Pralatrexate

文献解读  近九成缓解率的药，为何没能走到最后 一类罕见淋巴瘤新药研发的缩影：数据惊艳与产业夭折之间，隔着罕见病与免疫细胞自相残杀的双重难关 期刊：Biomarker Research（2026年，第14卷第95号，综述） 作者：Wee Lee Chan, Wee Joo Chng, Qi-Jing Li（新加坡国立大学医学组织） DOI：10.1186/s40364-026-00985-1 核心要点 一款双特异性抗体与脐血免疫细胞联用，曾在外周T细胞淋巴瘤取得近九成缓解率，却在两年后被药企终止开发。这篇综述梳理了该领域的分子机制与治疗进展，指出亚型碎片化与T细胞"自相残杀"是新药困局的两大结构性障碍。 一个戛然而止的成功故事 2025年6月，一款代号AFM13（通用名acimtamig）的药物被申办方悄然终止了开发。故事的前半段本该是个励志剧本：这是一款双特异性抗体：能同时结合两个靶点的工程抗体，一头识别肿瘤、一头招募免疫细胞。它一头瞄准肿瘤表面的CD30，另一头结合免疫细胞上的CD16A，把自然杀伤细胞（NK细胞，人体固有免疫中无需预先致敏即可杀伤肿瘤的效应细胞）拉到肿瘤身边。然而单药二期的REDIRECT研究未能达到主要终点，几乎提前宣判出局。 转机来自一个巧妙的组合设计：先在体外把这款抗体与脐血来源的NK细胞预先结合，再一起输回患者体内。二期研究中，24例可评估患者的客观缓解率达到88%。可就在所有人以为它将乘胜追击时，申办方在2025年6月按下了终止键。 近九成的缓解率，为何没能走到最后？答案藏在一种罕见淋巴瘤的结构性困局里。 掉队的十年 外周T细胞淋巴瘤（PTCL，起源于成熟T细胞的非霍奇金淋巴瘤，约占全部非霍奇金淋巴瘤的10%至20%，在东亚和南美人群更高发）并不是一个病，而是约30种亚型的集合，各亚型在肿瘤生物学、微环境组成和化疗敏感性上差异极大。 过去二十年，B细胞淋巴瘤的治疗版图大举扩张：三款靶向CD19的嵌合抗原受体T细胞（CAR-T，经基因工程改造、可识别特定肿瘤抗原的T细胞）疗法、三款CD3×CD20双特异性抗体相继获批，外加多款小分子药物。而同一条时间线上，外周T细胞淋巴瘤在过去十年仅有四款新药获得美国监管机构批准，其中罗米地辛的适应症还在三期确证研究失败后被撤回。一边井喷，一边枯水。 综述作者把掉队归因于三点：亚型碎片化导致单一亚型患者稀少、临床试验入组艰难、生物学认知长期滞后于B细胞淋巴瘤。 枷锁：免疫细胞的自相残杀 更深的枷锁写在这种疾病的生物学里。B细胞淋巴瘤的免疫治疗可以放心瞄准CD19、CD20这类B细胞特有的抗原——即便清除了正常B细胞，患者也可以耐受。T细胞淋巴瘤却没有这样的安全靶点：正常T细胞与恶性T细胞共享CD7、CD5等绝大多数表面抗原，免疫治疗打向肿瘤的同时必然误伤正常T细胞。这就是令研究者头疼的自相残杀（fratricide，效应免疫细胞把表达相同抗原的同伴当作攻击对象）问题。 这个领域的免疫治疗还埋着别的雷：PD-1抑制剂在复发难治患者中报告过疾病超进展病例；一度被寄予厚望的抗CD47单抗magrolimab，也在2024年因三期研究未能显示生存获益且死亡率更高，被药企全面停止开发。 原文图2：结内型外周T细胞淋巴瘤的分子全景图，标注各致癌通路、可成药靶点及在研新药分布 手里武器的真实成色 盘点已获批药物（见下表），表现最好的是抗CD30的抗体偶联药物（ADC，抗体携带细胞毒药物精准递送至肿瘤细胞的药物形式）维布妥昔单抗：关键三期研究ECHELON-2中，联合化疗的客观缓解率达83%，中位无进展生存48.2个月，对比传统方案的20.8个月接近翻倍，已成为CD30阳性患者的一线标准治疗。 但这份数据需要一点冷静的注脚：ECHELON-2入组的间变性大细胞淋巴瘤（尤其是ALK阳性型）本就是预后最好的亚型，整体数据的亮眼有相当部分由这类"优等生"拉动。其余多数亚型的五年总生存率仍停留在30%至40%，复发难治患者的中位生存仅5至7个月——掉队的整体格局，并未真正改变。 药物（机制） 关键数据与现状 维布妥昔单抗（抗CD30抗体偶联药物） ECHELON-2研究：客观缓解率83%，完全缓解率68%，中位无进展生存48.2个月，一线标准治疗 普拉曲沙（叶酸代谢抑制剂） PROPEL研究：客观缓解率29%，完全缓解率11%，中位缓解持续10.1个月 贝利司他（组蛋白去乙酰化酶抑制剂） BELIEF研究：客观缓解率26%，完全缓解率11%，复发难治获批 罗米地辛（组蛋白去乙酰化酶抑制剂） 首个获批的同类药物，后因三期确证研究未达主要终点，适应症被撤回 戈利多替尼（JAK1选择性激酶抑制剂） JACKPOT8研究：客观缓解率44%，完全缓解率24%，中位缓解持续20.7个月，2024年中国获批 绕开枷锁的路：基因编辑的细胞疗法 这篇综述最具观点性的判断是：细胞疗法恰恰是绕开自相残杀枷锁的路径。逻辑并不复杂——既然抗原躲不开，那就用基因编辑把效应细胞自身的那个抗原先敲掉。 靶向CD7的CAR-T通过敲除自体T细胞上的CD7，从源头消解自相残杀，是目前最热的方向；靶向T细胞受体β链恒定区1（TRBC1）的设计则更巧妙——恶性T细胞只会克隆性表达TRBC1或TRBC2二者之一，靶向TRBC1就能把肿瘤与正常T细胞区分开，一期/二期研究取得67%客观缓解率、40%完全缓解率。异体来源的CD70 CAR-T在39例可评估患者中也报告了46.2%的客观缓解率。 原文图1：以外周T细胞淋巴瘤生物学为指导的未来治疗算法，整合分子分型、微环境分层与新型靶向药物的选择路径 数据好看，不等于走得下去 回到开头那个终止开发的故事。单臂二期88%的缓解率当然惊艳，但罕见病药物要走到注册乃至商业化，拼的不只是疗效数字：患者流、生产成本、定价空间、后续确证研究的成败，每一环都可能让"数据好看"止步于论文。这款双抗不是孤例——抗CD47单抗magrolimab同样倒在了三期。 综述给出的出路，是分子分型加微小残留病灶（MRD，治疗后体内残存的微量肿瘤细胞，可反映缓解深度并预测复发）动态监测的个体化路径。方向合理，但就现阶段而言，这个领域最诚实的概括也许是：突破已经开始，账还没有算清。 参考文献 Chan WL, Chng WJ, Li QJ. From molecular pathogenesis to novel therapeutic approaches - a review of recent advances in the treatment of peripheral T cell Lymphomas. Biomarker Research, 2026, 14: 95. DOI: 10.1186/s40364-026-00985-1 声明 本文为个人文献解读笔记，仅供学术交流参考，不构成任何医疗建议或投资建议。内容如有疏漏，欢迎批评指正。 以上就是今天的内容 📖 点「赞 + 在看」就是最好的催更 ✨ ADC偶联 · 深度解读

