PDL1-t-haNK (ImmunityBio)

On April 22, 2024, ImmunityBio announced that the FDA has approved Anktiva (N-803) in combination with Bacillus Calmette-Guérin (BCG) for the treatment of BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS), with or without papillary tumors. The drug is expected to be available in the United States by mid-May 2024. Nogapendekin alfa inbakicept-pmln(N-803)N-803 (nogapendekin alfa inbakicept-pmln) is an interleukin-15 (IL-15) superagonist complex composed of a mutated variant of IL-15 (IL-15N72D) fused with the IL-15Rα sushi domain and an IgG1 Fc fusion protein. The IL-15Rα sushi domain allows for activation of downstream signaling pathways without the requirement for trans-presentation, as is necessary for natural IL-15, while the IgG1-Fc fragment significantly extends the drug's half-life. Previously, the FDA granted N-803 Fast Track designation and Breakthrough Therapy designation, and in October 2023, accepted the resubmission of the Biologics License Application (BLA) for N-803 in combination with BCG. In a single-arm, multi-center Phase 2 trial, 77 patients with high-risk non-muscle invasive bladder cancer (NMIBC) who were unresponsive to BCG and who had undergone transurethral resection with or without Ta/T1 papillary lesions were enrolled; patients received N-803 induction followed by intravesical instillation of Bacillus Calmette-Guérin (BCG), with maintenance therapy lasting up to 37 months. For up to 2 years, tumor status was evaluated every three months via cystoscopy and urinary cytology, with biopsies performed (randomly or under cystoscopic guidance) within the first 6 months after treatment initiation. The primary efficacy endpoints were the complete response (CR) at any time and the duration of complete response (DOR). CR is defined as a negative cystoscopy (with TURBT/biopsy where applicable) and negative urinary cytology. The results showed a CR rate of 62% (95 CI: 51, 73); 58% of patients with CR had a DOR of ≥12 months, and 40% had a DOR of ≥24 months. The most common adverse reactions (≥15%) included laboratory abnormalities such as increased creatinine, dysuria, hematuria, urinary frequency, urinary urgency, urinary tract infections, elevated potassium, musculoskeletal pain, chills, and fever. Beyond non-muscle-invasive bladder cancer (NMIBC), N-803 has also shown promising therapeutic potential in pancreatic cancer. At the 2022 ASCO GI, Immunity Bio revealed phase II data for N-803 combined with standard-of-care chemotherapy, albumin-bound paclitaxel, and PD-L1 t-haNK as a third-line treatment for pancreatic cancer. The results indicated a median overall survival (mOS) of 6.3 months, doubling compared to historical data. Regarding safety, grade 3 or higher adverse events mainly included anemia, neutropenia, and thrombocytopenia. Additionally, preclinical data published in the journal Science suggested that in combination with broadly neutralizing antibodies, N-803 might enable the immune system to control human immunodeficiency virus (HIV) without the need for antiretroviral therapy. IL-15IL-15, as a T cell growth factor, is mainly produced by monocytes and macrophages. It binds to the IL-15 receptor (IL-15R) on responsive cells, mediating the proliferation and activation of T cells, NK cells, and B cells, and inducing the generation of cytotoxic T lymphocytes (CTLs). IL-15 principally employs two distinct mechanisms for signal delivery: cis-presentation and trans-presentation. In cis-presentation, IL-15 binds to the transmembrane or soluble forms of IL-15Rα before associating with IL-15Rβγ. In trans-presentation, IL-15Rα is expressed on the surface of IL-15 producing cells, such as dendritic cells and macrophages, delivering IL-15 in a trans manner to responder cells carrying the IL-15Rβ/γc receptor, such as NK or memory CD8+ T cells. This may play a key role in coordinating the innate and adaptive branches of the immune system. The specific binding of IL-15 to its receptor IL-5R can activate the JAK-STAT5 signal transduction molecule, which then leads to the cascade activation of multiple signaling pathways including PI3K/Akt and Ras/Raf/MAPK, ultimately exerting its biological effects. Additionally, IL-15Rα can also shed from the membrane and exist in a free form after binding to IL-15, activating the IL-15Rβ/γc receptor at a distance. Due to IL-15’s ability to promote the activation and proliferation of immune cells, it plays a very important role in immunotherapy. IL-15 does not induce apoptosis in activated T cells and can maintain the survival of memory T cells, thereby achieving the goal of long-term treatment. However, the application of IL-15 in immunotherapy also faces some challenges. For example, excessive secretion of IL-15 may lead to an over-activation