Granulocyte colony-stimulating factor(Shire Pharmaceuticals Services Ltd.)

4WARD Phase 3 chronic neutropenia trial in full swing; full enrollment on track for 3Q or 4Q 2025 and top-line data in 2H 2026 Additional analyses of mavorixafor clinical trial data increase confidence in successful outcome of 4WARD trial XOLREMDI® net U.S. revenues $3.5 million since May 2024 launch Conference call and webcast today at 8:30 am ET BOSTON, May 01, 2025 (GLOBE NEWSWIRE) -- X4 Pharmaceuticals (Nasdaq: XFOR), a company driven to improve the lives of people with rare diseases of the immune system, today reported financial results for the first quarter ended March 31, 2025, and highlighted key recent events and expected upcoming milestones. “The first quarter of 2025 was an extremely productive and value-adding period for X4,” said Paula Ragan, Ph.D., President and Chief Executive Officer of X4 Pharmaceuticals. “Not only did we make significant progress in activating sites and enrolling participants in our ongoing mavorixafor Phase 3 trial in chronic neutropenia, but we also continued to support U.S. commercialization of XOLREMDI (mavorixafor) in WHIM syndrome, while also significantly expanding our global potential following acceptance of our EU regulatory submission in WHIM and the announcement of two international commercialization partnerships. We look forward to continuing to deliver on our milestones in the coming year toward our goal of maximizing the potential of mavorixafor to benefit patients with rare immunodeficiencies.” Key First-Quarter 2025 and Recent Corporate Highlights Advancing Mavorixafor in Chronic Neutropenia (CN) 4WARD Trial Updates. X4 continues to enroll participants in its ongoing global, pivotal Phase 3 clinical trial (NCT06056297), evaluating oral, once-daily mavorixafor in people with congenital, acquired primary autoimmune, or idiopathic CN who are experiencing recurrent and/or serious infections. As previously reported, an amendment to the 4WARD protocol has been implemented, focusing enrollment on those with the highest unmet needs and refining the definition of ANC response, making it consistent across all trial participants. Overall, the trial seeks to demonstrate statistically significant increases in ANC response and corresponding decreases in annualized infection rate between those on mavorixafor versus placebo.To date, the demographics of the enrolled population are balanced and representative of the targeted commercial CN patient populations; baseline absolute neutrophil counts (ANC) and historical infection rates are consistent with this high unmet need population.X4 continues to expect full enrollment in the trial in the third or fourth quarter of 2025, and disclosure of top-line data in the second half of 2026. Further Data Analyses Continue to Increase Confidence in Potential 4WARD Success. X4 recently applied the 4WARD trial ANC response criteria to individual participant results in the completed mavorixafor Phase 3 4WHIM trial and the Phase 2 CN trial to further assess the likelihood of 4WARD trial success. The company believes that the results of these analyses (details of which are available in the company’s updated investor presentation) further support the potential of mavorixafor to not only elevate ANC in the 4WARD trial participants, but that these ANC elevations should correspond with significant reductions in annualized infection rates in the mavorixafor treated trial population.Mavorixafor Patent Update: In March 2025, X4 received a Notice of Allowance from the U.S. Patent and Trademark Office on its