Data supports ongoing registration Phase 3 trial in r/r PTCL, Phase 2 trial in atopic dermatitis and planned trials for hidradenitis suppurativa and asthma Data in T cell lymphoma demonstrated anti-tumor activity based on tumor intrinsic and tumor extrinsic effects on microenvironment Highlights ITK inhibition novel mechanism of action, aligned with recently presented immunologic and biomarker data from the soquelitinib Phase 1 atopic dermatitis trial SOUTH SAN FRANCISCO, Calif., Aug. 27, 2026 (GLOBE NEWSWIRE) -- Corvus Pharmaceuticals, Inc. (Nasdaq: CRVS), a clinical-stage biopharmaceutical company, today announced the publication of peer-reviewed final data from its Phase 1/1b trial of soquelitinib in patients with T cell lymphoma. The publication in Blood , the journal of the American Society of Hematology, provides the medical and scientific community with clinical and immunologic data supporting the development of soquelitinib in oncology and immune and inflammatory diseases. “The publication of these data in Blood brings our soquelitinib findings to a wide audience of clinicians and researchers,” said Richard A. Miller, M.D., co-founder, president and chief executive officer of Corvus. “In patients with advanced, aggressive and difficult-to-treat T cell lymphomas, soquelitinib demonstrated durable responses, including complete responses, maintained for more than two years in some patients and a median overall survival exceeding two years. This compares favorably to currently available therapies, providing the rationale for our ongoing registration Phase 3 trial in relapsed/refractory PTCL. The peer-reviewed data also detail soquelitinib’s mechanism of action, with selective ITK inhibition driving Th1 skewing and blocking of Th2 and Th17 differentiation. We believe these data support soquelitinib’s broad potential across immune and inflammatory diseases, reinforcing our development strategy including our ongoing SIERRA1 Phase 2 trial in atopic dermatitis and planned trials in hidradenitis suppurativa and asthma.” The Phase 1/1b trial enrolled 75 heavily pre-treated patients (27 in dose escalation portion and 48 in dose expansion portion) with various T cell lymphomas, including peripheral T cell lymphoma (PTCL), T follicular helper cell lymphoma (TFHC), natural killer cell T cell lymphoma (NKTCL), cutaneous T cell lymphoma (CTCL), anaplastic large cell lymphoma (ALCL) and adult T cell lymphoma/leukemia (ATLL). The median number of prior therapies was three (range 1-18), with only 31% achieving an objective response to their most recent prior therapy. In the dose escalation portion, patients received a twice-daily dose of soquelitinib of 100 mg, 200 mg, 400 mg or 600 mg, and the 200 mg twice-daily dose was selected for the dose expansion portion based on biomarker studies which demonstrated that doses of 200 mg or higher achieved complete occupancy of the ITK target with the drug. Soquelitinib was well tolerated across all dose cohorts up to 600 mg twice-daily, with no dose-limiting toxicities or significant adverse events and, notably, no myelosuppression or immunosuppression. In the 200 mg twice-daily cohort (N=36), there were objective and durable tumor responses, including six complete responses. Within this group, patients with one to three prior therapies were determined to be most likely to respond to therapy (N=24) and achieved the following results: objective responses in 9 of 24 patients (six complete and three partial), a median progression-free survival of 6.2 months with 30% of patients progression-free at 18 months, and a median overall survival of 28.1 months with 67% of patients alive at 24 months. The