Lifileucel

Pictured: A collage representing cell and gene therapy/Taylor Tieden for BioSpace In 2023, cell and gene therapy saw an unprecedented surge with seven FDA approvals, and this year, an even greater number of these treatments could reach the market. So far in 2024, the regulator has given the green light to three new CGTs, and at least seven additional cell and gene therapy products are expected to receive approval by year’s end, according to a March report from the Alliance for Regenerative Medicine. “All signs point to 2024 surpassing 2023 as a landmark year for cell and gene therapy,” David Barrett, CEO of the American Society of Gene & Cell Therapy (ASGCT), told BioSpace. The first approval this year belonged to Vertex Pharmaceuticals and CRISPR Therapeutics’ Casgevy, which won the FDA’s nod in January for use in transfusion-dependent beta thalassemia. This followed the agency's December 2023 approval of Casgevy as one of the first two cell-based gene therapies to treat patients with sickle cell disease. It also represented the first FDA approval of a therapy using CRISPR/Cas9 technology. Then, in February, Iovance Biotherapeutics’ Amtagvi was approved as the first one-time cell therapy for a solid tumor and the first tumor-infiltrating lymphocytes therapy, for advanced melanoma patients who have worsened after being treated with certain other therapies failed. Finally, last month, the FDA greenlit Orchard Therapeutics’ Lenmeldy, which entered the U.S. market as the first gene therapy for children with metachromatic leukodystrophy, and the word’s most expensive drug, with a $4.25 million price tag. Looking forward, the FDA has upcoming PDUFA dates for several more novel CGTs, including a traditional in vivo gene therapy delivered via viral vector, a couple of gene-corrected cell therapies in which a patient’s cells are modified by gene therapy outside of the body and then reinfused, and a new CAR-T. Two Q1 reports, from ASGCT and the Alliance for Regenerative Medicine, highlight some of these regulatory actions as potential catalysts for the sector, with approvals poised to propel the CGT space. The ASGCT report includes a list of noteworthy events in Q1 2024, while ARM’s report makes the case that 2024 could be a banner year for cell therapy. Here, BioSpace reviews five products under regulatory review that were highlighted by both organizations. Pfizer’s Beqvez Indication: Hemophilia B Therapy type: In vivo gene therapy Action date: April 27 Later this month, the FDA will rule on Pfizer’s gene therapy for hemophilia B, Beqvez. This engineered version of the factor IX coagulation gene carried by an adeno-associated virus is administered via a single infusion. Beqvez has been approved by Health Canada to treat adults with hemophilia B based on positive data from the Phase III BENEGENE-2 study, which showed a significant reduction in bleeding rate and infusion frequency. The Big Picture An FDA approval would put Pfizer in competition with CSL Behring, whose gene therapy Hemgenix, which is also administered via a single intravenous infusion, became the first FDA-approved gene therapy for hemophilia B in November 2022. Pricing details for Beqvez are not yet available, but Hemgenix costs $3.5 million per dose. Chris Boshoff, Pfizer’s chief oncology officer, told BioSpace the company aims to leverage its experience to ensure smooth market entry and efficient delivery to eligible patients. Abeona Therapeutics’ pz-cel Indication: Recessive dystrophic epidermolysis bullosa Therapy type: Gene-corrected cell therapy Action date: May 25 Next up is Abeona Therapeutics’ pz-cel, which delivers a functional collagen-producing COL7A1 gene into a patient’s own skin cells using a retroviral vector, for the treatment of patients with recessive dystrophic epidermolysis bullosa (RDEB). RDEB, a rare connective tissue disorder, causes severe skin wounds, pain and life-threatening complications stemming from compromised immunity due to a deficiency in the COL7A1 gene, preventing the production of functional type VII collagen. In November 2023, the FDA granted priority review to pz-cel based on clinical data from the Phase III VIITAL study and long-term results from a Phase I/IIa study, which demonstrated sustained wound healing and pain reduction. The Big Picture Ira Leiderman, managing director of healthcare at Cassel Salpeter, underscored the importance of evaluating therapeutic options against the rarity and impact of the disease. A positive decision on Abeona’s pz-cel will help address the high unmet need of RDEB patients and may lead to transformative interventions in this challenging rare genetic disorder, Leiderman told BioSpace. If approved, pz-cel would follow Krystal Biotech’s Vyjuvek, the first gene therapy approved for recessive or dominant DEB in May 2023. Abeona said in March it is actively preparing for the potential U.S. launch of pz-cel, including discussions with treatment sites and payer engagement. Rocket Pharmaceuticals’ Kresladi Indication: Leukocyte adhesion deficiency-1 Therapy type: Ex-vivo vector gene therapy Action date: June 30 While Rocket Pharmaceuticals initially anticipated a decision on its gene therapy for leukocyte adhesion deficiency-I (LAD-I) by March, the FDA requested more review time and extended the deadline to June 30. Severe LAD-I, a rare genetic disorder affecting children, is caused by mutations in the ITGB2 gene that lead to life-threatening infections. Without regular bone marrow transplants, survival beyond childhood is rare. Kresladi contains patient-derived hematopoietic stem cells genetically modified with a lentiviral vector to carry functional copies of the ITGB2 gene, crucial for leukocyte adhesion and