CD19 CAR-T CELLS(Gaia Science)

近年来，CAR-T细胞治疗作为一种全新的肿瘤治疗手段，治疗效果优异，但是由于CAR-T治疗的生产成本、价格成本，使得CAR-T无法实现更大范围的供应，这也是CAR-T的销售增长缓慢的一大原因。延伸阅读：CAR-T 2022年大考成绩出炉！为了降低CAR-T生产成本，提高市场竞争力，研发人员进行了大量的工作，包括同种异体CAR-T、CAR-T自动化生产、CAR-T快速制备、体内CAR-T等等。延伸阅读：体内CAR-T细胞的技术路线CAR-T的快速制备，能够缩短生产时间，降低成本，包括生产空间和生产设备，以及人工费用等，能够大幅度缓解传统CAR-T生产所需要的生产资料，可以供给更多批次。CAR-T快速制备的机会当前全球范围内已有多款CAR-T产品获得批准上市，其大致生产制备流程基本相同：单采-分选-激活-转导-扩增-收获-包装和冻存-放行质检-回输。分选纯化：对单采产物进行T细胞分选纯化，获得目标的T细胞亚群，同时去除杂质，例如红细胞、抗凝剂等；激活/活化*：一般采用激活磁珠进行T细胞激活，然后将其放置于二氧化碳培养箱进行激活培养，T细胞激活能够提高CAR的转导率；转导CAR：完成激活的T细胞将进行CAR的转导，一般是通过病毒载体（慢病毒或逆转录病毒等）进行CAR的转导，使得T细胞转化为CAR-T细胞；扩增*：转导后，CAR-T细胞需要在生物反应器当中进行细胞扩增，直到细胞达到收获标准，包括活细胞数、体外效价、T细胞纯度；收获：收获工序包括清洗、去磁珠。包装和冻存：收获工序完成后，将在生物安全柜内完成分装，随后被保存于气相液氮罐中，放行质检合格后通知临床做回输准备。以上工序通常需要10-14天的工作时间，其中以细胞扩增所需的时间较长，为5天左右。延伸阅读：CAR-T生产工艺流程及优化考量在以上六个程序当中，CAR-T快速制备的机会在于激活与扩增这两个环节，通过删减和简化这两个环节，能够实现CAR-T在1-2天内的快速制备。挑战与一些解决方案但是激活与扩增两个环节在CAR-T细胞的生产中也具有重要意义：激活*：细胞激活能够促进CAR转导效率，静止T细胞的转导效率较低。如果要跳过或者优化这个环节，就必须解决静止T细胞的CAR转导效率过低的挑战。在现有的方案当中，对于这个环节有三种解决方式：a.使用具有更高转导效率的CAR基因载体；b.使用白介素等细胞因子进行促进转导效率；c.T细胞选用记忆T细胞，有部分研究显示，在不经活化的所有T细胞亚群中，记忆T细胞对CAR的转导率是最高的。扩增*：现在CAR-T剂量在106左右，通常从肿瘤患者体内采集到的T细胞数量制备成的CAR-T数量不足（主要也是CAR转导率低导致的），为了满足剂量要求达到最优疗效，需要在体外进行细胞扩增。因此快速制备平台还需要保证回输的CAR-T细胞剂量更低的同时，疗效不劣。不过由于快速制备不需要进行T细胞扩增，充分保留了T细胞干性，使得其在体内也可以进行一定的扩增，并且可能可以增强肿瘤细胞的清除效果。如何去考量和解决激活和扩增环节缺失，就成了CAR-T快速制备的关键，也是各家快速制备平台不同。举例：几个不同的快速制备平台（1）诺华 T-charge国际上，以诺华的CAR-T快速制备平台T-charge最为知名。T-charge平台的信息公开不多。根据诺华官网查询，T-charge平台删减了传统CAR-T细胞生产环节中的扩增部分，不需要在生物反应器当中进行CAR-T细胞扩增，而是将该环节置于患者体内。该平台能够保留T细胞干性，从而使得CAR-T产品具有更大的增殖潜力，以及更少的T细胞耗竭。这些特点可能会改善患者的预后，降低严重不良事件的风险。此前，诺华公布了其基于T-charge平台设计的一款靶向CD19的CAR-T细胞YTB323（rapcabtagene autoleucel）的数据，其door-to-door时间大约为10天左右；在DLBCL患者中CR（Month 3）可达到73%。延伸阅读：CAR-T“自卷”：生产周期降50%，剂量降25倍，CR73%（2）亘喜 FasTCAR在国内，亘喜生物的FasTCAR是进行比较早的CAR-T快速制备平台。根据公开资料，亘喜生物FasTCAR平台将传统生产中的激活、转导两个步骤简化和优化成同时进行，并且删减了扩增环节。FasTCAR平台利用专有的XLenti载体，同时激活和转导处于静息状态的T细胞。此外，亘喜生物表示，由于FasTCAR平台的产品具有较高的扩增和肿瘤细胞清除活性，因此可去除CAR-T细胞体外扩增的步骤，可以直接回输给患者。值得注意的是，亘喜生物基于FasTCAR平台开发的GC019F（CD19 CAR-T）和GC012F（BCMA/CD19 CAR-T）均已获得国家药品监督管理局的临床批件。（3）宾大团队 慢病毒转导静止T细胞2022年2月，宾大研究团队发表在期刊Nature Biomedical Engineering上的研究，就是一个经典的CAR-T快速制备方式。在该研究当中，研究人员通过慢病毒载体直接对静止T细胞进行转导，通过IL-7和IL-15等细胞因子的细胞培养基能够解决静止T细胞转导效率低下的问题，提高转导效率。此外，还可以通过工程病毒载体表达IL-7提高静止T细胞转导效率。同时，低浓度的核苷酸和其他限制性因子（如SAMHD1）均可限制静止T细胞逆转录率。小鼠模型中，通过这种方式设计的CD19 CAR-T可以显著地延长小鼠的生存期；与传统生产方式CAR-T相比，具有更优的抗白血病活性。（4）MASTER支架 CAR-T2022年3月，北卡罗来纳州立大学和北卡罗来那大学的研究人员开发了一种名为MASTER的多功能藻酸盐支架，MASTER技术集成了T细胞激活、重编程和体内扩增的步骤，将制造CAR-T的时间缩短到1天。图1 两种方法的路线图。研究人员从患者体内分离出T细胞，与CAR基因病毒载体混合，然后将混合物和藻酸盐支架（支架有激活T细胞的抗体以及促进增殖的白介素）混合后植入小鼠体内，CAR转导将发生在患者体内。在小鼠淋巴瘤异种移植模型中，这种基于MASTER支架在体内生成的CAR-T细胞，能够进入血液循环并控制远处肿瘤的生长。延伸阅读：120万的一针的CAR-T实现体内一天生产，期待成本下降 ！以上仅是举例，并不全面，如有缺漏，欢迎在留言区进行评论讨论。总结总结来说，CAR-T的快速制备平台关键在于激活，保证T细胞在静止状态下能够被转导成CAR-T，且具有高效率。不过目前来看，CAR-T快速制备还处于比较早期的状态，产品基本处于1期临床或以前。参考资料：1.https://ash.confex.com/ash/2022/webprogram/Paper162520.html2.https://www.novartis.com/research-development/technology-platforms/cell-therapy/charging-towards-next-generation-car-t3.亘喜生物官网：https://cn.gracellbio.com/4.Ghassemi, S., Durgin, J.S., Nunez-Cruz, S. et al. Rapid manufacturing of non-activated potent CAR T cells. Nat Biomed Eng 6, 118–128 (2022). https://doi.org/10.1038/s41551-021-00842-65.Agarwalla, P., Ogunnaike, E.A., Ahn, S. et al. Bioinstructive implantable scaffolds for rapid in vivo manufacture and release of CAR-T cells. Nat Biotechnol 40, 1250–1258 (2022). https://doi.org/10.1038/s41587-022-01245-x········

CLN-978 clinical development to focus exclusively on autoimmune diseases, pursuing systemic lupus erythematosus as a first indication Clinical observations from CLN-978 B-NHL study show rapid, deep, and sustained B cell depletion and clinical activity Corporate name change to Cullinan Therapeutics reflects strategic expansion into autoimmune diseases Cullinan Therapeutics to host a virtual investor event taking place on April 16 at 8:00 am ET CAMBRIDGE, Mass., April 16, 2024 (GLOBE NEWSWIRE) -- Cullinan Therapeutics, Inc., formerly Cullinan Oncology, Inc. (Nasdaq: CGEM), a biopharmaceutical company focused on developing