High-affinity CD16-expressing NK cell therapy (ImmunityBio)

Company’s first clinical trial studying CAR-NK (CD19 t-haNK) cellular therapy in liquid tumors First natural killer cell-based cellular therapy study conducted in the continent of Africa Complete enrollment currently expected in Q1 2025 CULVER CITY, Calif.--(BUSINESS WIRE)--Immunotherapy innovator ImmunityBio, Inc. ( NASDAQ: IBRX ), announced today that the first patients have been dosed in an initial trial studying the potential of the company’s CAR-NK cell therapy targeting CD-19 in the treatment of non-Hodgkin’s lymphoma (NHL). In the QUILT 106 trial, CD19-targeted high-affinity natural killer (t-haNK) cells are being tested initially as a single agent, and after demonstrating safety, then in combination with standard NHL treatment rituximab, in participants with selected CD19+ and CD20+ relapsed/refractory B-cell NHL. The phase 1, open label clinical study is designed to enroll up to 10 participants and is being conducted in Johannesburg, Pretoria, and Bloemfontein, South Africa. This is the first cellular-targeted natural killer (NK) cell therapy study ever to be conducted in South Africa, and is designed to provide important clinical information on a cancer with a significant rate of diagnosis in the region, but with few treatment options. Non-Hodgkin’s lymphoma is the 6 th most common malignancy among people in Sub-Saharan Africa and it is the 4 th most diagnosed cancer in men and the 5 th most diagnosed cancer in women in South Africa, according to the Cancer Association of South Africa. “This trial is important for ImmunityBio as our first clinical study of our CAR-NK, CD19 t-haNK cell line, as well as one of our first studies in liquid tumors,” said Patrick Soon-Shiong, M.D., Executive Chairman, Founder and Global Chief Scientific and Medical Officer at ImmunityBio. “We have chosen to undertake this trial because Sub-Saharan African and, in particular, South African populations are often overlooked when it comes to advanced clinical research, despite the need for innovative immunotherapies in the region.” Full patient enrollment in this Phase 1 study of CD19 t-haNK is currently expected in the first quarter of calendar year 2025 with topline data readout expected in the second half of the calendar year 2025. This study, being conducted in South Africa, is similar to ImmunityBio’s U.S.