TRBC1

A novel treatment for leukemias and lymphomas that arise from immune system T cells was found to be effective at killing these cancers in mice bearing human T-cell tumors. A novel treatment for leukemias and lymphomas that arise from immune system T cells, developed by investigators at the Johns Hopkins Kimmel Cancer Center and its Ludwig Center and Lustgarten Laboratory, was found to be effective at killing these cancers in mice bearing human T-cell tumors. The therapy, an antibody-drug conjugate (ADC), combines an antibody that targets a protein called TRBC1 expressed on the surface of T-cell cancers with an anti-cancer drug, called SG3249. The ADC works by using the antibody to seek out the cancer cells that express TRBC1. Then, those cancer cells ingest the ADC, where SG3249 is released and kills the cancer cells. A description of the work was published March 27 in Nature. Each year, about 100,000 patients worldwide are affected by T-cell leukemias and lymphomas. Adults with relapsed T-cell cancers have limited therapeutic options and five-year survival rates of 7-38%. "Developing treatments for T-cell leukemias and lymphomas is much more difficult than for leukemias and lymphomas arising from immune system B cells," explains senior study author Suman Paul, M.B.B.S., Ph.D., an assistant professor of oncology at the Johns Hopkins University School of Medicine. Effective therapies for B-cell cancers wipe out both cancerous and noncancerous B cells, but patients still do well even without the immune system B cells that help fight infections. However, if similar approaches are used and a treatment wipes out both normal and cancerous T cells, it would leave patients without a functioning immune system and at high risk of dying from infections. "Not much drug development has happened in this space of T-cell leukemias and lymphomas," Paul says. "We need new therapies for these cancers, but whatever therapies we develop in the space have to be cancer-specific. We have to preserve some of the normal T cells and wipe out cancerous T cells at the same time." T-cell cancers express either TRBC1 or TRBC2, while normal T cells express a mix of TRBC1 and TRBC2. Therefore, selective targeting of TRBC1 can potentially eradicate the normal and cancerous T cells expressing TRBC1 while preserving normal T cells expressing TRBC2. A recent clinical trial conducted elsewhere attempted to target TRBC1 cancers using chimeric antigen receptor (CAR) T-cell therapy. These CAR T cells are genetically engineered T cells that bind to and kill TRBC1 cells. CAR T-cell therapies are FDA-approved treatment options used in several B-cell cancers. However, after administering the TRBC1-targeting CAR T cell therapy in human patients, trial investigators reported that the CAR T cells were not persisting inside the patients. Such persistence is required for effective cancer cell-killing. Interested to understand why, Paul and colleagues found that the CAR T cells targeting TRBC1 could be killed by normal T cells, limiting their persistence. This lack of CAR T-cell persistence led the team to try TRBC1 targeting with the use of antibody-drug conjugates. Paul and colleagues tried two different formulations of ADCs in mouse models of T-cell cancers. After a single injection of one formulation of the treatment, the cancers initially regressed but then recurred. After a single treatment with the anti-TRBC1-SG3249 ADC combination, investigators observed signs of cancer elimination within seven days and the cancers were eventually undetectable, with no recurrences. "The tumors didn't come back, and we followed the mice for more than 200 days," Paul explains. The treatment was able to eliminate the cancer while preserving half of the remaining normal T cells. "The residual normal T cells should be sufficient to maintain some immune system protection against infectious diseases," Paul says. "Witnessing the successful elimination of T-cell cancers while sparing normal T cells in preclinical models was truly gratifying," adds Jiaxin Ge, a co-author of the study and third-year Ph.D. student in the Ludwig Center. "We believe this approach has the potential to address a critical unmet need in oncology, and we're committed to advancing it through further research." Tushar Nichakawade, first author on the study and a fourth-year Ph.D. student at the Ludwig Center, says, "There are so many lessons to learn from the clinic and it has been exciting to be a part of the iterative process of drug discovery. Every therapy has its pros and cons, but the preclinical efficacy of our ADC gives me hope that it can make a difference for patients suffering from these terrible cancers." Investigators are now working with an industry partner to conduct early-phase safety and efficacy trials in human patients. The study's co-authors were Brian J. Mog, Bum Seok Lee, Alexander H. Pearlman, Michael S. Hwang, Sarah R. DiNapoli, Nicholas Wyhs, Nikita Marcou, Stephanie Glavaris, Maximilian F. Konig, Sandra B. Gabelli, Evangeline Watson, Cole Sterling, Nina Wagner-Johnston, Sima Rozati, Lode Swinnen, Ephraim Fuchs, Drew M. Pardoll, Kathy Gabrielson, Nickolas Papadopoulos, Chetan Bettegowda, Kenneth W. Kinzler, Shibin Zhou, Surojit Sur and Bert Vogelstein of Johns Hopkins. The work was supported in part by The Virginia and D.K. Ludwig Fund for Cancer Research, Lustgarten Foundation for Pancreatic Cancer Research, Commonwealth Fund, Bloomberg~Kimmel Institute for Cancer Immunotherapy, Bloomberg Philanthropies and the National Institutes of Health Cancer Center Support Grant P30 CA006973. Paul was supported by the National Cancer Institute (grant K08CA270403), the Leukemia Lymphoma Society Translation Research Program Award, the American Society of Hematology Scholar Award and the Swim Across America Translational Cancer Research Award.