application 17/941,509, which claims include the use of mavorixafor in treating severe chronic, idiopathic, and autoimmune neutropenia in patients without a CXCR4 genetic variation. The patent is expected to expire in the U.S. in March of 2041; similar patent applications are pending in Europe, China, Japan, and Canada. Commercializing XOLREMDI® (mavorixafor) in WHIM Syndrome, a Rare Primary Immunodeficiency Revenue Update: X4 has now generated $3.5 million in U.S. sales of XOLREMDI (mavorixafor) from its mid-May 2024 launch through March 2025. The company also disclosed that newly identified patients on treatment are increasing in share of the overall current population on XOLREMDI, demonstrating the positive impact of ongoing WHIM education and awareness.Upcoming WHIM Clinical and Survey Data Presentations: Published abstracts accepted for poster presentation at the upcoming meeting of the Clinical Immunology Society (CIS) summarize the following results: Phase 3 Open Label Extension (OLE) Wart Data: Two-year data from the OLE phase of the 4WHIM Phase 3 clinical trial evaluating once-daily oral mavorixafor in people with WHIM syndrome revealed marked clinical improvement in wart severity as assessed by Clinical Global Impression of Severity across 70 defined wart areas.First-Ever WHIM Infection Burden Survey Results: Of the 20 WHIM patient respondents, 60% of those <18 years and 73% of those ≥18 years reported experiencing at least one infection in the previous 3 months, with 25% requiring overnight hospitalization due to infection. The study concludes that “the frequency and severity of infections requiring medical care and hospitalization underscores the urgency to proactively treat patients with WHIM syndrome.” Maximizing the Global Opportunity for Mavorixafor in WHIM Syndrome: MAA Acceptance. In January 2025, X4 announced that its submitted Marketing Authorization Application (MAA) for mavorixafor in the treatment of WHIM syndrome was validated for review by the European Medicines Agency (EMA), enabling possible approval in the first half of 2026.Ex-US Partnerships. In the first quarter of 2025, the company announced that it had entered into two ex-U.S. partnerships for the commercialization of mavorixafor: the first, an exclusive licensing and supply agreement under which Norgine Pharma UK will commercialize mavorixafor in Europe, Australia, and New Zealand and the second, with taiba rare to distribute and commercialize XOLREMDI for the treatment of WHIM syndrome in Saudi Arabia, United Arab Emirates, Qatar, Oman, Kuwait, Bahrain, and Egypt following the necessary regulatory approvals in those countries and/or regions. Strategic RestructuringIn February 2025, X4 announced a strategic restructuring to sharpen focus and maximize the opportunity for mavorixafor in chronic neutropenia while also optimizing its U.S. promotion of XOLREMDI. X4 continues to expect that these efforts will decrease spending by $30-35 million annually. Reverse Stock SplitOn April 24, 2025, X4 announced a one-for-thirty reverse stock split of the company’s common stock. The reverse stock split took effect at 12:01 a.m. ET on April 28, 2025, and the company’s common stock began trading on a split-adjusted basis on The Nasdaq Capital Market as of the opening of trading the same day under a new CUSIP number (98420X202). The reverse split reduced the number of outstanding shares of the company’s Common Stock from approximately 173.6 million shares to approximately 5.8 million shares. First-Quarter 2025 Financial Results Cash position: X4 had $87.7 million in