-based trial QUILT 3.092, a phase 1 open-label study of CD19 t-haNK as a single agent and in combination with the company’s IL-15 superagonist (N-803; ANKTIVA®) and rituximab in participants with relapsed or refractory NHL. About the QUILT 106 Study The Phase 1, first-in-human (FIH), open-label study is designed to enroll up to 10 participants at sites in Johannesburg, Pretoria, and Bloemfontein, South Africa with the primary endpoint of the trial to evaluate the safety and preliminary efficacy of CAR-NK, CD19 t-haNK as a single agent and in combination with rituximab in participants with selected CD19+ and CD20+ R/R B-cell non-Hodgkin lymphoma (NHL). Participants will initially receive a single 3-week cycle of the CD19 t-haNK as a single-agent regime. Following a 1-week safety pause, participants will then receive a 3-week cycle of CD19 t-haNK in combination with rituximab. Patients will undergo multiple assessments of safety and efficacy to help evaluate the safety of CD19 t-haNK as a single agent and in combination with rituximab in participants with R/R NHL, who have active disease after completing ≥ 2 lines of cytotoxic chemotherapy. About CAR-NK, CD19 t-haNK CD19 t-haNK is a human, allogeneic, stable clonal NK cell line generated from the parental activated NK (aNK) cell line (NK-92). Based on the demonstrated therapeutic efficacy of chimeric antigen receptor (CAR) targeting and on the important role of FcγR-mediated antibody-dependent cellular cytotoxicity (ADCC) in the effectiveness of therapeutic IgG1 monoclonal antibodies, it was hypothesized that modification of the parental aNK cell line to stably express both a CD19-targeted CAR and the high-affinity variant of CD16 would result in potent and selective antitumor activity. Therefore, the novel CD19 t-haNK cells have been genetically engineered to stably express 3 main proteins: (1) a human CD19-targeted CAR; (2) the high-affinity variant of the human Fcγ receptor (FcγRIIIa/CD16a 158V) for enhanced ADCC; and (3) endoplasmic reticulum-retained version of human interleukin-2 (ERIL-2) for independent growth. Non-Hodgkin Lymphoma Non-Hodgkin lymphoma (NHL) is a heterogeneous disease that most commonly originates in B lymphocytes. In 2020, according to the South Africa National Cancer Registry ( SANCR 2020 ), it is estimated that 1 in 174 men and 1 in 288 women will develop NHL. According to Global Cancer Observatory ( Sung 2021 ), the incidence of NHL is 4.1% of all cancers. A comparative study of the distribution of NHL subtypes in South Africa reported that Southern Africa had a significantly lower proportion of low-grade B cell NHL (34.3%) and a higher proportion of high-grade B cell NHL (51.5%) compared to Western Europe (54.5% and 36.4%) and North America (56.1% and 34.3%) ( Perry 2015 ). About ImmunityBio ImmunityBio is a vertically-integrated biotechnology company developing next-generation therapies and vaccines that bolster the natural immune system to defeat cancers and infectious diseases. The company’s range of immunotherapy and