撰文丨王聪T细胞白血病和淋巴瘤，统称为T细胞癌，在全世界范围内，每年新增约100000名患者。成年的复发性T细胞癌患者的5年生存率为7%-38%，他们的治疗选择有限。相比之下，B细胞癌患者有一系列靶向泛B细胞抗原的新型抗体药物和CAR-T细胞疗法，从而提高了生存率。但开发针对T细胞癌的类似治疗方法却一直具有挑战性。正常和肿瘤性T细胞或B细胞的细胞表面表达类似的抗原，靶向泛B细胞抗原是可行的，因为治疗导致的正常B细胞再生障碍被良好耐受。然而，靶向泛T细胞抗原是不可行的，因为这会导致严重的免疫抑制。因此，T细胞癌的治疗需要更特异性地靶向癌变T细胞。临床前研究表明，靶向T细胞受体β-链恒定区1（TRBC1）可以杀死癌变T细胞，同时保留足够的健康T细胞来维持免疫功能，这使得TRBC1成为治疗T细胞癌的有潜力的靶点。然而，首次在人类中进行的抗TRBC1 CAR-T细胞疗法临床试验报告了低反应率和CAR-T细胞的不明原因丢失。2024年3月27日，约翰-霍普金斯大学医学院 Suman Paul 团队在 Nature 期刊发表了题为：TRBC1-targeting antibody–drug conjugates for the treatment of T cell cancers 的研究论文【1】。该研究证实了抗TRBC1 CAR-T细胞由于被患者正常的TRBC1+ T细胞杀死而丢失，从而导致治疗反应不佳。为了解决这个问题，研究团队开发了一种靶向TRBC1的ADC药物，可以在体外杀死TRBC1+癌细胞，并在小鼠模型中治愈了人类T细胞癌。靶向TRBC1的ADC药物可能为TRBC1靶向提供最佳形式，并在T细胞癌患者中产生优异应答。抗体药物和CAR-T细胞介导的免疫疗法已经改善了实体瘤和血液系统恶性肿瘤患者的生存率。患有T细胞白血病和T细胞淋巴瘤（统称为T细胞癌）的患者，生存期短，缺乏此类免疫疗法。因此，T细胞癌症特别需要开发CAR-T细胞疗法和抗体药物来改善患者的预后。大多数T细胞，无论是正常T细胞还是肿瘤性T细胞，在其细胞表面都表达αβ T细胞受体（TCR）。在T细胞肿瘤中，超过90%的外周T细胞淋巴瘤（PTCL）和皮肤T细胞淋巴瘤（CTCL）都表达αβ TCR。此外，30%-50%的T细胞急性淋巴母细胞白血病（TALL）表达αβ TCR。每个T细胞表达一个独特的αβ TCR。由于T细胞白血病和T细胞淋巴瘤源于一个特定T细胞的克隆性生长，每个肿瘤性T细胞都表达相同的独特TCR序列。因此，靶向肿瘤性T细胞中的独特TCR序列进行靶向治疗应该能够保留足够的正常T细胞，以实现细胞免疫。一种创新的方法是靶向TRBC等位基因，T细胞选择两个可能的TRBC等位基因之一：TRBC1或TRBC2。正常T细胞由大约相同数量的表达TRBC1的T细胞和表达TRBC2的T细胞组成，而T细胞肿瘤则要么表达TRBC1，要么表达TRBC2。这一发现导致了一项1/2期临床试验，以测试抗TRBC1 CAR-T细胞疗法的安全性和有效性【2】。然而，在10名接受治疗的患者中，只有2名（20%）在12个月或更长时间内保持完全缓解，并且在这10名患者的外周血中未检测到CAR-T细胞扩增。而这种扩增对于CAR-T细胞的癌症治疗效果至关重要。在这项研究中，研究团队证明了抗TRBC1 CAR-T细胞会被正常的TRBC1+ T细胞杀死，这可能解释了在之前的临床试验中未观察到的CAR-T细胞的有效扩增。这一发现促使研究团队开发了一种治疗T细胞癌的新型抗体药物偶联物（ADC），其靶点同样是TRBC1，但其疗效不依赖于CAR-T细胞。研究团队首先确定了与抗TRBC1抗体结合的细胞毒性药物，其中表现最好的是SG3199，其作为一种ADC有效载荷，已在临床试验中得到了验证。