Institut d'Investigacions Biomèdiques August Pi I Sunyer

Some neurological disorders can be improved through photobiomodulation, a non-invasive technique based on the application of low-intensity light to stimulate altered functions in specific regions of the body. Now, a study reveals how photobiomodulation applied to the brain-gut axis is effective in recovering some cognitive alterations and sequelae caused by chronic stress. The study opens up new perspectives for applying the technique in future therapies for the treatment of neurological diseases in patients. Some neurological disorders can be improved through photobiomodulation, a non-invasive technique based on the application of low-intensity light to stimulate altered functions in specific regions of the body. Now, a study published in the Journal of Affective Disorders reveals how photobiomodulation applied to the brain-gut axis is effective in recovering some cognitive alterations and sequelae caused by chronic stress. The study opens up new perspectives for applying the technique in future therapies for the treatment of neurological diseases in patients. The article, based on the study of laboratory animal models, is led by Professor Albert Giralt, from the Faculty of Medicine and Health Sciences and the Institute of Neurosciences (UBneuro) of the University of Barcelona. Teams from the UB's Centre for the Production and Validation of Advanced Therapies (CREATIO) and the University of Girona, as well as from the University of Montpellier and the company REGEnLIFE (France) are also participating. Low-intensity light for activating the gut-brain axis In clinical practice, photobiomodulation applies light from lasers or other low-intensity sources to stimulate the activity of an organ with an altered physiology. Now, the new study applies, for the first time in the field of depression, the use of combined photobiomodulation to stimulate different organs, specifically the brain and the gut. "This is one of the most innovative scientific contributions of the study: to co-stimulate in a coordinated way the brain and the gut at the same time, i.e. the gut-brain axis. Today, the area of research into the gut-brain axis is generating great scientific interest and is a very promising field for the possible treatment of diseases of the nervous system," says Professor Albert Giralt, member of the August Pi i Sunyer Biomedical Research Institute (IDIBAPS) and the Network Centre for Biomedical Research on Neurodegenerative Diseases (CIBERNED). "The new therapeutic approach focuses on this now rediscovered scenario of intervention and manipulation of the gut-brain axis to address neurological and psychiatric disorders," says Giralt. "Photobiomodulation is a non-invasive technology that is very well tolerated by patients and lacks the side effects of pharmacological treatments. In addition, this advance could also be useful in the treatment of pathologies without clear or incomplete medical coverage, such as the treatment-resistant subtype of depression," adds the expert. The devices for the application of photobiomodulation, developed by the company REGEnLIFE, have been adapted from previous studies related to Alzheimer's patients. They combine multiple stimulation sources (laser, LED, etc.) associated with a magnetic ring to stabilise the emission of light in a pulsed -- and not continuous -- manner to avoid overheating the tissues, and are adapted for clinical application in patients. Psychiatric disorders: beyond the brain Another scientific objective of the study is to prove that psychiatric disorders are not only centred in the brain, "but that other tissues and organs also play a decisive role in their pathophysiology. If new therapies take all these factors into account, it is very likely that we will be able to obtain very satisfactory results in the future," says the researcher. But do both photobiomodulation and photobiomodulation act on the cervical-intestinal axis? To date, there have only been descriptive studies of the modifications induced by photobiomodulation. Now, the study delves into the molecular mechanisms and reveals how photobiomodulation is able to reverse the cognitive effects of chronic stress by restoring the sirta1 pathway, "related to senescence and neuronal death, the modulation of negative pyramiding and normalisation of diversity in the intestinal microbiota," notes researcher Anna Sancho-Balcells (UB-UBneuro-CIBERNED), first author of the article. "From other studies -- she continues -- it was known that the SIRT1 pathway is altered in preclinical models of stress and depression. However, the mechanisms by which photobiomodulation exerts its beneficial effects remained a mystery. In our study, we found that the SIRT1 pathway is the most altered physiological pathway in certain brain regions under chronic stress, and photobiomodulation has the capacity to restore it." In the digestive system, photobiomodulation would activate changes in the intestinal microbiota, effects that are superior in the case of dual brain-gut stimulation compared to treatment of the gut alone. As Professor Xavier Xifró, from the TargetsLab research group at the Faculty of Medicine of the University of Girona, explains, "the associated cellular mechanisms seem to be linked to the improvement of neuroinflammatory processes. Thus, the changes observed in the microbiota are strongly associated with some changes in neuroinflammation (for example, microgliosis and astrogliosis, which occur through the inflammation of specific cells of the nervous system)." Combined photobiomodulation in patients with depression Photobiomodulation could become a potential adjunctive treatment to be administered in coordination with pharmacological therapy in cases of major depressive disorders. In future research, the team would like to promote the design of clinical trials to test the efficacy of combined photobiomodulation in patients with depression. "Photobiomodulation is likely to be particularly suitable for specific forms of depression, such as treatment-resistant depression. We also want to explore the relationship with neuroinflammatory processes: this is one of the best-rescued parameters after photobiomodulation and treatment-resistant depression is strongly associated with neuroinflammation," concludes the research team.