cash, cash equivalents, restricted cash, and marketable securities as of March 31, 2025. The company continues to believe it has sufficient funds to support operations into the first half of 2026.Revenue and Cost of Revenue: For the first quarter ended March 31, 2025, X4 reported net revenue of $28.8 million and cost of revenue of $4.7 million. Revenue in the quarter included license and other revenues of $27.9 million associated with the completed Norgine agreement and XOLREMDI product revenue of $0.9 million. Cost of revenue included $4.5 million of sublicense royalties associated with the Norgine agreement.Research and Development (R&D) Expenses were $18.5 million for the first quarter ended March 31, 2025, as compared to $19.9 million for the comparable period in 2024. R&D expenses included $0.3 million of certain non-cash expenses for the first quarter ended March 31, 2025.Selling, General, and Administrative (SG&A) Expenses were $15.0 million for the first quarter ended March 31, 2025, as compared to $17.4 million for the comparable period in 2024. SG&A expenses included $0.3 million of certain non-cash expenses for the first quarter ended March 31, 2025.Net Income (Loss): X4 reported net income of $0.3 million for the first quarter ended March 31, 2025, as compared to a net loss of $51.8 million for the comparable period in 2024. Net income included $0.5 million of stock-based compensation expenses for the first quarter ended March 31, 2025. Conference Call and Webcast X4 will host a conference call and webcast today at 8:30 am ET to discuss these financial results and business highlights. The conference call can be accessed by dialing 1-800-343-4849 from the United States or 1-203-518-9848 internationally, followed by the conference ID: X4PHARMA. The live webcast will be accessible through the investor relations section of X4 Pharmaceuticals’ website at www.x4pharma.com. Following the conclusion of the call, a webcast replay will be available on the website. About WHIM SyndromeWHIM syndrome is a rare, combined primary immunodeficiency and chronic neutropenic disorder caused by CXCR4 receptor dysfunction that results in impaired mobilization of white blood cells from the bone marrow into peripheral circulation. WHIM syndrome is named for its four classic manifestations: warts, hypogammaglobulinemia, infections, and myelokathexis, although only a minority of patients experience all four manifestations in the acronym. People with WHIM syndrome characteristically have low blood levels of neutrophils (neutropenia) and lymphocytes (lymphopenia), and as a result, experience serious and/or frequent infections. About XOLREMDI® (mavorixafor)XOLREMDI (mavorixafor) is a selective CXCR4 receptor antagonist approved in the U.S. as a once-daily oral treatment for use in patients 12 years of age and older with WHIM syndrome to increase the number of circulating mature neutrophils and lymphocytes. XOLREMDI is the only treatment specifically approved for patients with WHIM syndrome in the U.S. About Chronic Neutropenia and MavorixaforChronic neutropenia is a primary, rare blood condition lasting more than three months, persistently or intermittently, and characterized by low levels of circulating neutrophils and increased risk of infections and reduced quality of life due to abnormally low levels of neutrophils circulating in the blood. Neutrophils are retained in the bone marrow by the CXCR4/CXCL12 axis, creating a reserve of cells. Downregulation of the CXCR4 receptor by mavorixafor, an orally active CXCR4 antagonist, has been shown to mobilize functional