Lentigen Technology, Inc.

Patients with a certain type of synovial sarcoma have a new treatment option for the first time in more than a decade as the FDA has approved Adaptimmune's Tecelra, which is the first engineered T-cell therapy for a solid tumor. Adaptimmune has won accelerated FDA approval for Tecelra (afami-cel), a treatment for metastatic or unresectable synovial sarcoma.Tecelra’s approval comes with several firsts. It’s the first engineered cell therapy for a solid tumor, the first TCR-T therapy to enter the market, and the first new treatment in the indication in more than a decade.It also is the initial approval for the 16-year-old company, which has attracted and lost partnerships with several pharma giants—including GSK, Astellas and most recently Roche—who were drawn to the potential of Adaptimmune’s unique engineered T-cell receptor (TCR) platform. It enables the engineering of T-cells to target and destroy many types of solid tumor cancers.As the first engineered T-cell therapy for solid tumors, Tecelra marks a significant milestone, not only for the company but also for the advancement of cell therapy.“It’s the first product where we use a lentiviral vector to insert our engineered T-cell receptor into the cell,” John Lunger, Adaptimmune’s chief patient supply officer, explained in an interview. Iovance’s Amtagvi (lifileucel), which was approved by the FDA in February for melanoma, was the first T-cell treatment for solid tumors. The difference with Tecelra is that it is engineered.Amtagvi uses immune cells, called tumor-infiltrating lymphocytes (TILs), which are collected from a patient’s tumor, as opposed to CAR-T cell therapies, which are collected from a patient’s circulating blood.“Ninety percent of cancer is solid tumors,” Lunger said. “The idea of a company like ourselves, going after solid tumors using cells, we’re finally getting to that place where we’re demonstrating this can actually work.”The list price for the one-time therapy is $727,000. The addressable patient population in the US is roughly 400 per year, Lunger said.  Tecelra’s endorsement covers adults with advanced MAGE-A4+ synovial sarcoma of certain human leukocyte antigen (HLA) types who have received prior chemotherapy. Patients undergo companion diagnostic screening for their genetic HLA types and MAGE-4A expression.Sarcomas are rare solid tumor cancers that develop in the bones and soft tissues including fat, muscle, nerves and blood vessels, which often strike young adults. Of the roughly 13,400 new soft tissue sarcomas diagnosed annually in the US, 5 to 10% are of the synovial type. The five-year survival rate is 20%, with most patients going through multiple lines of therapy, Adaptimmune said.The approval is based on results of the SPEARHEAD-1 study of 44 patients, in which afami-cel provided a 43% overall response rate, with 4.5% seeing the disappearance of their cancer. For those who respond to Tecelra, the median treatment-free interval seen in the trial was 17 months.“We’ve also seen for those responders about a 70% chance that they’re still alive after two years and that data is still developing,” Lunger said.There were no treatment deaths in the study, though Tecelra can cause serious side effects including cytokine release syndrome and neurotoxicity.“From the patient experience, when you compare what we have with a one-time therapy to the usual standard of care—which is chemotherapy, radiation and surgery—it’s extraordinary,” Lunger said.As part of the accelerated approval, a confirmatory trial will be required.  Adaptimmune, which is based in Oxford, England, plans to have six to 10 designated treatment centers in operation by the end of this year, growing to 30 across the US by the end of 2025.Adaptimmune went public in 2015 but found itself in dire straits in April when Genentech—in cost-cutting mode—exited a $3 billion partnership in which it was developing two allogenic T-cell therapies directed at up to five targets.But seven weeks later, Galapagos stepped up, signing a $665 million deal for the rights to uza-cel, a MAGE-4A TCR T-cell therapy which Adaptimmune has in phase 2 for ovarian cancer. The Belgian biotech wants to take uza-cel into head and neck cancer and potentially other solid tumors.The Galapagos deal, which includes $100 million up front, will help fund Adaptimmune’s launch of Tecelra.Adaptimmune manufactures drug product for Tecelra in Philadelphia and farms viral vector production out to Miltenyi Biotec’s subsidiary Lentigen, which is based in Maryland. Adaptimmune handles all the manufacturing itself for uza-cel, performing viral vector production at one of its two sites in the UK.“This approval represents a much-needed new option for people diagnosed with this sarcoma and an important milestone for the use of cell therapies in solid tumor cancers,,” Sandra D’Angelo, a sarcoma medical oncologist at Sloan Kettering Cancer Center, and the principal investigator of the SPEARHEAD trial, said.