cell therapy platforms, alone and together, act to drive and sustain an immune response with the goal of creating durable and safe protection against disease. Designated an FDA Breakthrough Therapy, ANKTIVA ® is the first FDA-approved immunotherapy for non-muscle invasive bladder cancer CIS that activates natural killer cells, T cells, and memory T cells for a long-duration response. The company is applying its science and platforms to treating cancers, including the development of potential cancer vaccines, as well as developing immunotherapies and cell therapies that we believe sharply reduce or eliminate the need for standard high-dose chemotherapy. These platforms and their associated product candidates are designed to be more effective, accessible, and easily administered than current standards of care in oncology and infectious diseases. For more information, visit and connect with us on X (Twitter), Facebook , LinkedIn , and Instagram . Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, such as statements regarding clinical trial plans and timing, patient enrollment and treatment, timing of data read outs, market and prevalence data, the regulatory review process and timing thereof, the development of therapeutics for cancer and infectious diseases, potential benefits to patients, potential treatment outcomes for patients, the described mechanism of action and results and contributions therefrom, potential future uses and applications of ANKTIVA and use in cancer vaccines and across multiple tumor types, and ImmunityBio’s approved product and investigational agents as compared to existing treatment options, among others. Statements in this presentation that are not statements of historical fact are considered forward-looking statements, which are usually identified by the use of words such as “anticipates,” “believes,” “continues,” “goal,” “could,” “estimates,” “scheduled,” “expects,” “intends,” “may,” “plans,” “potential,” “predicts,” “indicate,” “projects,” “is,” “seeks,” “should,” “will,” “strategy,” and variations of such words or similar expressions. Statements of past performance, efforts, or results of our preclinical and clinical trials, about which inferences or assumptions may be made, can also be forward-looking statements and are not indicative of future performance or results. Forward-looking statements are neither forecasts, promises nor guarantees, and are based on the current beliefs of ImmunityBio’s management as well as assumptions made by and information currently available to ImmunityBio. Such information may be limited or incomplete, and ImmunityBio’s statements should not be read to indicate that it has conducted a thorough inquiry into, or