RTEL1

Researchers introduce the 'Telomouse'. By making a subtle genetic alteration in standard lab mice, they've made the mouse telomeres, which protect the chromosome ends, more closely resemble those in humans. The Telomouse model, developed by incorporating a genetic variation from a mouse species with naturally shorter telomeres, provides a valuable resource for in-depth aging and cancer research. This discovery promises to reveal new insights into the genetics of aging and may contribute to enhanced longevity and well-being. In an exciting scientific breakthrough, a team of researchers led by Professor Yehuda Tzfati from the Institute of Life Science at the Hebrew University and Professor Klaus Kaestner from the University of Pennsylvania Perelman School of Medicine, has introduced the "Telomouse." This discovery involves changing just one tiny building block in one gene of ordinary lab mice, Mus musculus, to make their telomeres (our chromosome caps) look much more like the telomeres in humans. Telomeres hold a pivotal responsibility in safeguarding our genetic material and ensuring the orderly division of our cells. Maintaining their structural integrity and optimal length holds the potential to diminish the risk of cancer and facilitate a healthier aging process. However, a significant hurdle has emerged: conventional laboratory mice possess telomeres approximately five times longer than those in humans. This disparity has posed a formidable challenge in using mice models for comprehending the implications of telomeres for human aging and cancer. In the development of the Telomouse model, researchers turned their attention to a distinct mouse species, M. spretus, notable for its inherently shorter telomeres. Within the genetic code of these mice, a subtle variation within a pivotal protein known as RTEL1 was identified. By transferring this genetic distinction into typical laboratory mice, they succeeded in producing a lineage of mice with human-length telomeres. These novel Telomice exhibit robust health and reproductive capabilities, making them an exceptional resource for in-depth investigations into the complex realms of aging and cancer. This study illuminates the central role of RTEL1 as the arbiter of telomere length. A nuanced modification to this crucial protein has enabled scientists to fashion a mouse model that closely approximates the human telomere length. During the reaseach, the researchers also achieved an invaluable breakthrough in our ability to measure the length of each single telomere, and particularly the shortest telomeres in the cell which are the ones to dictate the cellular function and fate. They developed a novel method for measuring the precise length of individual telomeres using a new generation of DNA sequencing called nanopore sequencing. This method, termed 'NanoTelSeq', enables evaluating the 'telomeric health' in samples from blood or other tissues of healthy individuals, as well as patients of cancers and aging diseases, and improve diagnosis, prognosis and treatment of these patients. Professor Yehuda Tzfati, the principal investigator of this endeavor, posits, "The Telomouse model is promising to enrich our comprehension of the intricate nexus between telomeres, cancer and the aging process. I believe that NanoTelSeq will replace currently used methods, enable acurate evaluation of the telomere state in patients and healthy individuals, and reveal how it affects human health. Such insights will hopefully culminate in innovative strategies for combating cancer and fostering the well-being of aging individuals."