publication also characterizes soquelitinib’s mechanism of action. In vitro studies showed that appropriate doses resulted in Th1 skewing by blocking Th2 differentiation, and biomarker analyses of patient blood and tumor samples also demonstrated this effect in vivo, with increased Th1 cells and reduced serum IL-5. In six patients with paired tumor biopsies analyzed by RNA sequencing, treatment increased intratumoral Th1 cells by day 8, which Corvus believes reflects the direct linkage between the drug’s clinical activity and its underlying immunobiology. These findings are consistent with an anti-tumor mechanism of action involving both direct effects on the tumor (tumor intrinsic) as well as a tumor extrinsic effect on the tumor microenvironment leading to an enhanced host immune response against the tumor. The publication is available online at the Blood website and on the Publications and Presentations page of the Corvus website. It will also be published in an upcoming print edition of the journal. Corvus is currently enrolling patients in a registration Phase 3 clinical trial of soquelitinib in patients with relapsed/refractory PTCL at multiple clinical sites. This randomized controlled trial is anticipated to enroll a total of 150 patients with relapsed/refractory PTCL and is evaluating soquelitinib versus physicians’ choice of either belinostat or pralatrexate. The primary endpoint of the trial is progression-free survival. There are no FDA fully approved agents for the treatment of relapsed/refractory PTCL, and the FDA has granted soquelitinib Orphan Drug Designation for the treatment of T cell lymphoma and Fast Track designation for treatment of adult patients with relapsed or refractory PTCL after at least 2 lines of systemic therapy. About Blood Blood is the flagship journal of the American Society of Hematology, providing an international forum for the publication of original articles describing basic laboratory, translational, and clinical investigations in hematology. About Corvus Pharmaceuticals Corvus Pharmaceuticals is a clinical-stage biopharmaceutical company pioneering the development of ITK inhibition as a new approach to immunotherapy for a broad range of immune diseases and cancer. The Company’s lead product candidate is soquelitinib, an investigational, oral, small molecule drug that selectively inhibits ITK. Soquelitinib is being evaluated in a registration Phase 3 clinical trial for relapsed/refractory PTCL and in a Phase 2 clinical trial for the treatment of atopic dermatitis. Its other clinical-stage candidates are being developed for a variety of cancer indications. For more information, visit or follow the Company on LinkedIn . About Soquelitinib Soquelitinib (formerly CPI-818) is an investigational small molecule drug given orally designed to selectively inhibit ITK (interleukin-2-inducible T cell kinase), an enzyme that is expressed predominantly in T cells and plays a role in T cell and natural killer (NK) cell immune function. Soquelitinib has been shown to affect T cell differentiation and induce the generation of Th1 helper cells while blocking the development of both Th2 and Th17 cells and production of their secreted cytokines. Th1 T cells are required for immunity to tumors, viral infections and other infectious diseases. Th2 