neutrophils from the bone marrow into the peripheral blood across multiple disease states. The level of circulating neutrophils is typically measured by drawing blood to determine the absolute neutrophil count (ANC). About the 4WARD Clinical TrialThe 4WARD trial is a global, pivotal Phase 3 clinical trial (NCT06056297) evaluating the efficacy, safety, and tolerability of oral, once-daily mavorixafor (with or without G-CSF) in people with congenital, acquired primary autoimmune, or idiopathic chronic neutropenia who are experiencing recurrent and/or serious infections. The 52-week trial is a randomized, double-blind, placebo-controlled, multicenter study aiming to enroll 150 participants with confirmed trough ANC levels less than 1,000 cells per microliter at baseline screening and histories of two or more serious and/or recurrent infections in the prior year. The primary endpoint of the trial is based on two outcome measures: annualized infection rate and positive ANC response. About X4 PharmaceuticalsX4 is delivering progress for patients by developing and commercializing innovative therapies for those with rare diseases of the immune system and significant unmet needs. Leveraging expertise in CXCR4 and immune system biology, X4 has successfully developed mavorixafor, an orally available CXCR4 antagonist that is currently being marketed in the U.S. as XOLREMDI® in its first indication. The company is also evaluating additional uses of mavorixafor and is conducting a global, pivotal Phase 3 clinical trial (4WARD) in people with certain chronic neutropenic disorders. X4 is headquartered in Boston, Massachusetts. For more information, please visit www.x4pharma.com. X4 Forward Looking Statements This press release contains forward-looking statements within the meaning of applicable securities laws, including the Private Securities Litigation Reform Act of 1995, as amended. These statements may be identified by the words “may,” “will,” “could,” “would,” “should,” “expect,” “plan,” “anticipate,” “intend,” “believe,” “estimate,” “predict,” “project,” “potential,” “continue,” “target,” or other similar terms or expressions that concern X4’s expectations, strategy, plans, or intentions. Forward-looking statements include, without limitation, implied or express statements regarding the initiation, timing, progress, and results of our current and future preclinical studies and clinical trial; the timing and period during which the results of the trials will become available and reported, as well as our research and development programs; market opportunities for X4’s product candidates, including potential benefits from partnerships; expectations regarding the commercial potential of mavorixafor and ongoing engagement and feedback from regulatory authorities; and the sufficiency of X4’s cash resources and pro forma cash resources, including the potential impact of the 2025 strategic restructuring, and expectations regarding X4’s cash runway. Any forward-looking statements in this press release are based on management’s current expectations and beliefs. These forward-looking statements are neither promises nor guarantees of future performance, and are subject to a variety of risks and uncertainties, many of which are beyond X4’s control, which could cause actual results to differ materially from those contemplated in these forward-looking statements, including the risks that: X4’s restructuring activities may be more costly or time-consuming than expected or may not achieve their intended results and savings; X4’s future financial performance and