review of, all potentially available relevant information. Such statements reflect the current views of ImmunityBio with respect to future events and are subject to known and unknown risks, including business, regulatory, economic and competitive risks, uncertainties, contingencies and assumptions about ImmunityBio, including, without limitation, (i) risks and uncertainties regarding clinical trial patient enrollment and timing and potential results, including with respect to the trial described herein, (ii) risks and uncertainties related to the regulatory submission and review process, (iii) the ability of ImmunityBio to fund its ongoing and anticipated clinical trials, (iv) whether clinical trials will result in registrational pathways and the risks and uncertainties regarding the regulatory submission, review and approval process, (v) the ability of ImmunityBio to continue its planned preclinical and clinical development of its development programs through itself and/or its investigators, and the timing and success of any such continued preclinical and clinical development, patient enrollment and planned regulatory submissions, (vi) potential delays in product availability and regulatory approvals, (vii) ImmunityBio’s ability to retain and hire key personnel, (viii) ImmunityBio’s ability to obtain additional financing to fund its operations and complete the development and commercialization of its various product candidates, (ix) potential product shortages or manufacturing disruptions that may impact the availability and timing of product, (x) ImmunityBio’s ability to successfully commercialize its approved product and product candidates, (xi) ImmunityBio’s ability to scale its manufacturing and commercial supply operations for its approved product and future approved products, and (xii) ImmunityBio’s ability to obtain, maintain, protect and enforce patent protection and other proprietary rights for its product candidates and technologies. More details about these and other risks that may impact ImmunityBio’s business are described under the heading “Risk Factors” in the Company’s Form 10-K filed with the U.S. Securities and Exchange Commission (“SEC”) on March 19, 2024 and the Company’s Form 10-Q filed with the SEC on August 12, 2024, and in subsequent filings made by ImmunityBio with the SEC, which are available on the SEC’s website at . ImmunityBio cautions you not to place undue reliance on any forward looking statements, which speak only as of the date hereof. ImmunityBio does not undertake any duty to update any forward-looking statement or other information in this press release, except to the extent required by law. Contacts Investors Hemanth Ramaprakash, PhD, MBA ImmunityBio, Inc. +1 858-746-9289 Hemanth.Ramaprakash@ImmunityBio.com Media Sarah Singleton ImmunityBio +1 415-290-8045 Sarah.Singleton@ImmunityBio.com