抗体药物偶联物（antibody-drug conjugate，ADC）是一类由抗体（antibody）、细胞毒性药物（Cytotoxic Agent）以及将两者连接起来的连接子（Linker）组成的新型靶向药物，其利用抗体的靶向性将细胞毒性分子选择性递送到肿瘤细胞，在发挥抗癌作用的同时，避免对健康细胞的伤害。接下来，研究团队证实了正常T细胞不会影响抗TRBC1-ADC药物（抗TRBC1-SG3249）对三种TRBC1+癌细胞株的杀伤作用。此外，该ADC药物对四种TRBC1-癌细胞株没有观察到细胞毒性。研究团队还观察到该ADC药物对正常T细胞的TRBC1+亚群的剂量依赖性，而对TRBC2+亚群的毒性很小。总的来说，该ADC药物能够特异性杀伤TRBC1+细胞，而保留TRBC2+T细胞。为了评估该ADC药物在体内的治疗效果，研究团队使用人类Jurkat TRBC1+癌细胞构建了肿瘤异种移植小鼠模型，然后使用该ADC药物（抗TRBC1-SG3249）进行治疗。结果显示，接受抗TRBC1-SG3249治疗后，小鼠体内的癌症几乎无法检测到，且没有观察到复发，通过流式细胞检测进一步证实了癌症的消退，小鼠的骨髓中也没有可检测到的癌细胞，也就是说，抗TRBC1-SG3249似乎治愈了这些小鼠的癌症，且没有观察到体重减轻或其他肝脏和皮肤毒性迹象。总的来说，该研究观察到了正常的TRBC1+ T细胞与抗TRBC1 CAR-T细胞之间的双向杀伤作用，这一发现的意义超越了T细胞白血病和T细胞淋巴瘤的治疗。正常的T细胞和其他免疫效应细胞在其细胞表面含有许多蛋白，任何与这些蛋白反应的CAR-T细胞都可预期会显著降低CAR-T细胞的治疗效果。这一发现提示我们，不能期望用CAR-T细胞靶向TRBC1作为T细胞癌的最佳治疗剂。而该研究进一步证实，将抗TRBC1抗体与细胞毒性药物SG3249结合的ADC药物可作为一种有效的T细胞癌治疗剂，其在小鼠模型中的强大的治疗效果为在人类中进行临床试验奠定了有希望的概念和实践基础。论文链接：1. https://www.nature.com/articles/s41586-024-07233-22. https://doi.org/10.1182/blood-2022-165971免责声明“药渡”公众号所转载该篇文章来源于其他公众号平台，主要目的在于分享行业相关知识，传递当前最新资讯。图片、文章版权均属于原作者所有，如有侵权，请及时告知，我们会在24小时内删除相关信息。微信公众号的推送规则又双叒叕改啦，如果您不点个“在看”或者没设为"星标"，我们可能就消散在茫茫文海之中~点这里，千万不要错过药渡的最新消息哦！

▎药明康德内容团队编辑嵌合抗原受体（CAR）T细胞疗法已经在治疗多种B细胞血液癌症方面展现出卓越的疗效，并且让部分患者看到了治愈的曙光。然而，T细胞白血病或淋巴瘤患者却没有针对他们的CAR-T疗法。此前的研究显示，特异性靶向TRBC1的CAR-T疗法能够在杀伤癌变和正常TRBC1阳性T细胞的同时，保留了大量健康的TRBC2阳性T细胞，有望提供一种治疗T细胞血液癌症并保留正常免疫功能的CAR-T疗法。然而在首个人体临床试验中，这种CAR-T疗法没有显著疗效，而且令人意外的是，输注到患者身体里的CAR-T细胞很快都消失了！日前在《自然》上发表的最新研究揭开了这些CAR-T细胞意外消失的谜底，并且发现靶向TRBC1的抗体偶联药物（ADC）具有治愈T细胞血液癌症的潜力。