position may not improve resulting in difficulties in implementing X4’s business strategy, and plans and objectives for future operations; the expected decrease in annual spending could negatively impact X4’s commercial plans and strategy for mavorixafor; the expected sufficiency of X4’s existing cash resources and runway may not be accurate resulting in the need for additional financing sooner than anticipated or unexpected liquidity constraints; the internal and external costs required for X4’s ongoing and planned activities, and the resulting impact on expense and use of cash, may be higher than expected, which may cause the company to use cash more quickly than expected or to change or curtail some of X4’s plans or both; the expected availability, content, and timing of clinical data from X4’s ongoing clinical trials of mavorixafor may be delayed or unavailable, including the ongoing Phase 3 clinical trial; trials, studies and research programs may be delayed and may not have satisfactory outcomes, additionally earlier trials and studies may not be predictive of later trials and studies; the design and rate of enrollment for current clinical trials may not enable successful completion of the trial(s); the commercial opportunity for mavorixafor may be smaller than anticipated; X4 may be unable to obtain and maintain regulatory approvals; adverse safety effects may arise from the testing or use of X4’s product and product candidates; the need to align with collaborators may hamper or delay development and commercialization efforts or increase costs; business may be adversely affected and costs may increase if any of the company’s key collaborators fails to perform its obligations or terminates the collaboration; X4’s may be unable to advance and commercialize and increase sales in mavorixafor to treat chronic neutropenia or to optimize the U.S. promotion of XOLREMDI® (mavorixafor), approved for the treatment of WHIM; and other risks and uncertainties, including those described in the section entitled “Risk Factors” in X4’s most recent Annual Report on X4’s Form 10-K , as well as in other filings X4 makes with the Securities and Exchange Commission, including its quarterly report on Form 10-Q, from time to time. X4 undertakes no obligation to update the information contained in this press release to reflect new events or circumstances, except as required by law. (Tables Follow) X4 PHARMACEUTICALS, INC.CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS(in thousands, except per share amounts)(unaudited) Three Months Ended March 31, 2025 2024 License and other revenue $27,865 $— Product revenue, net 942 — Total revenue 28,807 — Costs and operating expenses: Cost of revenue 4,716 — Research and development 18,513 19,854 Selling, general and administrative 15,021 17,435 Total operating expenses 38,250 37,289 Loss from operations (9,443) (37,289)Other income (expense), net 9,759 (14,458)Income (loss) before provision for income taxes 316 (51,747)Provision for income taxes 34 19 Net income (loss) $282 $(51,766)Net income (loss) per share- basic $0.04 $(7.77)Weighted average common shares outstanding- basic 6,840 6,666 Net income (loss) per share- diluted $0.04 $(7.77)Weighted average common shares outstanding- diluted 6,869 6,666 X4 PHARMACEUTICALS, INC.CONDENSED CONSOLIDATED BALANCE SHEETS(in thousands)(unaudited) March 31,2025 December 31,2024Current assets: Cash and cash equivalents $40,257 $55,699 Accounts receivable 509 1,070 Marketable securities 46,694 46,361 Research and development incentive receivable 665 640 Inventory 3,089 2,817 