HONG KONG and SHANGHAI, China and FLORHAM PARK, N.J., Feb. 27, 2023 (GLOBE NEWSWIRE) -- HUTCHMED (China) Limited (“HUTCHMED”) (Nasdaq/AIM:​HCM, HKEX:​13) today announces that it has completed patient enrollment of Phase II registration trial of amdizalisib in patients with relapsed or refractory follicular lymphoma (“FL”), a subtype of non-Hodgkin’s lymphoma (“NHL”). The last patient was enrolled on February 24, 2023. The clinical trial is a multi-center, single-arm, open-label clinical study to evaluate the efficacy and safety of amdizalisib once a day oral monotherapy in patients with relapsed/refractory FL or marginal zone lymphoma (“MZL”). The primary endpoint is objective response rate (“ORR”), with secondary endpoints including complete response rate (CRR), progression-free survival (PFS), time to response (TTR) and duration of response (DoR). A total of 108 relapsed/refractory FL patients were enrolled. The trial is being conducted in over 35 sites in China. Additional details may be found at clinicaltrials.gov, using identifier NCT04849351. Topline results on the FL patients in this trial are expected to be reported in the second half of 2023, followed by submission of results for presentation at an appropriate medical conference. If positive, HUTCHMED would initiate plans to apply for marketing authorization of amdizalisib for relapsed/refractory FL from the China National Medical Products Administration (NMPA). About PI3Kδ and NHL PI3Kδ (phosphoinositide 3-kinase delta) is a lipid kinase that controls the activation of several important signaling proteins. Upon an antigen binding to B-cell receptors, PI3Kδ can be activated through the Lyn and Syk signaling cascade. The abnormal activation of B-cell receptor signaling is closely related to the development of B-cell type hematological cancers, which represent approximately 85% of all NHL cases. Therefore, PI3Kδ is a target for drugs that aim to prevent or treat hematologic cancer. FL accounts for approximately 17% of NHL and MZL accounts for approximately 8% of NHL. In the U.S., there were estimated 13,000 and 6,000 new cases of FL and MZL in 2020, respectively. In China, there were estimated 16,000 and 7,000 new cases of FL and MZL in 2020, respectively.1,2,3 About Amdizalisib Amdizalisib (HMPL-689) is a novel, selective and potent oral inhibitor targeting the isoform PI3Kδ. Amdizalisib’s pharmacokinetic (“PK”) properties are favorable with good oral absorption, moderate tissue distribution and low clearance in preclinical PK studies, suggesting a low risk of drug accumulation and drug-to-drug interaction. Because of its high target selectivity and optimal PK profile, amdizalisib has the potential to demonstrate an optimal benefit-risk pro this class. In addition to the current Phase II trial and the supportive Phase I trial in China, amdizalisib is also being evaluated in combination with tazemetostat (a methyltransferase inhibitor of