当CAR-T疗法在国内降到100万元一针，似乎并未溅起多大水花，但要是降到30万元以下呢？3月26日，美国一家非营利组织Caring Cross宣布与巴西卫生部所资助的基金会Fundação Oswaldo Cruz (Fiocruz)达成合作，共同开发用于白血病、淋巴瘤和艾滋病相关的CAR-T细胞疗法。而双方合作的第一个项目就预计打造3.5万美元/针的CAR-T疗法，用于治疗白血病和淋巴瘤。根据协议，Caring Cross负责提供技术和慢病毒载体制造工艺，Fiocruz的研究所负责开发产品和开展临床试验。在具体价格方面，Caring Cross自信其研发的慢病毒载体制造工艺能够将成本降低到目前已上市产品的十分之一。在巴西政府和本土制药商的支持下，未来产品价格将降至3.5万美元/剂，并将向巴西民众免费提供。双方还预计，首个产品将是针对白血病和淋巴瘤的CAR-T细胞疗法，并将于三年内上市。值得注意的是，Caring Cross的执行董事还是美国生物技术公司Lentigen Technology的创始人，该公司开发了FDA批准的第一个CAR-T疗法，诺华的Kymriah的慢病毒载体。如果说Caring Cross和巴西政府合作推出CAR-T疗法还是在纸面上的概念，而印度制药商早在去年就已经实现了CAR-T疗法的破冰价，还准备将其推至美国市场。2023年10月，脱胎于印度理工学院的生物技术公司ImmunoACT推出了其首款CAR-T产品靶向CD19的NexCAR19，根据外媒报道，NexCAR19的单次治疗费用仅在3万-4万美元左右，接近美国市场CAR-T疗法的十分之一。而ImmunoACT能够降低CAR-T疗法价格的关键原因之一，就是在印度本土完成了NexCAR19的开发和临床，并采用印度本土制造的慢病毒载体进行生产。不过，ImmunoACT并非首个除中国公司外，开发本土CAR-T疗法的亚洲生物技术公司，来自泰国的Genepeutic Bio也在开发CD19 CAR-T疗法，并预计于今年年底登陆市场。该疗法的早期研发也是来自泰国本土的玛希隆大学，通过玛希隆大学的支持，该公司预计通过降低慢病毒载体的成本，来使产品价格降低80%。而Genepeutic Bio本身也作为一家CDMO，拥有泰国首个获得 GMP 认证的细胞和基因治疗制造工厂。可以看到，无论是巴西的合作研发计划，还是来自印度的ImmunoACT、来自泰国的Genepeutic Bio，其降低CAR-T疗法价格的方式都是在慢病毒载体方面。此前，有业内人士在近期召开的BIOCHINA2024大会对E药经理人表示，通常可以在三个阶段来实现CAR-T疗法成本的降低。一是通过支付方式、竞争对手和新的研发管线进入市场来实现，预期实现20%-30%的降价空间；二是凭借生产工艺的进步，包括自动化生产、转染效率提高、工艺的稳定等来降低成本，从而实现30%-50%的降价空间；三是突破底层技术，如形成通用型产品的药品模式，来实现50%-90%的降价空间。其中，在载体生产环节是整个过程中技术壁垒最高、成本最高的一环。提高载体生产效率主要在三个环节：一是从基于贴壁细胞和细胞工厂的生产工艺升级到基于悬浮细胞和生物反应器的生产工艺；二是构建能稳定产毒的细胞系，使病毒生产不再依赖于质粒；三是设计与优化病毒载体分子，提高病毒原液滴度，降低病毒载体的细胞毒性。中国药企也在尝试从上述三个阶段来降低CAR-T疗法的成本。例如，复星凯特在今年年初宣布推出按疗效价值支付计划，若患者未能达到完全缓解（CR），将获得最高60万元的返还。与先声合作的普瑞金生物则通过自主研发的生产工艺、杂质研究、质量研究等全套CMC工艺，预计能够大幅降低CAR-T疗法的成本。科济药业在上海徐汇、金山及美国达勒姆市都设有生产基地，以通过自主生产的方式来降低综合成本。此外，被阿斯利康纳入麾下的亘喜生物，其专有的FasTCAR平台能将自体CAR-T细胞生产时间从行业标准的1到6周，显著缩短到次日生产完毕，从而降低生产成本。

Maryland non-profit Caring Cross and Brazil's Fundacao Oswaldo Cruz (Fiocruz) plan to develop and manufacture cell and gene therapies at one-tenth of their cost in the U.S. Maryland non-profit Caring Cross has unveiled a partnership with the Brazilian government that's designed to provide access to advanced cell and gene therapies for diseases like leukemia, lymphoma and HIV infection—and in the process provide a manufacturing model that demonstrates how to reduce the cost of these treatments in the United States and Europe. Caring Cross and Fundacao Oswaldo Cruz (Fiocruz)—a foundation funded by the Brazilian Ministry of Health—plan to develop and manufacture the medicines at a fraction of their cost in the U.S. Co-founded by cell and gene therapy manufacturing trailblazers Boro Dropulic, Ph.D. and Rimas Orentas, Caring Cross’ mission is to organize and support a community of healthcare professionals, scientists, engineers, advocates and business leaders to accelerate