CarThera SAS

脑胶质瘤是最常见的原发性恶性脑肿瘤，胶质母细胞瘤(GBM)是最高级别以及恶性程度最高的脑胶质瘤，占颅内原发性恶性肿瘤的45%，术后极易复发，患者五年生存率不足5%。GBM是神经外科治疗中最棘手的难治性肿瘤之一。治疗脑胶质瘤的一个主要障碍是血脑屏障(BBB)。血脑屏障是一种微观结构，可以保护大脑免受绝大多数循环药物的侵害，但同时血脑屏障也阻断了95%以上的小分子和100%的大分子药物在大脑中的渗透，连最有效的化疗药物也无法渗透血脑屏障抵达脑肿瘤。因此，如何穿透血脑屏障，将诊断或治疗性化合物递送到大脑是神经系统疾病治疗中主要的技术障碍。CarThera成立于2010年，是法国的一家创新医疗器械公司，专注于研发基于超声治疗脑肿瘤的医疗设备。公司旗下的SonoCloud是一种植入颅内的超声设备，原则上可用于治疗原发性脑肿瘤（神经胶质瘤，胶质母细胞瘤，星形细胞瘤等）以及继发性脑肿瘤。动脉网获悉，2023年6月27日，Carthera完成3750万欧元B轮融资，这笔新的资金将用于启动植入式设备SonoCloud的多中心试验。此前，Carthera已进行过6轮融资，融资总金额超6680万欧元。Carthera融资历史 数据来源：crunchbase 基于超声打开血脑屏障，设备已获FDA突破性设备认定2015年，来自加拿大多伦多桑尼布鲁克研究所的科学家们宣布，他们利用充气微泡和超声波成功打开了一位脑癌患者的血脑屏障。患者服药并注射微泡后，在聚焦超声装置的作用下，微泡会产生振动，迫使构成血脑屏障的内皮细胞分开，血液中的化疗药物便可从间隙中穿过，到达肿瘤细胞附近。CarThera团队的研究也有着类似的原理，利用低强度脉冲超声结合静脉注射微泡(LIPU-MB)打开血脑屏障，但他们的研究相对桑尼布鲁克研究所存在新突破。一、CarThera使用了新研发的可植入颅内的1MHz超声设备SonoCloud；二、参与研究的患者共15名，获得的实验数据会更充分；三、在脑肿瘤治疗的每个治疗周期会重复打开血脑屏障，但未对人体造成伤害，证明此技术的安全性；四、相对于桑尼布鲁克研究所的精准定向于未扩散的肿瘤，CarThera研究使用的超声更发散，对GBM这样侵入周边组织的肿瘤更有效。在CarThera的研究中，患者首先服用化疗药物，医生向患者血管中注射充气微泡，然后将SonoCloud植入脑部区域的颅骨窗口，该窗口是医生在手术切除复发性GBM时创造的。然后在每个治疗周期，使用一次性无菌透皮针头和电缆将植入物通过经皮通道连接到脉冲发生器，SonoCloud得到激活并释放低强度超声，引起微泡振动，从而增加大脑中血管的通透性，药物可以以更高、更有效的浓度到达大脑。2022年6月22日，SonoCloud已获美国FDA突破性设备认定。SonoCloud 图源：CarThera官网   完成复发性GBM Ⅰ/Ⅱ期试验，扩展AD、脑转移瘤等适应症● 针对治疗复发性GBM，增加4~6倍药物浓度紫杉醇是一种“抗癌神药”，广泛应用于乳腺癌、卵巢癌、非小细胞肺癌、胰腺癌、食管癌及胃癌等恶性肿瘤的治疗。但紫杉醇无法跨越血脑屏障到达脑肿瘤，在系统给药治疗恶性神经胶质瘤的Ⅰ/Ⅱ期试验中也没有显示出疗效。而SonoCloud可以协助紫杉醇抵达脑肿瘤。2020年，为了进一步验证SonoCloud协助紫杉醇治疗复发性GBM的安全性和有效性，CarThera与西北大学合作开展人体复发性GBMⅠ/Ⅱ期试验。2023年5月2日，西北大学的科研人员发表在《柳叶刀·肿瘤学》的首个人体临床试验结果表明，SonoCloud释放4分钟的低强度脉冲超声可使血脑屏障开放1个小时，让进入人脑中的紫杉醇和卡铂等化疗药物浓度增加约4~6倍。● 减少β-淀粉样蛋白含量，适应症扩展到AD据《2021年世界阿尔茨海默病报告》显示，全球阿尔茨海默症(老年痴呆症，AD)患者数量超5500万。随着老年化社会的加速到来，AD患者数量还会急剧上升，预计2050年会上升到1.39亿。AD一般伴随着两种特征，一是细胞产生的细胞外异常沉积形成老年斑（β-淀粉样蛋白堆积形成），二是AD患者脑内神经元纤维会形成缠绕影响大脑功能。因此β-淀粉样蛋白逐渐被认为是引发AD的元凶之一。使用Sonocloud设备治疗脑肿瘤的过程中，Carthera团队发现在没有任何施药的情况下，人体内的β-淀粉样蛋白和Tau蛋白减少。因此Carthera团队决定将Sonocloud适应症扩张到AD，开始着手准备针对AD患者的临床试验。在局部麻醉下，将Sonocloud植入到轻度AD患者的脑部左侧边缘上。每个月对AD患者进行两次超声检查，每次大约持续10分钟以暂时破坏血脑屏障。在这个过程中，用PET（正电子发射计算机断层扫描技术）监测经4、8个月治疗后患者的大脑代谢和β-淀粉样蛋白水平。临床研究结果证明，尽管治疗和观察期较短，但经Sonocloud打开血脑屏障后，大多数患者的β-淀粉样蛋白水平下降，AD患者的症状可以有效延缓或者改善。目前CarThera已完成AD治疗的Ⅰ/Ⅱ期临床试验，Sonocloud治疗AD的有效性和安全性得到验证。接下来CarThera将与制药企业合作，探究如何将Sonocloud与新的药物疗法相结合，以获得更好的疗效。同时，CarThera已经验证了SonoCloud技术可以增强CAR-T免疫疗法治疗脑肿瘤的疗效；CarThera还在研究Sonocloud单独使用或结合其他化疗药物治疗脑转移瘤、早期GBM等脑疾病的有效性。临床试验进度 图源：CarThera官网治疗方案不断更新，电场、超声为脑肿瘤治疗带来新选择近些年来，科学家不断研究，在经历传统的放疗、化疗，以及靶向药物之后，免疫疗法堪称癌症治疗的第三次革命，而新兴的电场治疗、超声治疗为治疗脑肿瘤带来了新的选择。由于普通化疗的治疗指数低、副作用强，科学家一直在寻找特异性杀死肿瘤细胞而不影响正常细胞的治疗手段。靶向治疗就是他们找到的第一个替代化疗的治疗方案，其原理是根据肿瘤细胞的基因突变进行精准打击。但是一旦靶点基因发生突变，靶向药物就会失去作用；一些癌症患者在经过靶向治疗几年后，还会出现耐药情况。肿瘤免疫治疗起源于19世纪末期，但在近30年才得以快速发展。其作用原理是通过激活人体免疫系统，调动机体免疫细胞活性，让失活的免疫细胞再次活跃起来间接消灭肿瘤细胞，这个过程往往较为漫长。CAR-T技术与PD-1和PD-L1抗体药物是免疫疗法中具有代表性的突破。肿瘤电场治疗(TTFields) 是一种新的癌症治疗方式，利用敷贴于头皮的无创传感器电极阵列，产生中低频肿瘤治疗场，通过抑制肿瘤细胞有丝分裂发挥抗肿瘤作用。2011和2015年，TTFields先后被美国FDA批准应用于复发性和新诊断GBM的治疗，目前已经在美国、中国、欧洲、日本相继进入临床应用。超声作为一种经济、有效、无创、实时和安全的治疗方式，除用于分子水平诊断和病理过程监测外，能通过机械效应和热效应深入机体内部定位组织和细胞，已逐渐用于药物和基因的靶向递送。低强度脉冲超声技术打开血脑屏障的研究已经持续了二十多年，但目前还没有产品真正走到临床应用。近期推荐声明：动脉网所刊载内容之知识产权为动脉网及相关权利人专属所有或持有。未经许可，禁止进行转载、摘编、复制及建立镜像等任何使用。动脉网，未来医疗服务平台