infection-fighting. In November 2023, the FDA accepted Rocket’s BLA for Kresladi with priority review, following positive efficacy and safety data from a global Phase I/II study, in which all nine LAD-I patients were alive 12 to 24 months post-infusion. Significant reductions in infection rates were observed compared to pre-treatment levels, along with the resolution of LAD-I–related skin lesions and restoration of wound healing capabilities. Kresladi also holds the FDA’s Regenerative Medicine Advanced Therapy, Rare Pediatric, Fast Track and Orphan Drug designations. The Big Picture This marks Rocket’s inaugural product filing and is a notable advancement for patients, offering an alternative to bone marrow transplant, which carries significant risks and may not be readily accessible. Rocket is enhancing its commercial infrastructure in preparation for a potential product launch, including center initiation, channel strategies, education and payer engagement. Rocket CEO Gaurav Shah told BioSpace the FDA is reallocating reviewers to focus on rare diseases and complex biologics, necessitating changes and a transition period. Shah noted that the delayed decision, based on the FDA’s request for clarity on chemistry, manufacturing and controls information submitted by Rocket, is common among CGTs and does not raise significant concerns beyond ensuring the regulator has sufficient resources for the approval process. Adaptimmune’s afami-cel Indication: Advanced synovial sarcoma Therapy type: T cell receptor therapy Action date: August 4 Adaptimmune is gearing up for the potential launch of its inaugural product in the sarcoma franchise, afami-cel, intended for treating advanced synovial sarcoma, with a PDUFA date set for August 4. Afami-cel received FDA priority review in January. Synovial sarcoma, which makes up 5% to 10% of soft tissue sarcomas, typically affects individuals under 30, with a five-year survival rate of 20% for metastatic cases. Recurrence is frequent, necessitating multiple lines of therapy and potential exhaustion of treatment options. Afami-cel is a single-dose engineered T cell receptor therapy targeting MAGE-A4-posititive tumor cells. The therapy’s clinical data from the SPEARHEAD-1 trial revealed that about 39% of patients experienced clinical responses, with a median response duration of around 12 months. Median overall survival was about 17 months, contrasting with historical data of less than 12 months for those who received two or more prior lines of therapy. Some 70% of responders to afami-cel were alive two years post-treatment. The FDA granted afami-cel Orphan Drug Designation for the treatment of soft tissue sarcomas and Regenerative Medicine Advanced Therapy designation. The Big Picture If approved, afami-cel would become the first approved engineered T cell therapy for this type of cancer. In November 2023, the Investigational New Drug (IND) for another T cell therapy, lete-cel, was transferred from GSK to Adaptimmune for the pivotal IGNYTE-ESO clinical trial, following an interim analysis showing a 40% response rate in synovial sarcoma or myxoid/round cell liposarcoma patients. Adaptimmune CEO Adrian Rawcliffe said that the clinical results from the pivotal trial position lete-cel as a complement to afami-cel, potentially allowing the company’s sarcoma franchise to significantly expand its reach. He noted that leveraging the same commercial infrastructure intended for afami-cel could facilitate the efficient delivery of lete-cel to the market. Afami-cel would become the first engineered T cell therapy for a solid tumor. The franchise, including both afami-cel and lete-cel, “is projected to deliver up to $400 million in U.S. peak year sales,” Rawcliffe said in March. Autolus Therapeutics’ obe-cel Indication: B cell acute lymphoblastic leukemia Therapy type: CAR-T cell therapy Action date: November 16 In accepting Autolus Therapeutics’ BLA for its lead next-generation CAR-T therapy obe-cel for relapsed/refractory adult acute lymphoblastic leukemia (ALL) in January, the FDA set a PDUFA target action date of November 16. Obe-cel, an investigational CD19 CAR-T cell therapy, is designed to enhance clinical activity and safety compared to existing therapies by incorporating a fast target binding off-rate, minimizing T cell activation. In December 2022, Autolus hailed the Phase II FELIX trial as a success, as interim analysis showcased an overall remission rate of 70% for obe-cel in leukemia patients. CAR-T cell concentration peaked and persisted at 75% in peripheral blood after a median of 166.5 days post-infusion. The trial also demonstrated positive safety findings. Obe-cel holds the FDA’s Orphan Drug and Regenerative Medicine Advanced Therapy status. Earlier this month, the company;’s obe-cel marketing application was accepted by the European Medicines Agency. The Big Picture The potential approval of a second cell therapy for solid tumors this year suggests breakthroughs in treating these cancers may be near, Stephen Majors, a spokesperson for the ARM, told BioSpace. There is an “increasing focus on solid tumors,” a previously elusive area for cell and gene therapy, he said. A recent $250 million deal granted BioNTech access to obe-cel, with the partner to aid in the launch and development program expansion and receive royalties based on net sales. Autolus expects obe-cel peak sales to exceed $300 million. Autolus could face competition from Gilead Sciences subsidiary Kite, which in 2021 gained FDA approval for its CAR-T therapy Tecartus, the first such treatment for ALL, achieving a 65% complete remission rate. Ana Mulero is a freelance writer based in Puerto Rico. She can be reached at anacmulero@outlook.com and @anitamulero on X.