Prepaid expenses and other current assets 4,483 5,588 Total current assets 95,697 112,175 Property and equipment, net 487 776 Goodwill 17,351 17,351 Intangible asset, net 9,813 10,000 Right-of-use assets 3,652 4,065 Other assets 3,013 2,080 Total assets $130,013 $146,447 Current liabilities: Accounts payable $11,115 $8,621 Accrued expenses 12,611 23,005 Deferred revenue 855 — Current portion of lease liability 1,303 1,251 Total current liabilities 25,884 32,877 Long-term debt, including accretion, net of discount 75,629 75,425 Lease liabilities 1,109 1,410 Warrant liability 2,925 13,755 Deferred revenue and other liabilities 1,522 831 Total liabilities 107,069 124,298 Total stockholders' equity 22,944 22,149 Total liabilities and stockholders' equity $130,013 $146,447 X4 Investor Contact:X4 Media Contact:Daniel FerryLifeSci Advisorsdaniel@lifesciadvisors.com(617) 430-7576Rhiannon JeselonisTen Bridge Communicationsrhiannon@tenbridgecommunications.com

引言当癌症的阴霾笼罩，当一次次治疗宣告失败，希望似乎变得遥不可及。对于许多罹患CD30阳性（CD30+）淋巴瘤，特别是霍奇金淋巴瘤（Hodgkin Lymphoma, HL）的患者而言，如果连靶向药物维布妥昔单抗（Brentuximab Vedotin, BV）和免疫检查点抑制剂（Checkpoint Inhibitors, CPI）都失去了效果，他们往往会陷入“双重难治”的困境，面临着极为有限的治疗选择和令人沮丧的预后。这不仅是医学上的挑战，更是患者与家庭难以承受之重。然而，科学的脚步从未停歇！4月4日一项发表在《Nature Medicine》上的突破性研究“Allogeneic NK cells with a bispecific innate cell engager in refractory relapsed lymphoma: a phase 1 trial”，正为这些身处绝境的患者点亮一盏希望之灯。研究人员巧妙地将人体免疫系统的“自然杀手”——NK细胞（Natural Killer cells），与一种名为AFM13的“分子桥梁”（CD30/CD16A Bispecific Innate Cell Engager）相结合，创造出一种全新的细胞免疫疗法。研究人员从健康的脐带血（Cord Blood, CB）中获取NK细胞，在实验室中对其进行“激活”和“扩增”，使其战斗力倍增，然后预先“武装”上AFM13这种能够同时抓住NK细胞和癌细胞（通过CD30标记）的特殊抗体。这项名为AFM13-NK的创新疗法，在一项针对42名经过多线治疗、病情极为顽固的CD30+淋巴瘤患者的早期（Phase 1）临床试验中，展现出了令人瞩目的初步结果。它不仅显示出良好的安全性，未观察到令人担忧的严重副作用，如细胞因子释放综合征（CRS）或神经毒性（Neurotoxicity），更取得了高达92.9%的总体缓解率和66.7%的完全缓解率！绝境逢生？当霍奇金淋巴瘤遭遇“无药可医”霍奇金淋巴瘤（Hodgkin Lymphoma, HL）是一种影响淋巴系统的癌症。得益于现代医学的进步，特别是BV和CPI等靶向及免疫药物的应用，许多HL患者的生存状况得到了显著改善。然而，医学的进步并非总能覆盖所有角落。一部分患者，他们的肿瘤细胞异常顽固，即使经历了多轮化疗、靶向治疗乃至免疫治疗，癌细胞依然卷土重来，甚至对这些先进的药物也产生了耐药性（Refractory）。对于那些同时对BV和CPI都无效的患者，医学界称之为“双重难治”（Double-refractory）。这些患者往往已经尝试过多种治疗方案，身体也可能因为之前的治疗而变得虚弱。他们面临的治疗选择屈指可数，生存前景堪忧（Dismal Outcomes）。据统计，这些患者的中位生存期往往不容乐观。寻找能够有效对抗这些“超级顽固”癌细胞的新疗法，成为了医学界面临的迫切挑战。同时，某些类型的T细胞淋巴瘤（T-cell Lymphoma, T-NHL），如间变性大细胞淋巴瘤（Anaplastic Large Cell Lymphoma, ALCL）等，也表达CD30，同样面临着治疗困境。这场与顽固淋巴瘤的战斗，亟需新的“武器”加入。免疫奇兵驾到！认识我们体内的“自然杀手”NK细胞在我们复杂的免疫系统中，有一类特殊的“战士”，它们不需要像T细胞那样经过“预先训练”（Previous Sensitization）就能识别并攻击癌细胞或被病毒感染的细胞，它们就是“自然杀手”细胞，简称NK细胞（Natural Killer cells）。NK细胞属于我们身体的“先天免疫”（Innate Immunity）系统，是抵抗肿瘤的第一道防线之一。它们天生具备识别异常细胞并启动杀伤程序的能力。然而，在某些癌症，特别是霍奇金淋巴瘤中，肿瘤微环境（Tumor Microenvironment）非常狡猾，它会分泌一些物质，或者通过细胞间的相互作用，抑制NK细胞和T细胞的功能，让这些免疫卫士变得“迟钝”甚至“失能”（Dysfunctional）。这时候，患者自身的NK细胞可能难以发挥有效的抗癌作用。那么，能不能从健康的捐赠者那里获取NK细胞呢？这就是“同种异体”（Allogeneic）NK细胞疗法的思路。研究人员发现，来自健康捐赠者的NK细胞，尤其是从脐带血（Cord Blood, CB）中提取并经过特殊处理的NK细胞，可能更具活力和杀伤力。脐带血来源丰富，获取相对容易，而且引发严重免疫排斥反应——移植物抗宿主病（Graft-versus-Host Disease, GVHD）的风险相对较低。更重要的是，研究人员已经开发出成熟的技术，可以在体外（实验室环境）对这些脐带血NK细胞进行“扩增”和“激活”。在这项研究中，研究人员使用了一种优化的流程。他们首先从脐带血中分离出NK细胞，然后用特定的细胞因子（Cytokines）——白细胞介素12（IL-12）、IL-15和IL-18进行短暂的“预激活”（Preactivation）。随后，将这些NK细胞与经过改造的“饲养细胞”（Feeder Cells，表达CD48、膜联IL-21和4-1BB配体）共同培养，并加入IL-2。这个过程就像是给NK细胞进行“特种兵训练营”，让它们在短短14天内数量急剧增加（研究中观察到超过2700倍的扩增！），并且变得功能更强大、更“能打”。最终得到的NK细胞产品，纯度极高，几乎不含可能引起GVHD的T细胞（研究中T细胞含量仅为0.02%）。“细胞导弹”精准制导：AFM13的神奇“搭桥”作用有了强大的NK“战士”，如何确保它们能精准地找到并攻击隐藏在体内的淋巴瘤细胞呢？这里就需要引入另一个关键角色——AFM13。AFM13是一种“双特异性抗体”（Bispecific Antibody），更准确地说，是一种“先天免疫细胞衔接器”（Bispecific Innate Cell Engager）。顾名思义，“双特异性”意味着它有两个不同的“抓手”：一个抓手可以紧紧抓住淋巴瘤细胞表面的特定标记——CD30；另一个抓手则能牢牢结合NK细胞表面的激活受体——CD16A。你可以把AFM13想象成一个高度特异性的“分子桥梁”或“红娘”。它一头连着癌细胞（通过CD30），另一头连着NK细胞（通过CD16A），强行将两者“撮合”到一起。