In the first in-human clinical trial, scientists used a novel, skull-implantable ultrasound device to open the blood-brain barrier and repeatedly permeate large, critical regions of the human brain to deliver chemotherapy that was injected intravenously. This is potentially a huge advance for glioblastoma patients because the most potent chemotherapy can't permeate the blood-brain barrier to reach the aggressive and deadly brain tumor. A major impediment to treating the deadly brain cancer glioblastoma has been that the most potent chemotherapy can't permeate the blood-brain barrier to reach the aggressive brain tumor. But now Northwestern Medicine scientists report results of the first in-human clinical trial in which they used a novel, skull-implantable ultrasound device to open the blood-brain barrier and repeatedly permeate large, critical regions of the human brain to deliver chemotherapy that was injected intravenously. The four-minute procedure to open the blood-brain barrier is performed with the patient awake, and patients go home after a few hours. The results show the treatment is safe and well tolerated, with some patients getting up to six cycles of treatment. This is the first study to successfully quantify the effect of ultrasound-based blood-brain barrier opening on the concentrations of chemotherapy in the human brain. Opening the blood-brain barrier led to an approximately four- to six-fold increase in drug concentrations in the human brain, the results showed. Scientists observed this increase with two different powerful chemotherapy drugs, paclitaxel and carboplatin. The drugs are not used to treat these patients because they do not cross blood-brain barrier in normal circumstances. In addition, this is the first study to describe how quickly the blood-brain barrier closes after sonication. Most of the blood-brain barrier restoration happens in the first 30 to 60 minutes after sonication, the scientists discovered. The findings will allow optimization of the sequence of drug delivery and ultrasound activation to maximize the drug penetration into the human brain, the authors said. "This is potentially a huge advance for glioblastoma patients," said lead investigator Dr. Adam Sonabend, an associate professor of neurological surgery at Northwestern University Feinberg School of Medicine and a Northwestern Medicine neurosurgeon. Temozolomide, the current chemotherapy used for glioblastoma, does cross the blood-brain barrier, but is a weak drug, Sonabend said. The paper will be published May 2 in The Lancet Oncology. The blood-brain barrier is a microscopic structure that shields the brain from the vast majority of circulating drugs. As a result, the repertoire of drugs that can be used to treat brain diseases is very limited. Patients with brain cancer cannot be treated with most drugs that are otherwise effective for cancer elsewhere in the body, as these do not cross the blood-brain barrier. Effective repurposing of drugs to treat brain pathology and cancer require their delivery to the brain. In the past, studies that injected paclitaxel directly into the brain of patients with these tumors observed promising signs of efficacy, but the direct injection was