modality-agnostic targeted therapies, today announced important updates about its plan to expand into autoimmune diseases, the scientific rationale for developing CLN-978 in autoimmune diseases, and initial clinical observations from its B cell non-Hodgkin lymphoma (B-NHL) study. In a separate announcement, the company also announced a $280 million private placement. The proceeds from the private placement, combined with current cash, cash equivalents, short term investments and interest receivable, are expected to fund Cullinan’s current operating plan into 2028. CLN-978 Development Plan Cullinan Therapeutics intends to pursue development of CLN-978 in autoimmune diseases, with systemic lupus erythematosus (SLE) as a first indication. The company believes that CLN-978 has the potential to be a first-in-class, off-the-shelf, disease-modifying treatment in autoimmune diseases with a differentiated safety profile​. The company plans to submit an investigational new drug application to study CLN-978 in patients with SLE in the third quarter of 2024 and is also planning for future development in other autoimmune diseases. The company has discontinued enrollment in its B-NHL study to focus ongoing development on autoimmune indications. Recent data demonstrated the potential of CD19 directed CAR T therapies in the treatment of 15 patients with autoimmune diseases (systemic lupus erythematosus, idiopathic inflammatory myositis, systemic sclerosis).1 While the efficacy was notable, challenges could limit broad uptake of CAR T therapy, such as the requirement for lymphodepleting chemotherapy, risk of secondary malignancies, complex manufacturing processes, and limited patient access. CD19-directed therapies afford significant potential for the breadth of B cell depletion and the necessary immune reset, since CD19 expression occurs across all B lineage cells, including the short-lived plasma cells and plasmablasts that produce the pathogenic autoantibodies present in autoimmune conditions. The company believes that CLN-978 could offer a novel solution for patients and providers as a T cell engager designed to deliver potency with off-the-shelf convenience and subcutaneous dosing​. On April 8, 2024, the Journal of Experimental Medicine published a Found in Translation article highlighting the potential advantages of CD19-directed T cell engagers to be superior to CD19 CAR-T cell engaging antibodies relative to CD19 CAR-T cells for the treatment of autoimmune diseases.2 Clinical Observations from CLN-978 B-NHL Phase 1 Trial Clinical observations from three patients treated in a Phase 1 dose escalation trial of patients with B-NHL show that CLN-978 was clinically active at the initial starting dose of 30 μg administered subcutaneously once weekly. Two of the three patients experienced objective clinical benefit including one patient who experienced a complete response. Grade 1 cytokine release syndrome occurred in two patients and no patients experienced immune effector cell-associated neurotoxicity syndrome. Other adverse events were low-grade, manageable, or mechanistically based (e.g. transient lymphopenia after the first dose only)​. Of the two patients with detectable B cells at baseline, both patients experienced rapid, deep, and sustained B cell depletion after administration of CLN-978. These data show that CLN-978 can deplete peripheral B cells and demonstrate clinical activity in a tissue resident disease at a dose with a favorable safety profile. Corporate Name Change to Cullinan Therapeutics The corporate name change to Cullinan Therapeutics reflects the company’s transformation as it pursues new indications for autoimmune diseases and continues to advance its clinical-stage oncology pipeline. The new corporate name represents both the expanded therapeutic focus area and Cullinan Therapeutics’ vision to evolve to a commercial-stage biotech company. The company’s common stock will continue to trade under its current ticker symbol “CGEM”. Along with the