关注并星标CPHI制药在线近日，医学界迎来一大突破——首个针对实体瘤的细胞疗法正式获得批准并上市。2月16日，美国生物技术公司Iovance Biotherapeutics报告称，FDA已快速通过了对AMTAGVI™（lifileucel）的生物制品许可申请（BLA）。Lifileucel作为一种肿瘤浸润淋巴细胞（TIL）疗法，专为那些在接受PD-1/PD-L1治疗后仍出现病情进展的晚期黑色素瘤患者设计。值得一提的是，lifileucel成为全球首个获得批准上市的TIL细胞疗法，标志着肿瘤治疗领域的一个新的里程碑。此疗法经过严格的临床试验与评估，被认为能够有效对抗多种实体瘤疾病，为广大癌症患者带来了新的治疗希望。此项技术的诞生，不仅代表了生物技术领域的又一巨大飞跃，更可能成为未来癌症治疗领域的指引灯塔。国际知名学术期刊Nature对此也给予了高度评价，称其为癌症治疗的新里程碑。       这一创新疗法，旨在利用细胞治疗技术的独特性能，直接针对肿瘤组织进行精确打击，旨在减少副作用、提高治疗效果。经过深入研究和临床试验，该细胞疗法在安全性和有效性方面均表现出色，为众多实体瘤患者带来了前所未有的治疗选择。       Nature杂志在其报道中明确指出，这一细胞疗法的获批上市，标志着癌症治疗进入了新的历史阶段。这一里程碑式的进展标志着免疫细胞疗法开始显现出治疗实体瘤的临床价值；此前，CAR-T等细胞疗法已被成功应用于血液系统恶性肿瘤。       图表来源：参考资料[1]       一、TIL细胞疗法：原理与操作流程的深入探讨       原理概述：       TIL（Tumor-Infiltrating Lymphocytes）细胞疗法是一种利用患者体内的抗肿瘤免疫反应来对抗恶性肿瘤的前沿疗法。这种方法的核心在于提取并扩增患者肿瘤组织中的浸润淋巴细胞（TILs），这些细胞已经在肿瘤微环境中被激活并具有特定的抗肿瘤活性。通过体外培养和扩增，可以进一步增强TILs的抗肿瘤效果，并将它们重新注入患者体内，以攻击和消除肿瘤细胞。       流程详解：       1. 样本采集与处理：首先从患者的肿瘤组织中采集细胞样本。这个过程通常通过微创手术或活检完成，以确保获得足够数量和质量的细胞。采集后的细胞需要立即进行处理，以保持其活力和功能性。       2. 细胞分离与培养：在采集的细胞样本中，通过先进的细胞分离技术，如流式细胞仪，将TILs从中分离出来。然后，在特定的培养基和条件下，对分离出来的TILs进行体外培养。这个过程通常需要特定的营养成分、细胞因子和其他生物活性物质来支持细胞的生长和扩增。       3. 细胞扩增：经过数天的培养，TILs的数量将显著增加。这个过程中，细胞会经历多轮的分裂和增殖，从而达到治疗所需的细胞数量。为确保细胞的质量和功能，扩增过程中需要进行严格的细胞活性和纯度检测。       4. 治疗准备：扩增完成后，这些经过改造和增强的TILs将被用于治疗。在治疗前，医生会根据患者的具体情况，制定个性化的治疗方案，包括细胞注射的剂量、时间和方式等。       5. 细胞回输：最后，经过扩增的TILs将通过静脉注射等方式重新注入患者体内。这些细胞将在患者体内继续发挥其抗肿瘤作用，通过直接攻击和消灭肿瘤细胞，以及激发体内的免疫反应，共同对抗癌症。       与CAR-T细胞疗法类似，TIL细胞疗法也是过继性免疫治疗的一种形式。这种方法从患者的肿瘤组织中提取出浸润的淋巴细胞，然后在体外进行大量的扩增，最后再将这些细胞回输给患者。由于这些细胞具有患者抗原特异性，因此它们能够精确地识别并攻击患者的癌细胞，从而达到治疗的效果。       二、振奋人心的临床研究结果       这次加快的审批过程是基于lifileucel对晚期黑色素瘤患者的II期临床试验C-144-01所得到的积极结果。在C-144-01研究中，参与的患者主要是那些之前已经接受过至少一次全身治疗，包括PD-1抗体，但病情仍然处于不可切除或转移性状态的黑色素瘤患者。若患者被诊断为BRAF V600突变阳性，则需要同时接受BRAF抑制剂与MEK抑制剂的联合治疗。       C-144-01是一场开放式的、涉及多队列及多中心的2期临床试验，其核心目标在于探索单次注射lifileucel在晚期黑色素瘤患者中的治疗效果和安全性。这些患者均在接受PD-1/PD-L1抑制剂治疗期间或之后病情出现了进展。根据已公布的研发成果表明，lifileucel的治疗效果持久且具备良好的安全性。