EZH2) in patients with relapsed or refractory lymphoma in a Phase II study in China. HUTCHMED currently retains all rights to amdizalisib worldwide. About HUTCHMED HUTCHMED (Nasdaq/AIM:​HCM; HKEX:​13) is an innovative, commercial-stage, biopharmaceutical company. It is committed to the discovery and global development and commercialization of targeted therapies and immunotherapies for the treatment of cancer and immunological diseases. It has more than 5,000 personnel across all its companies, at the center of which is a team of about 1,800 in oncology/​immunology. Since inception, HUTCHMED has focused on bringing cancer drug candidates from in-house discovery to patients around the world, with its first three oncology drugs now approved and marketed in China. For more information, please visit: or follow us on LinkedIn. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the “safe harbor” provisions of the U.S. Private Securities Litigation Reform Act of 1995. These forward-looking statements reflect HUTCHMED’s current expectations regarding future events, including its expectations regarding the therapeutic potential of amdizalisib for patients with NHL, the further clinical development for amdizalisib, its expectations as to whether such studies would meet their primary or secondary endpoints, and its expectations as to the timing of the completion and the release of results from such studies. Forward-looking statements involve risks and uncertainties. Such risks and uncertainties include, among other things, assumptions regarding enrollment rates, timing and availability of subjects meeting a study’s inclusion and exclusion criteria, changes to clinical protocols or regulatory requirements, unexpected adverse events or safety issues, the ability of amdizalisib, including as a combination therapy, to meet the primary or secondary endpoint of a study, to obtain regulatory approval in different jurisdictions, to gain commercial acceptance after obtaining regulatory approval, the potential market of amdizalisib for a targeted indication, the sufficiency of funding and the impact of the COVID-19 pandemic on general economic, regulatory and political conditions. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. For further discussion of these and other risks, see HUTCHMED’s filings with the U.S. Securities and Exchange Commission, on AIM and on The Stock Exchange of Hong Kong Limited. HUTCHMED undertakes no obligation to update or revise the information contained in this press release, whether as a result of new information, future events or circumstances or otherwise. CONTACTS Investor Enquiries Mark Lee, Senior Vice President +852 2121 8200 Annie Cheng, Vice President +1 (973) 567 3786 Media Enquiries Americas – Brad Miles, Solebury Trout +1 (917) 570 7340 (Mobile) / bmiles@soleburystrat.com Europe – Ben Atwell / Alex Shaw, FTI Consulting +44 20 3727 1030 / +44 7771 913 902 (Mobile) / +44 7779 545 055 (Mobile) / HUTCHMED@fticonsulting.com Asia – Zhou Yi, Brunswick +852 9783 6894 (Mobile) / HUTCHMED@brunswickgroup.com Nominated Advisor Atholl Tweedie / Freddy Crossley, Panmure Gordon +44 (20) 7886 2500 ______________________ 1 Source: NCCN® - 2 Source: SEER - 3 Source: GLOBOCAN -