new name, the company will adopt a new logo and will change its corporate website from www.cullinanoncology.com to www.cullinantherapeutics.com. “Today’s announcements represent a major step forward for Cullinan Therapeutics. Our ethos is to pursue the best science for patients by matching the right target with the right modality, and we believe that CLN-978 could offer a convenient modality and potentially disease-modifying treatment for patients with autoimmune diseases where current treatments often only address symptoms, rather than the underlying disease itself,” said Nadim Ahmed, Chief Executive Officer of Cullinan Therapeutics. “Our expertise in drug development and our robust financial resources, now with an additional $280 million through our recent financing activity, position us to execute and expand the development of CLN-978. We also plan to deliver multiple data catalysts from our ongoing oncology clinical programs throughout 2024. I look forward to continuing our positive momentum and I am proud of our team working relentlessly to deliver for patients in need.” Virtual Investor Event The company will host a virtual investor event on April 16 at 8:00 am ET. Investors and the general public are invited to listen to a live webcast of the call. A link to join the call and to find related materials will be available at: https://cullinantherapeutics.com/events-and-presentations/. A replay of the event will be available on the above link for 90 days. About CLN-978 CLN-978 is a novel, highly potent, half-life extended CD19xCD3 bispecific T cell engager construct. CLN-978 potently triggers redirected lysis of CD19-expressing target cells in vitro and in vivo. CLN-978 is engineered to achieve very high affinity binding to CD19 to efficiently target B cells expressing very low CD19 levels. An HSA-binding domain increases the serum half-life of CLN-978 and, with subcutaneous delivery, permits more patient-friendly dosing and potentially reduced toxicity. CLN-978 contains two single-chain variable fragments (scFv), one binding with very high affinity to the CD19 target and the other binding to CD3 on T cells, and a single-domain antibody (VHH) binding to human serum albumin (HSA). CLN-978 was developed by an internal Cullinan team supported by co-founder and Scientific Advisory Board member Patrick Baeuerle, a world-renowned expert in the development of T cell engagers and CD19 biology and is a wholly owned asset. CLN-978 has the potential to offer a convenient, off-the-shelf therapeutic option for patients with autoimmune diseases such as systemic lupus erythematosus. About Systemic Lupus Erythematosus Systemic lupus erythematosus (SLE) is a chronic, heterogeneous autoimmune disease in which the immune system attacks a patient’s own tissues. The most common manifestations of SLE include skin rashes, arthritis, swelling in the feet, and around the eyes, extreme fatigue, and low fevers. Lupus nephritis (LN) is a kidney disease and the most common severe manifestation of SLE. Approximately 40% of patients with SLE develop LN, which has a 10-year 30% mortality rate3,4. SLE is more prevalent in women, people of color, and women of childbearing age. The CDC estimates the prevalence of SLE in the US to be approximately 160,000 to 320,000 cases. Currently available treatments do not routinely induce treatment-free remission, and most patients require lifelong immune suppression that treats symptoms without modifying the course of disease. About Cullinan Therapeutics Cullinan Therapeutics, Inc. (Nasdaq: CGEM) is a biopharmaceutical company dedicated to creating new standards of care for patients. We have strategically built a diversified portfolio of clinical-stage assets that inhibit key drivers of disease or harness the immune system to eliminate diseased cells in both oncology and autoimmune diseases. Our portfolio encompasses a wide range of modalities, each with the potential to be best and/or first in class. Anchored in a deep understanding of oncology, immunology, and