A study has disentangled the mechanisms behind one of the ways melanoma cancer cells develop resistance to treatment. The study found that, in response to some drugs, melanomas can 'break' parts of their BRAF gene, which is mutated in 1 in 2 melanomas. This helps the tumor create alternative versions of the protein which lack regions targeted by one BRAF inhibitors, one of the main drugs used to treat this type of cancer, making treatment less effective. The findings pave the way for alternative strategies to treat BRAF-mutated melanoma, which leads to relapse in 50% of patients within a one-year period. Melanoma is the deadliest form of skin cancer. With global incidence rates rising, new, more effective treatments are necessary to alleviate the health burden of the disease. Important advances in recent years include doctors using genetic tests to look for specific mutations they can target for more personalised, effective treatment. Around 1 in 2 melanoma patients will have mutations in the BRAF gene. This gene normally makes a protein which helps control cell growth, but mutations can cause the cells to grow and divide uncontrollably instead, happening in many different types of cancer including melanoma. The discovery of BRAF mutations has led to development of targeted therapies to inhibit its function. One of the standard treatment options for melanoma over the last ten years has been to simultaneously target both BRAF mutations and MEK. These two genes are part of the MAPK signalling pathway, which, in cancer, is rewired for uncontrolled growth. Targeting two different critical points in the same domino chain helps slow or stop cancer growth. Despite great initial responses to the combined use of the first-generation inhibitors, around 50% of melanoma patients with BRAF mutations will relapse within one year. The cancer acquires resistance to the drugs, finding other ways to reactive the MAPK pathway through mechanisms which remain poorly understood. "Melanoma drug resistance is a huge clinical problem because it occurs in almost all BRAF-mutated patients under BRAF/MEK inhibitor therapy and there are few or no therapeutic alternatives. There is an urgent need to understand the many different underlying mechanisms and find new strategies to deal with this constantly evolving arms race," says Dr. Francisco Aya Moreno, a medically-trained oncologist and recent PhD graduate at the Centre for Genomic Regulation (CRG) in Barcelona. A study published today in the journal Cell Reports has disentangled the mechanisms behind one of the ways cancer cells develop resistance to targeted therapy. The study found that, in response to treatment, melanomas can 'break' parts of their BRAF gene, also known as genomic deletions. This helps the tumour create alternative versions of the protein (altBRAFs) which lack regions targeted by BRAF inhibitors, reactivating the MAPK pathway and making the drugs less effective. The finding was consistent across various lab models and patient tumour samples. The findings are important because altBRAFs were thought to be made through alternative splicing, which is when cells use the same gene to synthesise different proteins. The discovery that genomic deletions, and not splicing, are the cause means a shift away from previous proposals for using drugs that target splicing as a therapeutic strategy. "For years, we've known that some patients produce altBRAFs and these help the cancer resist treatment, but we misunderstood the mechanism behind their creation. Knowing that genomic deletions are the cause opens new avenues for developing therapies that could more effectively help patients with BRAF mutations," explains ICREA Research Professor Juan Valcarcel, co-author of the study and researcher at the Centre for Genomic Regulation. Surprisingly, the researchers found evidence of the same genomic deletions in melanomas which hadn't been treated yet. In other words, melanomas can naturally develop mechanisms that mimic drug resistance, even without exposure to drugs. Identifying and targeting these early resistance mechanisms through profound genetic testing in a clinical setting before treatment begins could improve the efficacy of first-line therapies. Even more surprisingly, further analyses revealed that genomic deletions might be a more widespread mechanism of oncogenesis and resistance than previously thought. Though uncommon, researchers found evidence of altBRAFs in melanomas with a normal-functioning BRAF gene, as well as in other types of cancer including non-small cell lung cancer, breast cancer, kidney cancer and prostate cancer. The findings could increase the patient population benefiting from targeted treatments which are currently under clinical development. "There is an emerging class of drugs known as second generation RAF inibitors. Unlike BRAF inhibitors, these drugs have a broad spectrum, and so could potentially inhibit the function of altBRAFs. Clinical trials which are assessing their effectiveness should also expand to include melanoma patients with a normal functioning BRAF gene as well, and possibly to other cancer types which express altBRAFs," explains Dr. Aya Moreno. Dr. Aya Moreno is part of the second cohort of the PhD4MD programme, a joint effort by Centre for Genomic Regulation (CRG), the Institute for Research in Biomedicine (IRB Barcelona), the August Pi i Sunyer Biomedical Research Institute (IDIBAPS) and the Vall d'Hebron Research Institute (VHIR) designed to leverage the medical insight of a doctor to drive research that benefits patients. "Having the opportunity to approach this research with both a clinician's perspective and a scientist's curiosity has been invaluable. It allowed us to uncover not just how melanomas resist treatment but also how this knowledge could lead to more effective therapies for patients. This fusion of clinical insight and scientific investigation is crucial for making real progress in our fight against cancer," concludes Dr. Aya Moreno. The study was led by Dr. Aya Moreno and co-supervised by Professor Juan Valcarcel at the Centre for Genomic Regulation and Dr. Ana Arance at IDIBAPS. It was also carried out in collaboration with Nuria López Bigas' research group at IRB Barcelona. Since completing his PhD at the CRG, Dr. Aya Moreno has returned to the Medical Oncology department in the Hospital Clinic in Barcelona.