and Th17 helper T cells are involved in the pathogenesis of many autoimmune and allergic diseases. Recent studies have demonstrated that ITK controls a switch between the differentiation of Th17 proinflammatory cells and T regulatory suppressor cells. Inhibition of ITK leads to a shift toward T regulatory cell differentiation, which has the potential to suppress autoimmune and inflammatory reactions. The Company believes the inhibition of specific molecular targets in T cells may be of therapeutic benefit for patients with autoimmune and allergic diseases and in cancers, including solid tumors. Based on interim results from a Phase 1/1b clinical trial in patients with refractory T cell lymphomas, which demonstrated tumor responses in very advanced, refractory, difficult to treat T cell malignancies, the Company is enrolling a registration Phase 3 clinical trial (NCT06561048) of soquelitinib in patients with relapsed/refractory PTCL. Soquelitinib is also now being investigated in a randomized placebo-controlled Phase 2 clinical trial in patients with atopic dermatitis. A publication describing the chemistry, enzymology and biology of soquelitinib appeared in npj Drug Discovery in December 2024 and is available online at the Nature website and on the Publications and Presentations page of the Corvus website. About Peripheral T Cell Lymphoma Peripheral T cell lymphoma is a heterogeneous group of malignancies accounting for about 10% of non-Hodgkin’s lymphomas (NHL) in Western populations, reaching 20% to 25% of NHL in some parts of Asia and South America. The most common subtypes are PTCL-not otherwise specified (PTCL-NOS) and T follicular helper cell lymphoma. First line treatment for these diseases is typically combination chemotherapy; however, approximately 75% of patients either do not respond or relapse within the first two years. Patients in relapse are treated with various chemotherapy agents but have poor overall outcomes with median progression-free survival in the three to four month range and overall median survival of six to 12 months. There are no approved drugs in relapsed/refractory PTCL based on randomized trials. PTCL is a disease of mature helper T cells that express ITK, often containing numerous genetic mutations and frequently associated with viral infection. Most often the malignant cells of PTCL express a Th2 phenotype. About Atopic Dermatitis Atopic dermatitis, also called eczema, is a chronic disease that can cause inflammation, redness, scaly patches, blisters and irritation of the skin. It affects up to 20% of children and up to 10% of adults, and treatments include topical therapies, oral therapies and systemic injectable biologic therapies. It is frequently associated with other allergic disorders such as food allergies and asthma. Atopic dermatitis, like asthma and allergy, involves the participation of Th2 lymphocytes which secrete cytokines that result in inflammation. Soquelitinib has been shown in preclinical and clinical studies to inhibit cytokine production from Th2 lymphocytes. Forward-Looking Statements This press release contains forward-looking statements, including statements related to Phase 1 data from the soquelitinib Phase 1/1b T cell lymphoma trial as support for ongoing and planned trials ; the potential