关注并星标CPHI制药在线新技术的发展，总是充满令人激动与失望的瞬间。细胞疗法过去几年的发展便是如此。自然杀伤（NK）细胞疗法因其“通用现货”等优势，被寄予厚望。作为先天免疫系统的一部分，NK细胞的作用是杀死病毒感染的细胞和癌变细胞。作为免疫疗法，NK细胞有可能是T细胞更安全、更“友好”的替代品，早期出色的临床数据，更是令人欣喜万分，也吸引了包括赛诺菲在内的大药厂持续加注。然而，就当投入3.57亿美元（约合人民币26亿元）收购Kiadis，却迟迟见不到成功的可能，赛诺菲已然心生退意。理想的细胞疗法与现实的困顿相碰撞，这注定是一个不太好啃的市场。赛诺菲决定关闭Kiadis，今年1月底，另一家biotech Catamaran Bio已计划停止运营，为其手头的CAR-NK资产寻找接盘者。NK细胞领头羊Fate的过山车般的股价走势，2021年最高达121美元，如今只有不足6美元，更是反映出市场对这一技术路径从狂热到心灰意冷。正如赛诺菲发言人所说，这一领域，研发成本高于其他治疗领域，而临床试验成功的概率非常低，近年来，赛诺菲已做出巨大努力，但并不总是达到其预期的成功。需要说明的是，任何一项新技术的发展，挫折与坎坷是常态。当下，NK细胞疗法研发仍在如火如荼地开展。根据Nature近期发表的一篇综述，在肿瘤领域，目前全球进展最快的NK细胞疗法正处于II期临床阶段，另有超40个项目正在开展I期临床，覆盖多发性骨髓瘤、白血病、淋巴瘤等多种血液瘤，以及胃癌、肺癌、乳腺癌等实体瘤。国内布局NK细胞疗法的公司也不在少数。其中，中盛溯源、达博生物、晨泰医药、英百瑞、先博生物、启函生物等公司的产品均已取得CDE临床试验默示许可，目前多款正在开展早期临床。未来，基因治疗的路还会继续往下走，只是需要更多的技术信仰。/ 01 /从支柱到“弃子”在以3.57亿美元收购Kiadis三年半后，赛诺菲正在与它分道扬镳。赛诺菲在临床试验注册网站更新了Kiadis研究的NK细胞疗法SAR445419（K-NK003）的临床试验状态——终止。此前，SAR445419正在开发治疗复发/难治性急性骨髓性白血病，如今因Kiadis的撤资而终止。而Kiadis之所以撤资，是因为赛诺菲要求关闭Kiadis的遗产业务。赛诺菲表示，这是在仔细考虑了市场状况和战略重点多种因素后作出的决定。这也意味着，这家成立27年的公司，即将走到尽头。Kiadis与赛诺菲的渊源，还要从2019年说起。当年，Kiadis在T细胞开发领域遭遇挫折，ATIR101的临床试验III期研究数据无法展示其治疗的优越性，极有可能被EMA拒绝上市批准。自此，Kiadis调整战略，专注于通过收购CytoSen Therapeutics 获得的同种异体（现货型）NK细胞疗法。2020年，赛诺菲先是引进了Kiadis临床前多发性骨髓瘤 NK细胞疗法K-NK004的权益，而后直接以3.08亿欧元（约合3.57亿美元）收购Kiadis，成为赛诺菲大力发展旗下细胞疗法管线以来的大动作之一。被收购时，依托K-NK细胞技术平台，Kiadis共有5款在研产品，其中4款已公布具体适应症，覆盖血液肿瘤、实体瘤和COVID-19新冠病毒等领域，其中K-NK002开发速度最快，已进入临床II期阶段。当时Kiadis首席执行官Arthur Lahr表示：“Kiadis董事会一致认为，赛诺菲拥有资源和财务实力，能够加速我们NK细胞产品的开发，造福患者。”2021年4月，交易完成。赛诺菲全球肿瘤学研究负责人Valeria Fantin博士曾表示，将持续探索“NK细胞用于癌症免疫治疗的潜力，这是我们肿瘤学战略的关键支柱。”次年9月，赛诺菲进一步加码，以2500万美元预付款以及高达 10 亿美元里程碑付款，与Scribe达成合作开发，希望用后者的专有CRISPR-CasX加强其现有的K-NK细胞平台。由于NK细胞在肿瘤微环境中容易被诱导为可逆的耗竭状态，特别是在实体瘤中。因此研发人员往往利用基因编辑CRISPR技术敲除CAR-NK细胞中的PD-1、TGFβ-R2等，增强NK细胞对抗肿瘤微环境的能力。但目前看来，基因编辑工具对NK细胞疗法的帮助也是杯水车薪。赛诺菲发言人表示：“在这一领域，研发成本高于其他治疗领域，而临床试验成功的概率非常低。近年来，赛诺菲已做出巨大努力，但并不总是达到我们预期的成功。”也正因此，在投入3.57亿美元后，赛诺菲决定关闭Kiadis。/ 02 /理想的细胞疗法当然，赛诺菲并没有彻底撤出NK细胞领域。2022年12月，赛诺菲加深了对基于抗体的NK细胞接合器的研发，扩大了与法国生物医药公司Innate Pharma的持续合作关系，价值超14亿美元。去年底，赛诺菲基于签订的合作条款，行使了对ANKET(或基于抗体的NK细胞接合疗法)平台用于实体肿瘤的自然杀伤细胞接合器项目的许可选择权。根据协议，Innate将获得1500万欧元的期权。所谓NK细胞接合器，是优化NK细胞疗效的方法之一，其可以将NK细引导到肿瘤部位，通过触发NK细胞上的激活受体来引发强烈的抗肿瘤反应，同时结合肿瘤细胞上的目标抗原。开发策略包括三个特异性或四个特异性设计，靶向肿瘤上的多种抗原，起到类似“桥梁”的作用，能够有效降低制造成本且增强NK细胞的活性。赛诺菲的选择不难理解。由于投入巨大且迟迟不见研发成果，在其战略调整，全力推进管线优先级项目的背景下，抛弃Kiadis的决定并不难做出。而考虑到NK细胞疗法的巨大的潜力，其也通过其他合作保留了“火种”。CAR-T疗法在肿瘤领域取得的革命性成果，让我们看到了免疫细胞疗法治愈癌症的巨大潜力。但由于CAR-T疗法存在的易引发细胞因子风暴、对实体瘤疗效差、生产成本高等局限性，让研究人员将目光转投到了NK细胞上。像T细胞一样，NK细胞可以被改造以更好地识别特定的肿瘤。此外，它们还有几个优点：NK细胞能比T细胞检测到更多的肿瘤化学信号；与T细胞相比，NK相对不容易攻击健康组织；其还可以异体使用，NK细胞疗法也被称为“现货”或“通用”细胞疗法。这意味着可以用来自健康供体的NK细胞治疗患者，并降低外来细胞攻击患者身体的风险。