the development of advanced medicines and make them available for all patients around the world. The program with Brazil is the first of its kind anywhere in the world, Dropulic and Orentas said in an interview with Fierce Pharma. “We’re pioneering something quite new in terms of teaching an organization, that is directly linked to the Ministry of Health, how to manufacture CAR-T cells and the vectors themselves,” said Dropulic, the executive director of Caring Cross. “We will start first in Rio de Janeiro at the Fiocruz campus—in collaboration with INCA, which is their equivalent of the NCI (National Cancer Institute)—to run clinical trials for leukemia and lymphoma.” Dropulic knows the drill. He founded Lentigen, which developed the lentiviral vector used by Novartis to produce the first FDA-approved cell therapy product, Kymriah, in 2017. Dropulic directed Lentigen’s CDMO business model before launching Caring Cross in 2021. The effort in Brazil will include the development of a product for HIV, which is currently in clinical trials in the U.S. A candidate to cure sickle cell disease and beta thalassemia could enter the clinic later this year.   Under the plan, the therapies will be available for free for patients, with an approximate cost of $35,000 per dose covered by the Brazilian public health system. Dropulic and Orentas believe an approved product could be available within three years. Caring Cross aims to slash production costs with its point-of-care manufacturing model. Development and manufacturing can be executed entirely in modular units which are 56 by 13 feet and can be set up anywhere.   “When you make these products at the point of care or close to a hospital, you significantly decrease these logistical costs,” Dropulic said. Orentas added that it’s already dawned on the managed care systems in countries such as Spain, Germany and Denmark that the way gene therapies are produced in the U.S. is “not sustainable.” Even with the high cost of doing business in the U.S., Caring Cross believes it could deliver CAR-T therapies for around $80,000, Orentas said. In the U.S., cell and gene therapy prices currently range from hundreds of thousands of dollars to millions of dollars.  Caring Cross's Brazilian partner has "biomanufacturing expertise" and "an experienced workforce," Orentas said. Fiocruz is the world’s largest producer of the yellow fever vaccine. It also served as Brazil’s home base for production of its AstraZeneca-partnered COVID vaccine. Meanwhile, through its for-profit CDMO spinout, Vector BioMed, Caring Cross is developing technologies to improve the accessibility of CAR-T and other therapies.