safety, tolerability, clinical benefit and efficacy of the Company’s product candidates, including soquelitinib; the potential use of soquelitinib to improve therapy for a broad range of patients with T cell lymphoma, atopic dermatitis, other immune diseases and cancers; and clinical strategy and the design of clinical trials, including the timeline for initiation, target or expected number of patients to be enrolled, dose levels, number of sites and other product development milestones.. All statements other than statements of historical fact contained in this press release are forward-looking statements. These statements often include words such as “believe,” “expect,” “anticipate,” “intend,” “plan,” “estimate,” “seek,” “will,” “may” or similar expressions. Forward-looking statements are subject to a number of risks and uncertainties, many of which involve factors or circumstances that are beyond the Company’s control. The Company’s actual results could differ materially from those stated or implied in forward-looking statements due to a number of factors, including but not limited to, risks detailed in the Company’s Quarterly Report on Form 10-Q for the quarter ended June 30, 2026, filed with the Securities and Exchange Commission on August 6, 2026, as well as other documents that may be filed by the Company from time to time with the Securities and Exchange Commission. In particular, the following factors, among others, could cause results to differ materially from those expressed or implied by such forward-looking statements: no head-to-head clinical trials have been conducted comparing soquelitinib to available therapies for patients with T cell lymphoma; the Company’s ability to demonstrate sufficient evidence of efficacy and safety in its clinical trials of its product candidates; the accuracy of the Company’s estimates relating to its ability to initiate and/or complete preclinical studies and clinical trials and release data from such studies and clinical trials; the results of preclinical studies and interim data from clinical trials not being predictive of future results; the Company’s ability to enroll sufficient numbers of patients in its clinical trials; the unpredictability of the regulatory process; regulatory developments in the United States and foreign countries; the costs of clinical trials may exceed expectations; and the Company’s ability to raise additional capital. Although the Company believes that the expectations reflected in the forward-looking statements are reasonable, it cannot guarantee that the events and circumstances reflected in the forward-looking statements will be achieved or occur, and the timing of events and circumstances and actual results could differ materially from those projected in the forward-looking statements. Accordingly, you should not place undue reliance on these forward-looking statements. All such statements speak only as of the date made, and the Company undertakes no obligation to update or revise publicly any forward-looking statements, whether as a result of new information, future events or otherwise. INVESTOR CONTACT: Leiv Lea Chief Financial Officer Corvus Pharmaceuticals, Inc. +1-650-900-4522 llea@corvuspharma.com MEDIA CONTACT: Julia Stern Real Chemistry +1-949-903-4750 jstern@realchemistry.com