of the immune system, which can induce inflammatory responses, autoimmune diseases, infectious diseases, and tumors. Because the IL-15 signaling pathway requires the sushi domain of IL-15Rα, it is limited by the expression level of IL-15Rα within the body. Moreover, the short half-life of IL-15 (less than 1 hour in humans) and strict post-transcriptional regulation significantly limit IL-15's clinical applications. The most common strategies to address this include increasing the molecular size to reduce renal elimination, or fusion with the neonatal Fc receptor (FcRn). Additionally, considering IL-15's unique ability to maintain the homeostasis and proliferation of memory CD8+ T cells, applying it in CAR-T engineering also promises to achieve stronger antitumor efficacy. According to incomplete statistics, there are currently only approximately 200 IL-15 drugs under research globally, with about 90 having entered the clinical stage. Apart from N-803, other drugs worth paying attention to include SOT101, a subcutaneous formulation developed by SOTIO, SHR-1501 by Jiangsu Hengrui Pharmaceuticals, ASKG315 by Aosaikang Pharmaceutical, and BJ-001 by BJ Bioscience. Regarding Non-Muscle Invasive Bladder CancerBladder Urothelial Carcinoma (UC) is the 13th most common cancer worldwide by incidence and is divided into two main categories: non-muscle invasive bladder cancer (NMIBC), which accounts for 70%, and muscle-invasive bladder cancer (MIBC), which accounts for 30%. The peak incidence age of this disease is between 50 and 70 years old, with the incidence rate of urothelial carcinoma in men being 3 to 4 times that in women. In 2020, there were 516,000 cases of urothelial carcinoma globally, and it is projected to reach 586,000 by 2025 and 663,000 by 2030. In China, there were about 77,000 new cases of urothelial carcinoma in 2020, and the number is expected to rise to 91,000 by 2025 and to reach 106,000 by 2030. NMIBC refers to bladder malignancies that are confined to the mucosal layer (Ta) and lamina propria (T1), with no invasion into the muscular layer. This includes Ta, T1, and Tis stages, with Ta accounting for 70%, T1 representing 20%, and Tis making up 10%. Based on the different risks of recurrence and prognosis, NMIBC is divided into low-risk NMIBC, intermediate-risk NMIBC, high-risk NMIBC, and very high-risk NMIBC. Treatment options, intravesical instillation, and follow-up plans are chosen according to the grouping of risk levels. The standard treatment for NMIBC is transurethral resection of bladder tumor (TURBT). Due to the high recurrence rate of NMIBC postoperatively, adjuvant intravesical instillation therapy is recommended for all NMIBC patients. Commonly used chemotherapeutic agents for instillation include mitomycin, gemcitabine, and epirubicin, and there is no evidence that maintenance instillation schemes using different chemotherapy drugs significantly differ in effectiveness. Despite guidelines recommending chemotherapy instillation and BCG intravesical therapy, about 50% of patients still experience tumor recurrence within five years. The standard treatment for patients after tumor recurrence is radical cystectomy, which makes patients lose their normal urine storage and voiding functions, severely affecting their quality of life and psychological health. Therefore, the development of new drugs is crucial for NMIBC patients who do not respond to chemotherapy and BCG. Representative drugs approved in recent years include: In January 2020, the FDA approved pembrolizumab ("Drug K") as a monotherapy for treating BCG-unresponsive, high-risk NMIBC patients with CIS, with or without papillary tumors, who are ineligible for or have elected not to undergo cystectomy. In December 2022, the FDA approved Ferring's gene therapy, nadofaragene firadenovec-vncg (commercial name Adstiladrin), for treating high-risk NMIBC patients unresponsive to BCG therapy, with CIS, with or without papillary tumors. ImmunityBioImmunityBio is a clinical-stage immunotherapy company headquartered in California, United States, dedicated to the development of a new generation of treatments that harness immunogenic mechanisms for the treatment of cancer and infectious diseases. In January 2024, Oberland Capital provided ImmunityBio with up to $320 million in royalty monetization and equity financing, with total proceeds of $210 million due on December 29, 2023. This additional financing provides the company with significant financial resources to accelerate its commercialization efforts, in anticipation of regulatory approval, and to expand its product line in the broader field of urologic oncology. The raised funds will also support ongoing business operations and clinical trials, extending the indications of N-803 to multiple solid tumors.