当中位随访时间设定为27.6个月时，对于那些经过大量预治疗（中位治疗线数：3）的患者，由独立审评委员会（IRC）评估的客观缓解率（ORR）达到了31.4%（95% CI：23.5-47.6）。其中，有8位患者实现了完全缓解（CR），40位患者实现了部分缓解（PR）。这一成果为lifileucel在未来黑色素瘤治疗领域的应用提供了有力支持。       Lifileucel在中位随访27.6个月时的疗效结果摘要（图表来源：参考资料[4]）       lifileucel在治疗过程中展示出了显著且持久的疗效。主要疗效分析所涵盖的73名患者，是从指定的生产厂接受推荐剂量的lifileucel的群体。在这些患者中，有31.5%的患者根据实体瘤应答评价标准（RECIST 1.1）实现了客观缓解。进行了18.6个月的随访后，发现其中位缓解持续时间仍未达到上限，且有43.5%的患者的缓解持续时间超过了12个月。此外，综合疗效集的数据则包括了来自队列4和队列2的共计153名患者。在这153名患者中，有31.4%的患者通过RECIST 1.1标准达到了客观缓解。经过21.5个月的随访，这些患者的中位缓解持续时间也尚未达到上限，且有54.2%的患者的缓解持续时间超过了12个月。       经过与FDA的深入讨论，Iovance公司成功敲定了lifileucel药物的III期注册试验（代号为TILVANCE-301）的设计方案。该试验的核心内容在于探索lifileucel与K药的联合疗法在针对一线晚期黑色素瘤治疗效果。研究的主要目标是为了全面支撑lifileucel在PD-1单抗治疗无效后的黑色素瘤患者中的应用，并期望为lifileucel与K药联合在一线晚期黑色素瘤治疗方案中的注册申请提供坚实依据。       Iovance旗下lifileucel相关管线图（图表来源：Iovance Biotherapeutics公司官网）       三、lifileucel副反应       在经过前序化疗与IL-2治疗后，采用TIL疗法可能出现如贫血、发热等常见副作用。此外，还存在风险，即TILs可能误攻击正常细胞，从而诱发白癜风等自身免疫性问题。       与CAR-T细胞类似，TILs的个体化特征极为明显。由于每位患者的TILs所识别的抗原各不相同，因此它们在体内的效应也相对独立。       Iovance公司所获得的批准是基于FDA对TILs的增殖工艺及给药流程的严格审核与认证，而并非仅仅基于特定的细胞类型。值得一提的是，TILs的天然非专利性特点为其工艺的不断改进与优化提供了极大的便利。       四、TIL疗法巨大成本与投资未来潜力       Iovance公司推出的lifileucel单次疗程定价高达51.5万美元，这比市面上部分CAR-T疗法的价格还要昂贵。然而，值得注意的是，包括丹麦哥本哈根大学医院在内的多家大学附属机构已经以较低成本（约5.5万美元）成功地实施了TIL疗法来治疗       经典的CAR-T疗法曾备受推崇，但其应用主要局限于血液科癌症，在实体瘤治疗中屡遭挫折。然而，令人振奋的是，CAR-T疗法在自身免疫性疾病的治疗中取得了新的突破。更值得一提的是，TILs细胞疗法已首次获批用于治疗实体瘤，这标志着医疗领域的一大进步。医生科学家们通过不懈努力，逐步推动着医疗技术的发展。       Iovance公司的lifileucel获批上市意义重大，它创新性地证明了TILs治疗部分实体瘤的有效性，从而鼓舞着其他类似公司继续拓展细胞疗法的应用领域。目前，TIL疗法正在针对一系列实体瘤进行研究和开发，其中包括宫颈癌和肺癌，这两种癌症在临床试验中已经显示出了一定的治疗效果。未来，通过基因改造等手段，我们有望进一步增强TILs的浸润与杀伤能力，并通过阻断癌细胞对TILs的反制信号通路，实现患者的完全缓解。       尽管Iovance公司面临着与其他CAR-T研发公司相同的困境，即个体化治疗流程的制约，但TILs细胞疗法的批准仍为该公司带来了喜讯。然而，TILs的未来应用很可能取决于医疗机构自主开发的TIL疗法中心。       目前，许多创新型企业正致力于推动TIL疗法的进步，并已研发出多款进入临床试验阶段的疗法。优化TIL疗法的一个重要策略是从中筛选出抗癌活性最强的细胞亚型进行扩增。TIL包含多样的T细胞克隆，各自具有独特的免疫特性和靶向不同的癌症抗原的能力。作为TIL领域的先驱，Steven Rosenberg博士透露，第一代TIL疗法中仅有三分之一的细胞在与肿瘤细胞共培养时能有效识别肿瘤细胞。