你最怕接到什么电话？大概是从医院打来的吧。生病就像随机摇号，谁也不知道哪天会摇到谁的头上。而生病后最残酷的现实是，你发现自己拼命存钱，却看不起病。腰包还没鼓，医疗账单却接踵而至。根据世界卫生组织（WHO）发布的《全球癌症统计数据2020》，2020年全球新发癌症病例为1929万例，其中印度新发癌症病例达到132万例，约占全球新发癌症病例的6.84%。2020年全球癌症死亡病例996 万例，其中印度癌症死亡人数为85万，死亡率高达64%。尽管印度的癌症发病率较低，但死亡率却相对较高。CAR-T细胞疗法是目前国际上治疗肿瘤的前沿免疫治疗方法，即从人体血液中提取T细胞，应用基因工程技术将其改造为能识别并消灭肿瘤的CAR-T细胞，再重新输入患者体内。体内的癌细胞理论上将会在一定周期内被清除掉。目前全球已上市的CAR-T细胞产品主要有以下几个：不完全统计  动脉网制图由于CAR-T细胞疗法价格高昂，许多患者望而却步。尽管印度自1949年起实行全民免费医疗，但由于其医疗体系尚不完善，穷人想要看病依旧很难，更别说接受治疗。此外，不少印度人的收入仅能维持日常生活开销，根本无法承受因轻微的不适而去医院所产生的额外费用。这使得许多印度人在面对癌症这一重大疾病时，往往选择忽视身体的警报，从而错失了早期治疗的良机。一家印度初创公司正试图解决这一难题。  “中心辐射”模式，CAR-T低至5万美元Immuneel Therapeutics（以下简称“Immuneel”）成立于2019年，总部位于班加罗尔。创始人包括印度制药巨头Biocon的创始人Kiran Mazumdar Shaw、肿瘤学家兼作家Siddhartha Mukherjee以及风投机构5AM Ventures的管理合伙人Kush Parmar。2022年6月，Immuneel宣布完成1500万美元A轮融资。本轮融资由Eight Roads Ventures、True North和F-Prime Capital共同领投，现有投资者跟投。融资所得资金将用于进一步开展临床试验和扩大生产规模。迄今为止Immuneel总融资金额约2800万美元。Immuneel的目标是以5万美元的价格（包括医院和医疗费用）在印度开发所有人可使用且负担得起的CAR-T疗法，这比Kymriah和Yescarta的美国价格低了近20-40倍。为此，Immuneel开发了一种低成本模型——基于对CAR-T细胞技术的授权许可(in-licensing)，致力于简化工程步骤以及在现行良好生产规范(cGMP)条件下培养患者细胞的过程。目前，CAR-T细胞药物尚且处于新药阶段，临床应用的病例数据有限。此外，CAR-T疗法的研发、贮存和管理等方面的成本极高。最重要的是，CAR-T疗法对适应症有严格的要求，要想应用在癌症患者身上，需“量身定制”才能使用。而这种个性化定制的方法往往会推高成本，并且耗费时间。那为何Immuneel能将CAR-T疗法的价格降低近20-40倍？Immuneel的创始人之一Mazumdar Shaw认为降低成本的关键在于简化供应流程。CAR-T疗法的成本中，相当大一部分实际上来自为患者提供供应链的费用。通过在供应链的各个环节上进行优化，形成“中心辐射”模式，可以显著降低成本。Mazumdar Shaw计划将这一低成本模型提供给“以付费服务模式”独立运营的医院，并在每家医院建立cGMP制造设施，由Immuneel团队为临床人员提供加工技术和培训。三位创始人都认为，这种新的商业模式将首先在印度试行，随后在其他国家推广，以进一步降低CAR-T疗法的成本。Mukherjee表示，他们希望利用当地在工程、制造和生产方面的专业知识来从根本上降低成本。此外，Immuneel的“中心辐射型”模型将会更节省时间。传统CAR-T疗法接受细胞改造的地点可能远离接受手术的患者所在的医疗中心。但Shaw表示，医院的生产计划将消除昂贵的物流成本，确保周转时间更短。对于已经用尽其他治疗方案且病重的患者而言，缩短获得治疗的时间可能意味着生与死之间的差异。  IMN-003A反应快速、深入且持久，安全性好Immuneel的首要任务是治疗血癌。