能很大，但癌症患者们长年的昂贵治疗和反复入院的费用或许更高。Novartis公司表示，考虑到疗程十分复杂，并且患者需要专家来处理不良反应，公司打算先将疗法的应用限制在30到35家医疗中心的范围，只有这里的雇员可以接受培训并获准使用新疗法。至于这种名为CTL019——又称tisagenlecleucel(念作"提丝A珍赖克鲁塞奥")——的疗法能否推广至其他国家，Masow女士在邮件中表示："一旦CTL019在美国获批，是否接受外国病人就由各中心决定了。我们正致力于将CTL019引进全球各国。"她补充说公司将在今年晚些时候向欧盟提交申请。截止2016年11月下旬，该研究中进入缓解期的52名患者中有11人复发，29人仍在缓解期中，11人接受了骨髓移植等进一步的治疗，1人无法评估。复发的病人中有3人死亡，未复发的病人中有1人死于缓解期接受的新治疗。缓解期的中位时长无法计算，因为一些病人在上次随访中还活得好好的。研究者们还在争论到底哪一类患者可以安全地放弃进一步的治疗，哪一类患者还需要骨髓移植已达到最佳治愈率。这种疗法需要从患者身上分离数以百万的的T细胞——这是一种白细胞，常被称作是免疫系统中的"士兵"——并对其进行基因工程改造，使之成为癌细胞杀手。该技术用到了一种失活的HIV病毒，将新的遗传物质送进T细胞，对其进行编辑改造。这一过程将激发T细胞来攻击白血病中恶变的B细胞。T细胞可以锚定到B细胞表面一个名为CD-19的蛋白上。改造后的T细胞将输注回患者体内，在那里它们可以扩增，开始对抗癌症。宾夕法尼亚大学研究团队的领导人Dr. Carl H. June将这些激活的细胞称为"连环杀手"。1个T细胞就能摧毁多达10万个癌细胞。由于该疗法不仅会摧毁白血病B细胞，同时也会摧毁那些帮助对抗细菌的健康B细胞，患者需要预防感染的治疗措施。每隔几个月他们都要接受免疫球蛋白输注。在这项研究中，改造T细胞用于治疗的过程有时长达4个月，一些患者病情太重，等不到细胞送回来就死了。会上，Novartis称目前的往返时间已缩短至22天。公司还将采用条形码标识等措施，以免生产规模扩大后可能将不同患者的样品搞混。Michael Werner是华盛顿Holland and Knight事务所的一名律师，也是基因与细胞技术方面的法律专家。他表示目前的结果证明T细胞治疗是有效的。他补充说："这个成功的案例意味着会有更多的人进入这一领域，也会有更多的公司开始开发同类产品。我认为我们进入了一个激动人心的时代。"

Novartis CAR-T cell therapy CTL019 unanimously (10-0) recommended for approval by FDA advisory committee to treat pediatric, young adult r/r B-cell ALL  Basel, July 12, 2017 - Novartis announced today that the US Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC) unanimously (10-0) recommended approval of CTL019 (tisagenlecleucel), an investigational chimeric antigen receptor T cell (CAR-T) therapy, for the treatment of relapsed or refractory (r/r) pediatric and young adult patients with B-cell acute lymphoblastic leukemia (ALL). "The panel's unanimous recommendation in favor of CTL019 moves us closer to potentially delivering the first-ever commercially approved CAR-T cell therapy to patients in need," said Bruno Strigini, CEO, Novartis Oncology. "We're very proud to be expanding new frontiers in cancer treatment by advancing immunocellular therapy for children and young adults with r/r B-cell ALL and other critically ill patients who have limited options. We look forward to working with the FDA as they complete their review." Acute lymphoblastic leukemia comprises approximately 25% of cancer diagnoses among children under 15 years old and is the most common childhood cancer in the US[1]. Effective treatment options for patients with r/r ALL are limited. In pediatric and young adult patients with B-cell ALL that have relapsed multiple times or become refractory to treatment, the five-year disease-free survival is less than 10-30%[2],[3],[4]. The ODAC recommendation is based on review of the CTL019 r/r B-cell ALL development program, which includes the Novartis-led ELIANA study (NCT02435849), the first pediatric global CAR-T cell therapy registration trial. Findings from a US multicenter trial and a single site trial examining the safety and efficacy of CTL019 among pediatric and young adult patients with r/r B-cell ALL also supported the recommendation and the Biologics License Application (BLA)[5]. CTL019 was first developed by the University of Pennsylvania (Penn) and uses the 4-1BB costimulatory domain in its chimeric antigen receptor to enhance cellular responses as well as persistence of CTL019 after it is infused into the patient, which may be associated with long-lasting remissions in patients. In 2012, Novartis and Penn entered into a global collaboration to further research, develop and commercialize CAR-T cell therapies, including CTL019, for the investigational treatment of cancers. Children's Hospital of Philadelphia (CHOP) was the first institution to investigate CTL019 in the treatment of pediatric patients and led the single site trial. "It is encouraging to see the FDA panel's recommendation and continued momentum behind this innovative therapy, which has potential to help young patients with relapsed/refractory B-cell ALL," said the Penn team's leader, Carl June, MD, the Richard W. Vague Professor of Immunotherapy, director of the Center for Cellular Immunotherapies in Penn's Perelman School of Medicine and director of the Parker Institute for Cancer Immunotherapy at Penn. "We look forward to continuing to work with Novartis to help make a lasting impact on the way this disease is treated." "We know firsthand from treating children and young adults with relapsed/refractory B-cell ALL that they desperately need innovative medicines that provide a new approach to managing this aggressive disease," said Stephan Grupp, MD, PhD, the Yetta Deitch Novotny Professor of Pediatrics at the Perelman School of Medicine at Penn, Director of the Cancer Immunotherapy Frontier Program and Chief of the Section of Cellular Therapy and Transplant at CHOP. "Today's vote in favor of CTL019 is a positive step and we appreciate Novartis' commitment to pediatric patients." Earlier this year, Novartis submitted a BLA for CTL019 to the FDA, marking the first submission by Novartis for a CAR-T cell therapy. CTL019 previously received FDA Breakthrough Therapy designation and is under Priority Review by the FDA. The FDA will consider the vote as it reviews the BLA, although it is not obligated to follow the recommendation. Novartis continues to invest in the necessary infrastructure for the potential commercialization of CTL019, including manufacturing and the establishment of a network of certified treatment centers. Novartis plans additional filings for CTL019 in the US and EU later this year, including applications with the FDA and European Medicines Agency (EMA) for the treatment of adults with r/r diffuse large B-cell lymphoma (DLBCL).