associated with toxicity such as brain irritation and meningitis, Sonabend said. Blood-brain barrier recloses after an hour The scientists discovered that the use of ultrasound and microbubble-based opening of the blood-brain barrier is transient, and most of the blood-brain barrier integrity is restored within one hour after this procedure in humans. "There is a critical time window after sonification when the brain is permeable to drugs circulating in the bloodstream," Sonabend said. Previous human studies showed that the blood-brain barrier is completely restored 24 hours after brain sonication, and based on some animal studies, the field assumed that the blood-brain barrier is open for the first six hours or so. The Northwestern study shows that this time window might be shorter. In another first, the study reports that using a novel skull-implantable grid of nine ultrasound emitters designed by French biotech company Carthera opens the blood-brain barrier in a volume of brain that is nine times larger than the initial device (a small single-ultrasound emitter implant). This is important because to be effective, this approach requires coverage of a large region of the brain adjacent to the cavity that remains in the brain after removal of glioblastoma tumors. Clinical trial for patients with recurrent glioblastoma The findings of the study are the basis for an ongoing phase 2 clinical trial the scientists are conducting for patients with recurrent glioblastoma. The objective of the trial -- in which participants receive a combination of paclitaxel and carboplatin delivered to their brain with the ultrasound technique -- is to investigate whether this treatment prolongs survival of these patients. A combination of these two drugs is used in other cancers, which is the basis for combining them in the phase 2 trial. In the phase 1 clinical trial reported in this paper, patients underwent surgery for resection of their tumors and implantation of the ultrasound device. They started treatment within a few weeks after the implantation. Scientists escalated the dose of paclitaxel delivered every three weeks with the accompanying ultrasound-based blood-brain barrier opening. In subsets of patients, studies were performed during surgery to investigate the effect of this ultrasound device on drug concentrations. The blood-brain barrier was visualized and mapped in the operating room using a fluorescent die called fluorescein and by MRI obtained after ultrasound therapy. "While we have focused on brain cancer (for which there are approximately 30,000 gliomas in the U.S.), this opens the door to investigate novel drug-based treatments for millions of patients who suffer from various brain diseases," Sonabend said. Other Northwestern authors include: A. Gould, C. Amidei, R. Ward, K. A. Schmidt, D.Y. Zhang, C. Gomez, J.F. Bebawy, B.P. Liu, I.B. Helenowski, R.V. Lukas, K. Dixit, P. Kumthekar, V. A. Arrieta. Lesniak, H. Zhang and R. Stupp. This work is funded by the grants 1R01CA245969-01A1 and P50CA221747 from the National Cancer Institute of the National Institutes of Health and SPORE support from the Moceri Family Foundation and the Panattoni family.