“大部分注入患者体内的细胞并不具备活性，”他强调，“因此，选择具备理想特征的细胞将极大地提升治疗效果。       部分在研TIL疗法（数据来源：参考资料[6] &公开资料）       另一种策略则集中在利用基因工程来优化TIL细胞的功能，增强其对抗癌症的效果。举例来说，借助先进的基因编辑技术，可以使PD-1受体的表达得到抑制，这样一来，TIL细胞在肿瘤微环境中就不易受到PD-L1的制约，从而更好地发挥其抗癌活性。除此之外，其他的基因编辑目标可能包括CISH这一免疫检查点蛋白，以及抑制细胞因子信号的SOCS1等。这些基因工程的改造举措有望进一步提升TIL细胞的扩增和植入效率，从而拓展其应用领域，使更多的癌症患者受益于这种治疗方法。       全球每年约有32.5万新发黑色素瘤患者，其中约有5.7万患者因此病而死亡。而在美国，每年约有10万人被诊断出患有黑色素瘤，约有7700人因此病致死。随着FDA的批准，TIL疗法将成为晚期黑色素瘤治疗的全新选择。       参考文献：       [1]https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-lifileucel-unresectable-or-metastatic-melanoma       [2]https://www.nature.com/articles/d41586-024-00673-w       [3] Iovance’s AMTAGVI (lifileucel) Receives U.S. FDA Accelerated Approval for Advanced Melanoma. Retrieved February 16, 2024 from https://www.globenewswire.com/news-release/2024/02/16/2830923/0/en/Iovance-s-AMTAGVI-lifileucel-Receives-U-S-FDA-Accelerated-Approval-for-Advanced-Melanoma.html       [4] Chesney J, Lewis KD, Kluger H, Hamid O, Whitman E, Thomas S, Wermke M, Cusnir M, Domingo-Musibay E, Phan GQ, Kirkwood JM, Hassel JC, Orloff M, Larkin J, Weber J, Furness AJS, Khushalani NI, Medina T, Egger ME, Graf Finckenstein F, Jagasia M, Hari P, Sulur G, Shi W, Wu X, Sarnaik A. Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study. J Immunother Cancer. 2022 Dec;10(12):e005755. doi: 10.1136/jitc-2022-005755. PMID: 36600653; PMCID: PMC9748991.       [5] LONG-TERM EFFICACY AND PATTERNS OF RESPONSE OF LIFILEUCEL TUMORINFILTRATING LYMPHOCYTE (TIL) CELL THERAPY IN PATIENTS WITH ADVANCED MELANOMA: A 4-YEAR ANALYSIS OF THE C-144-01 STUDY. Retrieved January 15, 2024 fromhttps://www.iovance.com/uploads/ESMO-IO-C-144-01-4-year-2577-publication.pdf       [6] Asher Mullard. (2023). Tumour-infiltrating lymphocyte cancer therapy nears FDA finish line. Nature Reviews Drug Discovery, doi: https://doi.org/10.1038/d41573-023-00206-6【智药研习社近期直播预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~