为打造全球ADC/RDC未来产业高地，成都医学城拟于2024年4月18日-19日举办首届未来XDC新药大会！大会以“共创偶联药物产业未来”为主题，由同写意策划，安排一场主论坛和九场主题论坛，邀请“政、产、学、研、金、媒”各领域专家，通过“成果发布、主题演讲、热点对话、表彰颁奖、展览展示”五位一体的多元化的组织形式，迸发更多XDC产业新科技、新业态、新模式，构建XDC产业全新生态，触摸医药产业未来脉动。尽管CAR-T疗法仍被视为癌症治疗领域的一项重大突破，但CAR-NK疗法似乎将与这些免疫疗法一较高下。NK细胞是人体固有免疫的重要组成部分，也是抵御病毒感染和肿瘤细胞的第一道防线。CAR-NK疗法旨在克服CAR-T疗法的局限性。例如，接受CAR-T疗法的患者有时会出现细胞因子释放综合征（CRS）等副作用，这发生于免疫系统因CAR-T细胞的存在而过度运转时。如果不及时治疗，CRS会引发细胞因子风暴，导致器官衰竭甚至死亡。既往研究提示，包括CAR-NK在内的NK细胞疗法，出现CRS和神经毒性以及移植物抗宿主病（GvHD）的风险较低。科学家还发现，NK细胞能更有效地杀死癌细胞，而且与T细胞不同，NK细胞的目标细胞死亡不受肿瘤抗原的影响。关于NK细胞治疗方案的临床试验数量不断走高。尤其自2016年起，NK细胞临床试验项目大幅度增加，平均每年达到47项。赛诺菲、默沙东、BMS、艾伯维等巨头，正通过各种方式参与其中。公开数据显示，2022年NK细胞疗法的全球市场约为3.48亿美元并，预测以16.2%的CAGR在2028年突破10亿美元。但也要看到，该细分赛道整体尚处于早期临床阶段。而与CAR-T疗法类似，跟最大化CAR-NK在实体瘤中的作用，也是肿瘤学领域的挑战。去年发布的一篇论文指出，将CAR-NK疗法带向更广阔的实体瘤治疗，有赖于最佳的CAR结构设计，以及对NK细胞的内在抑制和激活途径进行基因改造。研究表明，抑制性TME对CAR-NK在实体瘤中的有效应用构成了重大障碍。这注定是一个不太好啃的市场，并且已经出现受挫的公司了。今年1月底，Catamaran Bio首席执行官Alvin Shih证实，这家Biotech计划停止运营，为其手头的CAR-NK资产寻找接盘者。Catamaran成立于2020年，但由于外部环境的恶化，该公司不得不提前结束其航程。尽管如此，还有不少场内选手在探索。下文关注10家开发CAR-NK疗法的Biotech，它们有的已经凭借初步数据收到巨头的追捧，有的则选择自身免疫性疾病等领域展开探索。1Artiva Biotherapeutics去年，FDA批准了AlloNK（也被称为AB-101）的新药研究许可（IND），用于治疗狼疮肾炎。这款NK细胞疗法由美国公司Artiva开发，成为同类产品中首个进入自身免疫性疾病临床试验的药物。作为一种异体、非基因修饰的NK细胞疗法，AlloNK旨在增强单克隆抗体的抗体依赖性细胞毒性（ADCC）效应。这样，该药物就能杀死产生自身抗体的B细胞。AlloNK还在针对癌细胞进行评估。Artiva的肿瘤管线涉及CD30阳性淋巴瘤和B细胞恶性肿瘤，目前分别处于II期和I期试验阶段。根据在2023年ASCO年会上公布的I期剂量递增疗效数据，AlloNK在与单克隆抗体利妥昔单抗联用后，7名复发/难治性B细胞非霍奇金淋巴瘤（B-NHL）患者的ORR达到了57.1%。Artiva认为，鉴于AlloNK可以通过冷冻保存，这种现货疗法有望在社区环境中实现治疗，不会出现与已批准的自体CAR-T疗法相关的继发性恶性肿瘤类别警告。今年2月，AlloNK治疗狼疮性肾炎获得FDA快速通道指定。官网显示，除了进入I期临床的狼疮肾炎研究，AlloNK在自身免疫性疾病领域还探索其他适应症。在“2023年生物技术突破奖”评选中，AlloNK获得了“年度免疫学创新奖”。2Dragonfly Therapeutics美国公司Dragonfly致力于将其NK细胞疗法推向市场，目前正在开发基于其专有平台TriNKETs的多种候选药物。TriNKETs可激活NK细胞和CD8 T细胞，从而调动先天性免疫系统和适应性免疫系统，并将细胞毒性细胞重新导向靶向癌细胞。该平台衍生的药物可与化疗和放疗等其他治疗方法结合使用。