WEDNESDAY, May 3, 2023 -- Brain cancers are notoriously difficult to treat because most chemotherapy drugs can’t breach the blood-brain barrier, a microscopic layer of cells that protect the brain from toxins. But researchers now say they can temporarily open that barrier and get more chemo to brain tumors, using an experimental ultrasound device. The technology led to a four- to sixfold increase in chemo drug concentrations within the brains of patients. The researchers observed this increase with two different powerful chemotherapy drugs, paclitaxel and carboplatin. These drugs aren’t typically used to treat brain tumors because they normally can’t cross the blood-brain barrier. For this study, doctors surgically removed patients’ glioblastoma — the most common malignant brain tumor in adults — and then implanted a grid of nine ultrasound emitters in their skulls. Within a few weeks of surgery, patients started chemo treatment to kill any residual cancer cells in their brains. The experimental emitter grid, designed by French biotech company Carthera, opened the blood-brain barrier at large, critical regions of the brain. This allowed the intravenous chemo drug paclitaxel to seep into the brain. The ultrasound procedure takes about four minutes and is performed with the patient awake, the researchers reported. Patients go home after a few hours. The blood-brain barrier quickly reestablishes itself following the procedure, with most of its integrity restored within one hour, the study authors said. The report was published May 2 in The Lancet Oncology journal. “There is a critical time window after sonification when the brain is permeable to drugs circulating in the bloodstream,” said lead researcher Dr. Adam Sonabend , an associate professor of neurological surgery at Northwestern University Feinberg School of Medicine, in Chicago. The doctors escalated the dose of paclitaxel delivered every three weeks, using the ultrasound implant to make sure the chemo got to the brain. The treatment was safe and well-tolerated, the researchers said. Some patients got up to six chemo treatment cycles for their brain tumors. The findings of this study have formed the basis for a clinical trial in which patients will receive a combination of paclitaxel and carboplatin to their brains, to see if the treatment prolongs their survival. Glioblastomas are the fastest-growing brain tumors, and they are nearly always advanced when detected. Five-year survival rates are 22% for people aged 20 to 44, 9% for adults 45 to 54, and 6% for those aged 55 to 64, according to the American Cancer Society. The researchers said the ultrasound technique could be used to help deliver many different types of medication to the brain. “While we have focused on brain cancer (for which there are approximately 30,000 gliomas in the U.S.), this opens the door to investigate novel drug-based treatments for millions of patients who suffer from various brain diseases,” Sonabend said in a university news release. Sources Northwestern University, news release, May 2, 2023 Posted May 2023