嵌合抗原受体（CAR）T细胞（CAR-T细胞）疗法代表了人类癌症个性化免疫治疗的重大突破。CAR-T疗法已广泛应用于血液病的治疗，但对实体瘤的治疗效果并不理想。肿瘤抗原逃逸、治疗相关毒性和免疫抑制肿瘤微环境(TME)限制了它们的应用。最近，中南大学湘雅医院团队在Molecular Cancer上提出了在临床中使用的所有治疗靶点或显示出有潜力的靶点，并对CAR-T疗法在实体瘤和血液系统癌症存在的问题和应对方法提出了见解。https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-022-01669-8#Sec27CAR-T细胞治疗的发展 01 针对肿瘤抗原的CAR-T细胞治疗是一个快速发展的概念，它在临床应用时显示出显著的效果，并改变了血液系统恶性肿瘤的治疗范式。2017年8月，美国食品和药物管理局(FDA)批准使用CAR-T细胞疗法治疗复发或难治性b -急性淋巴细胞白血病(r/r B-ALL)患者。从那时起，该领域进入了一个快节奏、创新发展的时代。CAR的结构一直在不断更新中。第一代CAR由一个识别抗原的细胞外结构域和一个单一的细胞内基序组成。然而，在这种结构中并没有共刺激分子，这使得CAR-T细胞很难在患者体内持续存在，并且对肿瘤无效。第二代CARs在其结构中增加了一个由共刺激受体信号域组成的胞内基序。即使在没有外源性共刺激分子的情况下，二代CAR-T细胞仍能持续增殖并释放细胞因子发挥抗肿瘤作用，成为了临床应用最广泛的一种。第三代CAR包含两个共刺激分子，旨在进一步增强CAR- T细胞的杀伤能力。第四代CARs插入额外的分子元素来表达功能性的转基因蛋白，如白介素基因或自杀基因，增强了CAR-T细胞的杀伤能力和安全性。为了提高CAR靶识别的灵活性，采用BBIR CAR或 SUPRA CAR设计了通用CAR- t细胞。这种设计允许抗原靶向结构域与T细胞信号单元分离，从而赋予CAR-T细胞识别多种抗原的能力。与此同时，CAR-T细胞仅在提供adapter时起识别和攻击细胞的作用，因此增加了用户对CAR-T细胞的控制，促进了其在体内的使用。此外，单结构域抗体，也称为重链单变量结构域(VHH)或纳米抗体，也被用作CAR-T的靶向结构域。基于纳米体的CAR-T细胞已经被证明可以抑制免疫小鼠实体肿瘤的生长。此外，纳米体由于其单体结构而不能在T细胞表面聚集。并且纳米体不具有亲和力损失的限制，这被认为是在设计传统的单链片段变量(scFv)作为CAR的抗原靶向结构域时可能出现的副作用。肿瘤识别不依赖于主要组织相容性复合物（MHC）这一特点构成了它们的主要益处。尽管CAR-T细胞治疗在临床试验中显示出有希望的结果，但使用CAR-T细胞治疗癌症仍存在相当大的挑战。由于肿瘤抗原异质性，难以运输和浸润肿瘤部位以及免疫抑制TME的挑战，用于实体瘤的CAR-T细胞疗法面临更显著的困难。血液系统癌症 02 目前的证据证实CAR-T细胞疗法与血液系统恶性肿瘤患者的良好应答率相关。在B-ALL、B-NHL和MM中已有完善的靶点，FDA已经批准了四种靶向CD19的CAR-T产品和两种靶向BCMA的CAR-T产品来治疗这些疾病。AML和HL中也有具有良好临床效果的靶点，CAR-T细胞疗法针对这些靶点。在T-ALL、CLL和T-NHL中，CAR-T细胞治疗的疗效有待进一步提高，合适的靶点仍在探索中。癌症的高度异质性以及在治疗压力下由抗原逃逸机制介导的抗原阴性复发导致恶性细胞复发的倾向，使得靶向单一靶点的CAR-T细胞治疗难以取得良好效果。其次，许多靶点在非恶性组织中表达。这种较差的靶点特异性导致了CAR-T细胞攻击正常造血组织的严重后果，如CAR-T细胞治疗T细胞肿瘤导致T细胞自残。此外，最近研究发现，在小鼠白血病模型中，CAR-T细胞会通过吞噬作用诱导癌细胞向T细胞转移抗原，导致抗原丢失，降低肿瘤细胞靶密度，降低治疗效果。实体瘤 03 研究成熟的实体肿瘤主要有消化系统癌、MEL、胶质瘤等。虽然CAR-T细胞治疗的研究的注意力已转移到实体肿瘤上，但由于多种因素的影响，实体肿瘤的研究仍然面临困难。首先，实体瘤细胞具有异质性，在肿瘤细胞表面发现的 TSA 很少。另一方面，实体瘤微环境复杂，血管塌陷程度不同，间质结构致密刚性，异常程度高。此外，肿瘤微环境中还存在免疫抑制细胞和抑制因子的耐药性。以上因素的综合作用导致CAR-T细胞难以浸润，导致了治疗失败。针对上述问题，CAR-T改良和联合治疗是两个较好的方向。首先，中南大学的研究人员认为可以增强CAR-T细胞的抗原特异性识别，克服肿瘤细胞抗原的异质性。其次，靶向TME是很有吸引力的，因此改善CAR-T细胞的TME浸润和靶向免疫抑制和代谢肿瘤微环境将是带来帮助。此外，CAR-T细胞的制造过程也可能存在问题。循环的肿瘤细胞在收集过程中与淋巴细胞一起收集。CAR可能被转导到这些肿瘤细胞中，与同一细胞表达的靶标结合，导致肿瘤细胞逃逸。研究人员还提出，使用健康捐献者的异基因CAR-T细胞，通过CRISPR技术将其从HLA和内源性TCR中剔除，或许可以帮助解决CAR-T细胞的制造的耗时和昂贵问题。CAR-T细胞疗法的未来 04 研究人员认为不应该停止对新目标的探索。首先，进一步确定最佳治疗靶点对于完善CAR-T细胞疗法至关重要。对此，靶向多种抗原可以弥补靶标覆盖和稳定性的不足。此外，可以对CAR-T细胞进行修饰以承认肿瘤趋化因子，以克服实体瘤治疗中CAR-T细胞向恶性组织转运的困难，延长自身在癌组织中的持续时间并增强抗肿瘤作用。另外，结合开关可以控制CAR-T细胞活性，以减少毒副作用。此外，在使用CAR-T疗法时，可以采用多种组合策略来提高治疗效果。例如，mRNA技术可以提高肿瘤细胞中隐藏抗原的表达，编码靶向特异性CAR。溶瘤病毒(OV)调节TME，影响宿主抗肿瘤免疫反应的能力。近年来，纳米技术也被用于改善CAR-T细胞治疗。前瞻性筛选患者的表面抗原表达，以提高后续临床试验的效率。通过不断探索合适的靶点和优化设计方案，CAR-T最终将成为一种肿瘤终结者。CAR-T细胞疗法有望给癌症患者带来光明的未来。参考资料：https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-022-01669-8#Sec1