当NK细胞通过AFM13与癌细胞接触时，CD16A受体被激活，NK细胞就会收到强烈的“攻击”信号，释放出细胞毒性物质，从而高效地杀死癌细胞。即使癌细胞想要“伪装”或“逃跑”，只要它还表达CD30，AFM13就能帮助NK细胞将其锁定。更巧妙的是，这项研究并非简单地将NK细胞和AFM13分别注入患者体内，而是采用了“预复合”（Precomplexed）的策略。在输注给患者之前，研究人员先在体外将扩增激活后的NK细胞与AFM13“捆绑”在一起，形成“AFM13-NK”复合物。这样做的好处是，NK细胞一进入体内就已经是“武装到牙齿”的状态，能够更直接、更有效地靶向CD30+的淋巴瘤细胞，其作用方式甚至有点类似于更复杂的CAR-T细胞疗法，但理论上可能更安全。先前的动物实验（Mouse Xenografts）已经证明，这种预复合的AFM13-NK细胞比单独使用NK细胞或单独使用AFM13具有更强的抗肿瘤活性。安全性惊艳！“温和版”细胞疗法告别可怕风暴？对于任何一种新的疗法，尤其是在病情危重、身体虚弱的患者群体中进行试验，安全性永远是第一位的考量。细胞疗法，特别是CAR-T疗法，虽然效果显著，但其潜在的严重副作用，如细胞因子释放综合征（Cytokine Release Syndrome, CRS）和免疫效应细胞相关神经毒性综合征（Immune cell associated Neurotoxicity Syndrome, ICANS），常常让患者和医生心有余悸。CRS可能导致高烧、低血压、呼吸困难等，严重时甚至危及生命；ICANS则可能引发意识模糊、癫痫、脑水肿等神经系统症状。然而，这项AFM13-NK疗法的Phase 1（一期）临床试验结果，在安全性方面给出了一个令人惊喜的答案。在接受治疗的全部42名患者中，研究人员密切监测了各种不良反应，结果发现：没有发生任何级别的CRS！ 这意味着患者在治疗过程中没有经历那种可能危及生命的“细胞因子风暴”。没有发生任何神经毒性（ICANS）！ 这大大降低了治疗的风险和复杂性。没有发生移植物抗宿主病（GVHD）！ 尽管使用的是来自无关捐赠者（脐带血）的NK细胞，且这些细胞与患者的人类白细胞抗原（Human Leukocyte Antigen, HLA）通常不匹配（研究中大部分是0-2个位点匹配），但并未观察到NK细胞攻击患者正常组织的现象。这与NK细胞本身的特性以及产品中极低的T细胞含量有关。这项研究的主要安全性终点（Primary Endpoint）得以顺利达成，并且确定了最高的NK细胞剂量（1x10⁸ cells/kg⁻¹）作为后续研究的推荐剂量（Recommended Phase 2 Dose, RP2D）。当然，治疗也并非完全没有副作用。由于在输注AFM13-NK细胞前，患者需要接受“淋巴细胞清除”（Lymphodepletion）的化疗方案（包含氟达拉滨Fludarabine和环磷酰胺Cyclophosphamide），目的是为输入的NK细胞“腾出空间”并创造更有利的生存环境，这种化疗本身会导致可预期的骨髓抑制（Myelosuppression），即白细胞、红细胞和血小板的暂时性降低。研究中观察到了较高比例的中性粒细胞减少（Neutropenia，3/4级约占71%）和血小板减少（Thrombocytopenia，3/4级约占38%）。但这些血细胞减少通常是暂时的、可逆的，并且可以通过支持性治疗（如使用升白针G-CSF）进行管理。值得注意的是，即使治疗延长到四个周期，严重中性粒细胞减少的发生率并未累积增加，但血小板减少在第三、四个周期后似乎更为明显，不过并未导致任何患者出现出血事件。此外，输注AFM13本身可能引起轻微的输液相关反应（Infusion-related reactions），在总共349次AFM13输注中发生了27次（占比7.7%），绝大多数（26次）为1级或2级的轻度反应，只有1次达到3级。而输注AFM13-NK细胞的反应则更为罕见，仅有1例（占比2.4%）为2级反应。令人遗憾的是，研究中有3名患者因病毒性肺炎（Viral Pneumonia）死亡，其中一例为COVID-19（发生在疫情期间），发生在最后一次治疗后的6至18个月。这提醒我们，这些本身经过多线治疗、免疫系统可能本就脆弱的患者，在接受强效免疫抑制（化疗）和细胞疗法后，长期来看可能面临更高的感染风险。研究者也注意到，这三位患者的基线免疫球蛋白G（IgG）水平较低。这提示未来可能需要更关注患者的免疫重建和感染预防。此外，还有一名患者在治疗结束后4个月死于病因不明的缺血性中风（Ischemic stroke）。另有两名患者在淋巴瘤复发后被诊断出骨髓增生异常综合征（Myelodysplastic syndrome），这可能与之前的多线治疗有关。但总体而言，与现有的一些细胞疗法相比，AFM13-NK展现出的“温和”安全性特征，特别是完全避免了CRS和ICANS这两大棘手难题，无疑是其巨大的优势和亮点。战果斐然！点燃希望的数据：高达93%的缓解率！安全性过关是基础，疗效才是最终目的。尽管这只是一项旨在评估安全性和剂量的早期（Phase 1）试验，其揭示的初步疗效数据已经足够令人振奋，尤其考虑到参与试验的都是病情极其复杂的难治性患者。研究结果显示（评估时间点为每个治疗周期第28天及之后每3个月）：总体缓解率（Overall Response Rate, ORR）高达92.9%！ 这意味着在42名接受治疗的患者中，有39人的肿瘤出现了客观上的缩小。这个数字在如此难治的患者群体中是极为罕见的。完全缓解率（Complete Response, CR）达到了66.7%！ 这表示有28名患者体内的肿瘤病灶甚至完全消失（通过PET-CT影像学评估达到-100%代谢活性降低）。达到完全缓解是获得长期生存的关键一步。在霍奇金淋巴瘤（HL）患者亚组（n=37）中，效果更为突出：ORR为97.3%，CR率高达73%！疗效快速且广泛： 肿瘤缓解在所有三个剂量水平（10⁶, 10⁷, 10⁸ cells/kg⁻¹）都观察到了，并且无论是淋巴结内的病灶，还是扩散到肝脏、肺、骨骼、心包等淋巴结外的病灶，都对治疗产生了反应。缓解程度随治疗加深： 值得注意的是，有10名患者在第一个治疗周期后仅获得部分缓解（Partial Response, PR），但在接受第二个周期治疗后，成功转化为完全缓解（CR）。这提示多周期治疗可能带来更深层次的疗效。攻克CAR-T耐药难题： 试验中纳入了4名曾接受过CD30 CAR-T细胞治疗但最终失败（疾病进展）的HL患者。令人惊喜的是，这4名患者在接受AFM13-NK治疗后，全部达到了完全缓解！这表明AFM13-NK疗法对于那些对CAR-T产生耐药的患者，可能提供了一条新的有效途径。那么，这些缓解能持续多久呢？在中位随访时间达到20个月（范围12-40个月）时：中位无事件生存期（Median Event-Free Survival, EFS）为8.8个月。 EFS是指从治疗开始到发生疾病进展、复发、死亡或出现第二肿瘤等任何不良事件的时间。虽然中位EFS不算特别长，但考虑到患者的基线情况，这已是相当不错的结果。两年的EFS率为26.2%。中位总生存期（Median Overall Survival, OS）尚未达到！ 这意味着超过半数的患者在随访期间仍然存活。两年的总生存率（OS rate）高达76.2%！ 这个数字在双重难治淋巴瘤患者中是非常鼓舞人心的。长期缓解成为可能： 共有11名患者在研究结束时仍然维持完全缓解状态，缓解持续时间长达14至40个月！其中，有5名患者是在完成AFM13-NK治疗后，没有接受任何后续巩固治疗（如干细胞移植）的情况下，就保持了长期缓解。另外6名患者则在达到CR后接受了干细胞移植（Stem Cell Transplantation, SCT）作为巩固治疗，进一步稳定了疗效。这部分患者（11人）都曾是病情极其顽固、预后极差的，如今却获得了长期生存的机会。虽然这只是早期试验，还需要更大规模的研究来确认这些结果，但这些初步数据显示出的高缓解率、克服耐药性以及潜在的持久缓解，无疑为难治性CD30+淋巴瘤患者及其家人点燃了新的、强烈的希望之火。追踪“杀手”足迹：解码AFM13-NK细胞的作用机制为了更深入地了解AFM13-NK细胞是如何在患者体内发挥作用的，研究团队进行了一系列精密的“侦查”工作，也就是所谓的“相关性研究”（Correlative Studies）。他们采集了患者的外周血样本，甚至在治疗后早期获取了部分患者的淋巴结活检组织，利用先进的技术手段，追踪这些“免疫战士”的行踪和状态。