其第一批开发项目是针对成人淋巴瘤、成人白血病和儿童白血病的单受体和双受体的CAR-T细胞疗法，用于治疗现有疗法失败的患者。Immuneel管线（图源：Immuneel官网）Varnimcabtagene autoleucel（IMN-003A）是一种新型CD19定向嵌合抗原受体T（CAR-T）细胞疗法，用于治疗急性淋巴细胞白血病（B-ALL）和非霍奇金淋巴瘤（B-NHL）等B细胞恶性肿瘤。2022年6月，Immuneel宣布已开始在一项名为"IMAGINE "的CAR-T试验中为患者配药。该试验包括24名儿童和成人癌症患者。Immuneel从西班牙巴塞罗那Clínic医院和Institut d'Investigacions Biomèdiques August Pi i Sunyer获得了ARI-0001/IMN-003A的独家代理权，通过技术转让在印度进行开发、生产和商业化。Immuneel表示，现有数据与美国FDA批准的CAR-T产品相比非常有利。同年12月，Immuneel宣布了Varnimcabtagene autoleucel（IMN-003A）的早期研究结果。该研究是印度首个针对复发/难治B细胞恶性肿瘤患者的新型自体CD19导向CAR-T细胞疗法的第二阶段试验。结果显示，IMN-003A在自体T细胞上转导的平均百分比为34.77%（范围15.49-58.35），中位数转基因拷贝/基因组为2.25（范围1.49-3.83）。IMN-003A CAR-T细胞在中位10d（范围10-14）显示出最大的PB扩增（Tmax）。在所有CAR-T扩张患者中均观察到b细胞再生障碍。说明在cGMP封闭系统中生产IMN-003A是可行且快速的，CAR-T扩增的高峰出现在中位输注10d，得到的中期响应较深。根据这些临床数据，该试验证明了Varnimcabtagene autoleucel的治疗反应快速、深入且持久，并表现出良好的安全性。与标准治疗方案相比，Varnimcabtagene autoleucel为印度复发/难治性B细胞恶性肿瘤患者提供了更显著的优势。未来，Immuneel的目标是提供非个性化、现成的细胞和基因药物。这些药物被称为异基因药物，将使用人类免疫细胞，而不使用患者自身的免疫细胞。免疫细胞治疗研发热度不减，中国位居全球第二据Nature报道，截至2022年4月15日，全球免疫细胞治疗药物共计2756种，较2021年2031种活性药物，仍维持36%的快速增长。图源：蛋壳研究院《2022免疫细胞治疗行业报告》据蛋壳研究院，中国研发数量位居全球第二，紧随美国。2021年，中国管线合计695项，增速47%超过美国（美国合计791项，增速40%）。进一步来说，2021年中国的商业研究数量增速高达74%，占比从51%快速增至60%（同期美国的商业研究数量增速为48%，占比83%）。图源：蛋壳研究院《2022免疫细胞治疗行业报告》自从2021年阿基仑赛注射液、瑞基奥仑赛注射液先后在中国获批上市，2022年西达基奥仑赛获美国FDA批准上市，2023年靶向BCMA CAR-T疗法的伊基奥仑赛注射液及靶向CD19的纳基奥仑赛注射液在中国纷纷获批上市，这表示CAR-T疗法已然进入井喷期。然而，CAR-T疗法药物仍无法摆脱“天价”标签。想靠患者自付打开市场，无异于天方夜谭。据有关媒体报道，合源生物的纳基奥仑赛国内定价99.9万元，这是目前国内价格最低的CAR-T疗法，打破了CAR-T疗法百万定价门槛。但这也仅仅只是药物本身的价格，加上治疗成本，患者的负担仍会进一步上升。虽然价格降至100万，但距离坐上医保谈判桌还有较大的差距。在2021年国家医保药品目录调整新闻发布会上，国家医保谈判药品基金测算专家组组长郑杰表示，按照限定的支付范围，目前国家医保目录内所有药品年治疗费用均未超过30万元。2022年进入医保的天价药诺西那生钠，价格从70万元被“灵魂”谈至3.3万元。价格过高，难以进入医保，商业保险的覆盖面有限，加之药物成本高，支付市场较小，以CAR-T疗法为代表的天价药，在国内到底该如何生存？这仍是需要各方去持续思考、解决的一个问题。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