translational medicine, we create differentiated ideas, identify the most appropriate targets, and select the optimal modality to develop transformative therapeutics across a wide variety of cancer and autoimmune indications. We push conventional boundaries from candidate selection to differentiated therapeutic, applying rigorous go/no go criteria at each stage of development to fast-track only the most promising molecules to the clinic and, ultimately, commercialization. With deep scientific expertise, our teams exercise creativity and urgency to deliver on our promise to bring new therapeutic solutions to patients. Learn more about our company at www.cullinantherapeutics.com, and follow us on LinkedIn and X. Forward Looking Statements This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. These forward-looking statements include, but are not limited to, express or implied statements regarding the company’s beliefs and expectations regarding: our preclinical and clinical developments plans and timelines, the clinical and therapeutic potential of our product candidates, the strategy of our product candidates, our research and development activities, our cash runway, and the completion, timing and size of the private placement. The words “believe,” “continue,” “could,” “estimate,” “expect,” “intends,” “may,” “plan,” “potential,” “project,” “pursue,” “vison,” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements in this press release are based on management's current expectations and beliefs of future events and are subject to known and unknown risks and uncertainties that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. These risks include, but are not limited to, the following: uncertainty regarding the timing and results of regulatory submissions, including the IND that we intend to file for CLN-978; the risk that any INDs we may file are not cleared by the United States Food and Drug Administration or are not cleared on our expected timelines, or at all; success of our clinical trials and preclinical studies; risks related to our ability to protect and maintain our intellectual property position; risks related to manufacturing, supply, and distribution of our product candidates; the risk that any one or more of our product candidates, including those that are co-developed, will not be successfully developed and commercialized; the risk that the results of preclinical studies or clinical studies will not be predictive of future results in connection with future studies; and success of any collaboration, partnership, license or similar agreements. These and other important risks and uncertainties discussed in our filings with the Securities and Exchange Commission, including under the caption “Risk Factors” in our most recent Annual Report on Form 10-K and subsequent filings with the SEC, could cause actual results to differ materially from those indicated by the forward-looking statements made in this press release. While we may elect to update such forward-looking statements at some point in the future, we disclaim any obligation to do so, even if subsequent events cause our views to change, except to the extent required by law. These forward-looking statements should not be relied upon as representing our views as of any date subsequent to the date of this press release. Moreover, except as required by law, neither the company nor any other person assumes responsibility for the accuracy and completeness of the forward-looking statements included in this press release. Any forward-looking statement included in this press release speaks only as of the date on which it was made. Contacts InvestorsChad Messer+1 203.464.8900cmesser@cullinanoncology.com Media Rose Weldon 215-801-7644rweldon@cullinanoncology.com Mueller, F. et al. NEJM 2024Michaelson, J. and Baeurle, P. Journal of Experimental Medicine, April 2024Mahajan, A. et al. Lupus. 2020 Aug; 29(9): 1011–1020.Hocaoglu, M. et al. Arthritis & Rheumatology 2023 Apr.; 75(4): 567-573