NK细胞的体内动态： 通过检测血液中的NK细胞数量，发现输入的供体（Donor）NK细胞在输注后第1天达到峰值，显示出良好的早期扩增能力。这些细胞可以在患者体内持续存在长达3周之久，虽然不如CAR-T细胞那样长久，但对于NK细胞来说已经是不错的持久性（Persistence）。并且，每次治疗周期（无论是第一周期还是后续周期）都观察到相似的扩增和持续动力学模式，这表明重复输注似乎没有引发明显的免疫排斥，导致细胞过早被清除。精准抵达“战场”： 更重要的是，研究人员在4名患者治疗后不久的淋巴结活检样本中，成功检测到了输入的供体NK细胞！这直接证明了AFM13-NK细胞能够有效地从血液循环迁移（Trafficking）到肿瘤所在的淋巴结组织，也就是抵达了需要它们发挥作用的“战场”。变身“超级赛亚人”： 利用飞行时间质谱流式细胞术（Cytometry by Time of Flight, CyTOF）的高维分析技术，研究人员得以精细描绘出NK细胞在治疗前后的“表型”（Phenotype）变化。结果发现，输注前的AFM13-NK产品本身（主要为C1群）就处于一种高度活化和准备增殖的状态。而输注到患者体内后（尤其是在早期，第2-7天），无论是输入的供体NK细胞还是患者自身的NK细胞（Recipient NK），都涌现出一个独特的、更为强大的细胞亚群（标记为C4群）。这个C4群的NK细胞就像变身后的“超级赛亚人”，其特征是：高表达增殖标记物（Ki67）： 说明它们在体内仍在活跃分裂增殖。高表达细胞毒性武器（Perforin, Granzymes, CD95）： 拥有更强的杀伤能力。高表达多种活化分子（DNAM-1, NKp46, NKp30, 2B4, HLA-DR）： 处于高度激活状态。高表达参与淋巴结归巢和组织迁移的趋化因子受体（如CD62L, CX3CR1）： 这解释了它们为何能有效迁移到淋巴结。随着时间的推移（第14-28天），这种高度活化的C4群逐渐减少，转向一个相对“平静”的C5群，其活化和增殖标记物表达有所下调。这可能反映了NK细胞生命周期的自然过程或体内环境的变化。AFM13结合情况： 研究还发现，即使在治疗周期中后续补充输注了AFM13，该抗体也能同等地结合到供体NK细胞和患者自身NK细胞上，没有表现出明显的偏好性。探究耐药机制： 对于那些最终复发的患者，是否存在逃避NK细胞攻击的机制呢？研究团队分析了7名患者治疗前和复发时的配对肿瘤活检样本。结果显示，肿瘤细胞表面的“靶标”CD30在治疗后和复发时仍然持续表达，并未丢失。同时，肿瘤细胞上常见的、可能抑制NK细胞功能的分子，如HLA I类分子（HLA-ABC）和HLA-E，也持续强阳性表达，没有出现明显的下调（下调HLA有时是肿瘤逃避免疫监视的一种方式）。而另一个可能影响NK细胞活性的分子MICA，其表达在不同患者中存在差异，但没有观察到一致的上调或下调模式。这些结果初步表明，至少在这部分患者中，治疗失败似乎不是因为丢失了CD30靶点，也不是因为肿瘤细胞通过上调常见的抑制性信号分子来“关闭”NK细胞。耐药的具体机制仍需进一步探索。免疫平静： 与CAR-T治疗后常伴随的炎症因子飙升不同，这项研究中患者血清中的主要炎症因子，如IL-6、肿瘤坏死因子（TNF）和干扰素-γ（IFN-γ），在整个治疗过程中都保持在稳定且较低的水平。这与之前观察到的良好安全性特征（无CRS）高度吻合。这些深入的机制探索，不仅帮助我们理解了AFM13-NK细胞疗法为何有效，也为其未来的优化和改进提供了宝贵的线索。未来可期！“即用型”NK细胞疗法开启淋巴瘤治疗新篇章？这项发表在《自然·医学》上的Phase 1临床试验，虽然规模不大，随访时间也有限，但它所传递的信息是清晰的：对于那些身处绝境的难治性CD30+淋巴瘤患者，基于脐带血来源、经过体外激活扩增并预先装载了双特异性抗体AFM13的同种异体NK细胞疗法（AFM13-NK），展现出了前所未有的组合优势——惊艳的安全性和令人鼓舞的初步疗效。这项研究的成功，其意义可能超越了治疗本身：安全性优势凸显： 完全避免CRS和ICANS这两大细胞治疗常见“拦路虎”，使得治疗过程更平稳、更可控，有望惠及更广泛、身体状况可能更差的患者群体。“即用型”（Off-the-Shelf）潜力巨大：同种异体来源： 无需使用患者自身的细胞，避免了自体细胞可能存在的数量不足或功能缺陷问题。脐带血优势： 来源相对充足，免疫原性较低，GVHD风险小。研究中采用的“优化脐带血单位”筛选标准也可能对其良好表现有所贡献。无需HLA配型： 试验中并未根据HLA匹配来选择脐带血，这大大简化了流程，增加了找到合适细胞来源的机会。标准化生产： 采用GMP流程进行细胞扩增和制备，可在约2周内完成，实现了相对快速的治疗供给。未来，如果能将这些细胞预先制备好并冷冻保存，理论上可以实现真正的“即用型”治疗，患者一旦需要，就能快速获得，极大地提高了治疗的可及性。克服耐药性： 对既往治疗（包括BV、CPI甚至CD30 CAR-T）耐药的患者依然有效，显示了其独特的作用机制和潜力。桥接移植或长期缓解的希望： 对于部分患者，AFM13-NK可以作为一个有效的“桥梁”，帮助他们达到深度缓解，从而有机会接受治愈性的干细胞移植；而对于另一些患者，它甚至可能带来无需移植的长期缓解。当然，我们也要清醒地认识到，这还只是万里长征的第一步。这项研究也存在局限性：Phase 1试验样本量小；NK细胞的持久性相比CAR-T仍然有限，需要多周期治疗来维持疗效；部分患者接受了巩固移植，使得评估AFM13-NK本身的长期疗效更为复杂；研究对象以HL为主，在其他CD30+ T-NHL中的疗效还有待进一步验证。未来的研究方向是明确的：需要进行更大规模的Phase 2甚至Phase 3临床试验来确证其疗效和安全性；探索进一步提高NK细胞持久性的方法，例如通过基因工程改造NK细胞，让它们能够自分泌IL-15（一种促进NK细胞存活和功能的因子）或表达共刺激分子（如CD28）；尝试将AFM13-NK与其他疗法联合使用，以期达到更好的协同效应。尽管前路仍长，但这项研究无疑为我们描绘了一幅充满希望的蓝图。通过巧妙地结合强大的“自然杀手”NK细胞和精准的“分子桥梁”AFM13，研究人员可能为难治性淋巴瘤患者开辟了一条全新的、更安全、更有效的治疗途径。我们有理由期待，随着研究的不断深入，这种创新的“即用型”NK细胞疗法，将在未来改写更多淋巴瘤患者的命运，让他们在绝望中看到生命的曙光，迎来真正的“绝境逢生”。参考文献Nieto Y, Banerjee P, Kaur I, Basar R, Li Y, Daher M, Rafei H, Kerbauy LN, Kaplan M, Marin D, Griffin L, Barnett M, Bassett R, Uprety N, Shrestha R, Silva FR, Islam S, Ganesh C, Borneo Z, Ramdial J, Ramirez A, Hosing C, Alousi A, Popat U, Qazilbash M, Ahmed S, Iyer S, Sainz TP, Vega F, Fowlkes NW, Alexis K, Emig M, Harstrick A, Overesch A, Shpall EJ, Rezvani K. Allogeneic NK cells with a bispecific innate cell engager in refractory relapsed lymphoma: a phase 1 trial. Nat Med. 2025 Apr 4. doi: 10.1038/s41591-025-03640-8. Epub ahead of print. PMID: 40186077.责编|探索君排版|探索君转载请注明来源于【生物探索】声明：本文仅用于分享，不代表平台立场，如涉及版权等问题，请尽快联系我们，我们第一时间更正，谢谢！End往期精选围观Nature | 靶向线粒体VDAC2：破解实体瘤免疫治疗抵抗的"死亡密钥"热文Nature Medicine | 多囊女性子宫内膜藏着什么秘密？——全球首份单细胞图谱揭示治疗新方向热文Nature | 颠覆认知！大脑学习的惊人秘密：你的“潜伏知识”是如何瞬间爆发的？热文Cell | 颠覆认知！染色体形成并非依赖“骨架”，自组织模型重塑教科书热文Science | 为什么我们回想不起三岁前的经历?