About CAR-T and CTL019 CAR-T is different from typical small molecule or biologic therapies because it is manufactured for each individual patient using their own cells. During the treatment process, T cells are drawn from a patient's blood and reprogrammed in the manufacturing facility to create T cells that are genetically coded to express a chimeric antigen receptor to recognize and fight cancer cells and other B-cells expressing a specific antigen. ELIANA (NCT02435849) is the first pediatric global CAR-T cell therapy registration trial, with study enrollment having occurred across 25 centers in the US, Canada, EU, Australia and Japan. Because CTL019 is an investigational therapy, the safety and efficacy profile has not yet been established. Access to investigational therapies is available only through carefully controlled and monitored clinical trials. These trials are designed to better understand the potential benefits and risks of the therapy. Because of the uncertainty of clinical trials, there is no guarantee that CTL019 will ever be commercially available anywhere in the world.

About CTL019 Manufacturing The Novartis leukapheresis process using cryopreservation allowed for manufacturing and treatment of patients from around the world. Cryopreserved leukapheresis involves removing white blood cells from a patient's blood and preserving them at very low temperatures. Cryopreserved leukapheresis gives physicians the flexibility to schedule apheresis at a time that is in the best interest of their patients. Novartis commercial manufacturing for CTL019 continues to build on its experience in its Morris Plains, New Jersey facility, which has already manufactured CTL019 for hundreds of patients in global clinical trials. Novartis believes that experience is important in cell therapy manufacturing, and the experience gained at the Morris Plains, New Jersey facility will be a foundation for commercial manufacturing of CAR-T therapies. Novartis has made and continues to make investments in manufacturing.

References

[1] Howlader, N., Noone, A.. M, Krapcho, M., et al. SEER Cancer Statistics Review, 1975-2010. National Cancer Institute, April 2013; Section 28.9 (12).

[2] Oudot, C.., Auclerc, F.., Levy, V., et al. Prognostic Factors for Leukemia Induction Failure in Children With Acute Lymphoblastic Leukemia and Outcome After Salvage Therapy: The FRALLE 93 Study. Journal of Clinical Oncology, March 2008; Volume 28 (9).

[3] Chessels, J., Veys, P., Kempski, H., et al. Long-term follow-up of relapsed childhood acute lymphoblastic leukaemia. British Journal of Hematology, 2003; 123 (3).

[4] Reismuller, B., Peters, C., Dworzak, M., et al. Outcome of children and adolescents with a second or third relapse of acute lymphoblastic leukemia (ALL): a population-based analysis of the Austrian ALL-BFM (Berlin-Frankfurt-Münster) Study Group. Journal of Pediatric Hematology/Oncology. July 2013; 35 (5).

[5] Novartis CTL019 ODAC Briefing Document.