在该平台的帮助下，Dragonfly的DF1001正在进行治疗实体瘤的I/II期试验。去年，Dragonfly公布了DF1001的I期剂量爬坡试验结果。该研究对HER2阳性的晚期实体瘤患者进行了候选药物测试，发现67%的患者配对活检显示出药效学反应，DF1001已完成安全性评估。Dragonfly似乎也很受MNC的欢迎。目前，它已与艾伯维、吉利德、默沙东和BMS合作，将其他NK细胞疗法推向临床，不仅用于肿瘤，还用于治疗神经系统疾病。3Fate Therapeutics总部位于美国的Fate，其产品管线中有四种候选药物是针对癌细胞设计的。候选药物FT576是一种现成的CAR-NK免疫疗法，由克隆主iPSC系开发而成。它利用Fate专有CAR靶向B细胞成熟抗原（BCMA）蛋白，并含有改良的不可裂解CD16Fc受体以提高ADCC，以及IL-15受体融合以增强NK细胞活性。除此之外，Fate还有三个CAR候选疗法，分别是治疗复发和难治性B细胞淋巴瘤的FT522、治疗白血病的FT819和针对HER2阳性实体瘤的FT825，它们都是基于公司的iPSC平台。这种多能细胞平台可以对iPSC细胞进行基因工程改造和扩增，从而创造出现成的细胞治疗药物。目前，FT825正处于临床前阶段，正与日本的小野制药合作开发。此前的2020年4月，Fate还和杨森达成超30亿美元的协议，但到2023年1月，该协议被终止。4Glycostem Therapeutics荷兰公司Glycostem Therapeutics专注于NK细胞疗法，并基于其两种平台技术开发了候选药物。第一个候选产品是oNKord，旨在治疗实体瘤以及急性髓性白血病（AML）和多发性骨髓瘤（MM）等血癌。oNKord由未经修饰的NK细胞组成，已获得EMA和FDA的AML孤儿药指定。在与荷兰Radboud医疗中心的临床合作中，10名受试老年AML患者第一年的生存率数据显示为80%，而没有干预的人群数据显示为35%。去年，inaleucel作为oNKord的国际非专有名称（INN）被列入WHO推荐名单。这使得Glycostem可以在标签、药品法规和出版物中使用inaleucel一词。Glycostem的另一款产品viveNK是一种CAR细胞疗法，可以增强抗癌反应，同时最大限度地降低患GVHD的风险。目前viveNK正在进行临床前试验，针对OGD2阳性实体瘤。5ImmuneBridgeCAR-NK细胞疗法公司ImmuneBridge，最近获得了1200万美元的种子轮融资，用于推进其血液恶性肿瘤和实体瘤的免疫疗法。该公司的扩增技术可扩增造血干细胞（HSC），它们是NK细胞的天然前体。HSC可通过美国和全球公共脐带血库的脐带血轻松获得。这种方法可以对脐带血进行系统筛查，以确定每个适应症中最有效的细胞，然后对细胞进行基因改造，以在其先天基线的基础上增强其效力。这家总部位于美国的公司，正在开发能够识别和攻击肿瘤细胞的异体NK细胞疗法，虽然这些疗法还处于早期开发阶段，但ImmuneBridge希望能将安全、可扩展的候选免疫疗法推向临床。6ImmunityBio今年1月，美国公司ImmunityBio完成了3.2亿美元的最新融资，该公司的目标是通过临床试验支持其膀胱癌候选药物Anktiva与卡介苗（BCG）的联合治疗。最近，FDA批准了该药物组合的生物制品许可申请（BLA）。Anktiva是一种IL-15超拮抗剂融合蛋白，旨在增强NK和CD8阳性T细胞，同时不激活T调节（Treg）细胞。该公司目前正在进行的临床试验有10多项，有几个免疫疗法平台正在合作开发其产品线，其中包括ImmunityBio的CAR-NK细胞疗法平台t-haNK。基于这一CAR定向平台，该公司创建了PD-L1 t-haNK，这是一种低温保存的双特异性候选细胞疗法，通过CAR靶向PD-L1。该候选药物含有可与抗体结合的受体CD16，可增强其抗癌效果。该候选药物将与单克隆抗体和Anktiva结合使用。ImmunityBio还在研究M-ceNK，这是一种记忆类细胞因子增强型NK细胞，因其能诱导数月的抗癌效果而以免疫记忆著称。7NkartaNkarta被认为是NK细胞工程的先驱之一，它是一家总部位于美国的Biotech，旨在解决CAR-T细胞疗法的局限性，包括某些副作用。