研究团队想到，靶向TRBC1的CAR-T细胞不但会与癌变的TRBC1阳性T细胞结合，也会与TRBC1阳性的正常T细胞结合，TRBC1是T细胞受体的一部分，嵌合抗原受体与TRBC1结合可能导致健康T细胞的激活，从而反过来杀死靶向TRBC1的CAR-T细胞。细胞培养实验结果验证了这个假说，当科学家将靶向TRBC1的CAR-T细胞与表达TRBC1的健康T细胞放在一起培养时，发现CAR-T细胞和TRBC1阳性健康T细胞都被消灭了。而且，体外细胞培养实验结果显示，TRBC1阳性健康T细胞会通过消灭靶向TRBC1的CAR-T细胞，降低CAR-T细胞杀死肿瘤细胞的活性。▲表达TRBC1的健康T细胞通过杀死靶向TRBC1的CAR-T细胞，降低CAR-T细胞的抗癌活性（图片来源：参考资料[1]）研究人员表示，这一结果可能是在人体试验中，TRBC1靶向CAR-T疗法效果不佳的原因，因为人体中的TRBC1阳性健康T细胞会杀死这些CAR-T细胞，让它们无法扩增，限制了CAR-T疗法的疗效。他们同时表示，健康T细胞上表达着多种可以激活T细胞的抗原，开发未来的CAR-T疗法时应该加上将CAR-T细胞与健康T细胞一起培养的检测过程，以预防健康T细胞杀死CAR-T细胞的问题。既然CAR-T疗法这条路面临重大挑战，科学家们想到了使用ADC来治疗T细胞血液癌症的策略。T细胞受体（TCR）的激活会诱发受体复合体的内吞，正适合将ADC携带的毒性载荷带入细胞内部。因此研究人员将细胞毒性药物SG3199和MMAE偶联到抗TRBC1抗体上，并且在体外和体内实验中检验了它们的抗癌活性。体外实验显示，靶向TRBC1的ADC可以与表达TRBC1的癌变细胞和正常细胞相结合，并且在杀死这些细胞的同时，不影响大量表达TRBC2而不表达TRBC1的健康T细胞，让TRBC2阳性健康T细胞仍然能够维持机体的正常免疫功能。▲靶向TRBC1的ADC表现出杀伤TRBC1阳性癌变细胞和正常细胞的活性（图片来源：参考资料[1]）在癌症动物模型中，携带SG3199和MMAE毒性载荷的ADC均表现出缩小肿瘤的活性，而以SG3199为载荷的ADC表现更为突出，小鼠体内的肿瘤细胞几乎完全消失，小鼠的生存率在整个研究期间达到100%。科学家表示，偶联SG3199的ADC具有治愈T细胞血液癌症的潜力。▲靶向TRBC1的ADC的体内实验结果（图片来源：参考资料[1]）下一步，研究人员希望将这款ADC推进人体临床试验，他们已经对偶联SG3199的ADC进行了改造，降低人体免疫系统对这款ADC的免疫反应。研究人员表示，虽然从成功的临床前实验到临床应用的道路并非坦途，但是这款ADC在小鼠模型中消灭扩散到全身的癌细胞的能力提供了很好的概念验证，为人体临床试验打好了基础。大家都在看药明康德为全球生物医药行业提供一体化、端到端的新药研发和生产服务，服务范围涵盖化学药研发和生产、生物学研究、临床前测试和临床试验研发、细胞及基因疗法研发、测试和生产等领域。如您有相关业务需求，欢迎点击下方图片填写具体信息。▲如您有任何业务需求，请长按扫描上方二维码，或点击文末“阅读原文/Read more”，即可访问业务对接平台，填写业务需求信息▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料：[1] Nichakawade et al., (2024). TRBC1-targeting antibody–drug conjugates for the treatment of T cell cancers. Nature, https://doi.org/10.1038/s41586-024-07233-2免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新