作为免疫疗法，NK细胞（天然的和工程化的）是T细胞更安全、更“友好”的替代品。无论是在血液瘤还是实体瘤领域，NK细胞疗法也曾展现出令人欣喜的疗效。2020年12月4，NK细胞疗法明星公司Fate，公布了其iPSC-derived NK 细胞疗法 FT516的一期临床数据。数据表明，FT516 结合Rituximab（一种靶向CD20的抗体药）在复发性B细胞淋巴瘤患者中获得了十分乐观的临床数据。在一期治疗的所有四名患者中，没有发现与剂量相关的药物毒性，没有产生任何级别的细胞因子风暴及神经毒性；疗效方面，三名患者产生应答，其中两名患者更是达到了完全应答率。两天后，Fate趁热打铁公布了FT 596，旗下另一种NK细胞疗法的可观临床数据。这一系列临床数据的发布，使得Fate股价在几天内上涨了52%。实体瘤方面，2021年1月，CAR-NK 头部玩家NantKwest公布PD-L1和t-haNK与ImmunityBio的IL-15联合治疗转移性胰腺癌的数据，在11位接受治疗的受试者中，前10位得到了部分缓解，最后一位患者得到了完全缓解。除此之外，NK细胞在EGFR突变肺癌、难治性HER2阳性乳腺癌、胃癌以及肝癌等领域的早期临床中，也展现出不错的战斗力。基于此，过去几年，NK细胞成为癌症细胞治疗领域的热门，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，相关临床试验项目大幅度增加，平均每年达到47项。包括赛诺菲、默沙东、BMS、艾伯维在内的巨头，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，预测以16.2%的CAGR在2028年突破10亿美元。但这注定是一个不好啃的市场。/ 03 /现实的困顿NK细胞疗法曾因为其“通用现货”的特性，被视为肿瘤细胞疗法的良药。可惜临床I期的数据就暴露了 NK 细胞疗法的各项短板——仍然无法突破实体瘤治疗、快速耗竭导致肿瘤迅速复发……Fate的股价走势，足以反映出市场对这个技术路径从狂热到心灰意冷。2023年1月，Fate宣布终止与J&J的合作，并终止FT596项目开发，将所剩只够三年运营的现金集中到二代靶向CD19的CAR-NK等项目。在此之前，Fate股价一直跌跌不休，从最高的108亿美元暴跌至最新的6亿美元，不及高点的零头。不止是Fate，包括Innate、Nkarta在内的一批昔日明星NK细胞疗法公司，市值从高点至今均腰斩不止，如今，赛诺菲更是决定关闭Kiadis。任何一个医药技术领域，如果出现这种集体价值崩塌，那基本反映市场在未来一段时间内，对该领域不抱以太大的希望。那么，NK细胞疗法到底遇上了什么问题？赛诺菲肿瘤研究全球负责人Valeria Fantin曾表示：“提高体内持久性和改善实体瘤浸润是两个重点领域。”尽管NK细胞疗法具有潜在的优势，但它的开发已经落后于T细胞疗法。原因在于NK细胞本身：事实证明，在工业规模上扩增、培养和基因改造NK细胞具有挑战性。现阶段多数CAR-NK细胞所使用的CAR分子结构都是为CAR-T细胞设计的，虽然在NK细胞中也可以发挥作用，但仍需要改进。不少研究者仍在对CAR分子进行设计和优化，使其更适合NK细胞。除了优化CAR分子，如何更好地改造NK细胞也是一个问题。在缺乏细胞因子支持的情况下，输注细胞在体内缺乏耐久性是NK细胞治疗的主要缺点之一。虽然它可能是安全的，但它可能会限制 NK细胞免疫疗法的疗效。外源性细胞因子已被证明可以增加过继输注NK细胞的增殖和持久性，但它们也会引起不良副作用，包括抑制性免疫亚群的生长，例如Tregs。针对这一问题，研究人员尝试利用基因工程技术，修饰NK细胞以提升其持久性，如采用携带补充细胞因子信号的基因工程化策略，利用自分泌来维持细胞效力。而由于NK细胞占外周单核细胞的10%左右，在用于治疗时需要进行筛选和扩增，同时需要完全清除T细胞，以减少其带来的移植物抗宿主病。目前，人外周单核细胞（PBMC）是最主要的NK细胞来源，具有较强的细胞毒性，但增殖能力较弱。NK细胞的另一个主要来源是脐带血（UCB），通过这种方式产生的NK细胞表现出不成熟的表型，但细胞毒性较低。这两种来源均难以实现标准化。针对这一困难，目前已有在研的iPSC诱导的NK细胞，这种方式制备的NK细胞与UCB来源相同，都以不成熟的NK细胞为主。另一个NK细胞制造问题是需要供应外源性细胞因子，如白介素-15（IL-15），以扩增细胞并确保其持续存在。T细胞产生自己的生长因子，它们可以克隆扩张，而NK细胞却不能。一些开发人员通过工程化设计NK细胞来解决这个问题，但过度激活会导致钝化。与此同时，NK细胞靶向疗法是否能比T细胞疗法更成功地治疗实体瘤仍是一个悬而未决的问题。即使在肿瘤微环境中获得足够的活性NK细胞，如何克服免疫抑制环境仍是细胞疗法需要面对的挑战。由于肿瘤微环境具有含有免疫抑制分子、低氧、缺乏葡萄糖和氨基酸、酸性等异质特点，NK细胞可在该环境中被诱导为可逆的耗竭状态，表现为功能受损、肿瘤相关免疫检查点表达上调，特别是实体瘤中。因此，研发人员往往利用基因编辑CRISPR技术敲除CAR-NK细胞中的PD-1、TGFβ-R2等，增强NK细胞对抗肿瘤微环境的能力。但赛诺菲放弃Kiadis，说明基因编辑技术的作用似乎也不大。当我们跳出个体，会发现包括NK细胞在内的细胞疗法当前的困局在于，我们看似掌握了相当多在细胞层面进行“操作”的工具，却对于细胞本身及其在体内发挥作用的理解层面仍然匮乏，毕竟细胞的体量和复杂程度比小分子和抗体等不可同日而语。事实上，为什么NK细胞比T细胞对实体瘤更有效，至今依然没有依据。再比如，细胞因子释放综合征如果发生在NK细胞治疗期间，往往会温和很多，但个中原因尚未完全理清。这似乎也注定了其坎坷的发展之路。当然，未来细胞疗法仍将继续向前，只是何时能够真正突破，不得而知。/ 04 /总结在目前的发展阶段，相比于NK细胞潜在临床效用探索得到的答案，基于NK细胞的疗法产生了更多的问题。体外扩增难、转染效率低、肿瘤趋向能力、肿瘤微环境抑制等，一系列不确定性和挑战，还有待解决。技术的发展经常伴随着泡沫，大多数人容易高估一项新技术的短期变化，而低估它的长期影响。NK细胞技术的发展也不例外，如赛诺菲般的大药厂也未能坚持到底。那么，你还愿意为技术充值信仰吗？文／张曦【智药研习社近期直播预告】来源：氨基观察声明：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~