细胞因子风暴有时会在身体的先天免疫系统对抗自身时发生。为了降低细胞因子风暴的风险，NK细胞疗法可以帮助减轻这些副作用。最重要的是，NK细胞疗法不一定依赖于患者特异性免疫细胞的产生。该公司的四种候选药物正处于不同的开发阶段，其中，NKX101是针对NKG2D配体设计的，这种配体往往在癌细胞中过度表达。目前，NKX101正处于治疗实体瘤的临床前研究和治疗AML的临床阶段。NKX019也已进入临床阶段，用于治疗B细胞恶性肿瘤，并已完成狼疮性肾炎患者的临床前试验。对于后者，Nkarta已获得FDA的IND批准，因此，Nkarta去年10月宣布，将很快在临床上对该药物进行研究。该公司还希望治疗其他自身免疫性疾病。8NKGen Biotech美国公司NKGen致力于利用人体的NK细胞来对抗疾病，该公司开发了超级自然杀伤细胞（SNK），这是一种免疫疗法，通过向体内注入个人自身的活化NK细胞来增强免疫活性并杀死病变细胞。SNK使用从患者血液中提取的自然杀伤细胞，然后将其激活并送回患者体内。与CAR-T疗法相比，这些自体细胞疗法出现副作用的几率较低。在该公司的产品线中，涵盖了自体NK、异体NK和CAR-NK等不同疗法。自体NK疗法正处于治疗神经退行性疾病和难治性实体瘤的I期研究中，后者正与阿维鲁单抗和帕博利珠单抗联合进行评估。而其CAR-NK候选疗法SNK02正在进行临床前测试，以治疗HER2阳性实体瘤。去年12月月，加拿大卫生部批准其自体NK疗法在中度阿尔茨海默病患者中开展I/IIa期临床试验。9ONK TherapeuticsONK利用人体NK细胞的力量，采用基因编辑和抗体疗法来增强肿瘤微环境中NK细胞的细胞毒性。这家爱尔兰公司的产品组合不断壮大，包括表达CAR的工程化NK细胞候选疗法等。该公司的三个候选药物是基于CAR-NK的，拟用于治疗AML、MM、胰腺癌、卵巢癌和三阴性乳腺癌。去年，欧洲专利局（EPO）向ONK授予NK细胞中CISH基因敲除（KO）专利，这使公司获得了将NK细胞中CISH基因敲除用于癌症疗法的关键知识产权。CISH基因敲除是ONK用于优化NK细胞疗法的一种机制。最近，这家生物技术公司宣布与美国公司NAYA Biosciences合作，评估ONK的NK细胞疗法和后者的FLEX-NK双特异性抗体联合治疗癌症的效果。这种联合疗法有望提高肝细胞癌患者的应答率。10Senti Biosciences位于美国的现成CAR-NK公司Senti拥有一个基因回路技术平台，该平台旨在利用基因回路对基因疗法进行编程。这些基因回路由DNA序列组成，可以重新编程细胞，使其能够计算决策并对细胞环境做出反应。该公司的目标是用一种药物针对多种疾病途径，并整合多种靶点，挑出患病细胞，保留健康细胞。SENTI-202是其产品线的一部分，旨在治疗AML和骨髓增生异常综合症等血癌。去年12月，SENTI-202获得FDA批准，可以开始在AML等复发或难治性血液恶性肿瘤患者中进行I期试验。作为一种现成的CAR-NK细胞候选疗法，SENTI-202以血癌中表达的CD33和FLT3蛋白为靶点，能有效杀死白血病干细胞。该Biotech还与其他公司合作，包括罗氏子公司Spark Therapeutics和拜耳子公司Bluerock Therapeutics，以使用智能传感器。Senti的智能传感器技术有助于捕捉人体变化的信号，并识别疾病的位置和状态。这些传感器可以检测不同种类的生物标记物，包括RNA、DNA和蛋白质。参考资料：1.Ten NK cell therapy companies to look out for this year；Labiotech2.The Next Generation of Cellular Immunotherapy: Chimeric Antigen Receptor-Natural Killer Cells；ScienceDirect3.Catamaran Bio sends out life raft in tough financing climate, ending day-to-day operations；Fierce Biotech更多优质内容，欢迎关注↓↓↓