Systemic Inflammatory Response Syndrome

点上方蓝字“ioncology”关注我们，然后点右上角“…”菜单，选择“设为星标”ELCC 2025 微专辑扫描二维码可查看更多内容在2025年欧洲肺癌大会（ELCC）上，ESMO前任主席、瑞士洛桑大学医院肿瘤科主任Solange Peters教授以“双特异性抗体和T细胞衔接器：对抗免疫荒漠”为题发表专题报告。《肿瘤瞭望》就这些创新疗法及当前免疫治疗领域的热点问题对Peters教授进行了独家专访。请谈谈双特异性抗体和T细胞衔接器在改善肺癌治疗方面的潜力。Dr. Peters：双特异性抗体同时针对两个靶点，令人惊讶的是，其疗效竟然优于两种单抗联合使用。需要记住，双特异性抗体的定义很广泛，这类药物靶向两种肿瘤相关抗原，但大多靶向两个免疫检查点，通过抑制或刺激免疫反应发挥抗肿瘤作用。例如，双特异性抗体的两个靶点可能是PD-1/PD-L1与CTLA-4，可能是VEGF与PD-1。这是一种免疫反应的调节剂（刺激或抑制）。2025 ELCC发布了首批靶向PD-1和LAG-3两种通路的双特异性抗体的数据（摘要7MO：Tobemstomig/含铂化疗对比帕博利珠单抗/含铂化疗一线治疗局部晚期或转移性NSCLC患者的II期临床研究）。我们希望联合PD-1和LAG-3治疗，理想情况下是使用双特异性抗体，或使用两种药物分别治疗。但罗氏研发的双特异性抗体Tobemstomig联合化疗对比帕博利珠单抗/化疗是阴性结果，所以以上概念可能并不成立。 目前尚不清楚CTLA-4/PD-1双特异性抗体为何比CTLA4单抗联用PD-1单抗更有效，可能是同步靶向两个免疫检查点可以增强肿瘤内部的协同效应，从而有效整合免疫反应的各个组成部分（向肿瘤细胞抗原呈递的细胞、T细胞衔接器等），我们希望这种机制产生作用，但尚缺乏研究数据支持。T细胞衔接器是不同作用机制的药物，它通过结合CD3激活T细胞，促进其细胞增殖并分泌细胞因子。这是T细胞的启动过程。T细胞衔接器不依赖于预先存在的免疫反应。虽然T细胞衔接器可能引发一些副作用，例如细胞因子释放综合征（CRS）和免疫效应细胞相关神经毒性综合征（ICANS），但它为针对性治疗策略带来了巨大的希望，通过激活T细胞并招募免疫细胞大军来攻击肿瘤。制药行业正在针对这类药物进行大量研发，临床试验覆盖多种肿瘤和疾病不同阶段，其中200个双特异性抗体正在II期临床试验阶段。（上下滑动可查看）Dr. Peters: My name is Solange Peters. I am Director of Oncology at the University Hospital of Lausanne in Lausanne, Switzerland.First of all, it is quite surprising to see how a bispecific with two targets might potentially be more active than two drugs together. Remember, bispecifics define many things. You could target two tumor-associated antigens, but most of these bispecifics target two checkpoints, inhibitory or stimulatory. For example, PD-1 and PD-L1/CTLA4, VEGF/PD-1 – modulators of the immune response, stimulatory or not. Why does it work better to give a bispecific CTLA4/PD-1 compared to giving both drugs together? We still don’t know. We think that when you target two checkpoints, you may promote collaboration within the tumor to bring together components of the immune response – antigen presenting cells to tumor cells, and T-cell engagers in the immune response. We hope it will work. Do we have data? Yes and no. Today, we saw the first data on a bispecific targeting PD-1 and LAG-3, two pathways. We would like to combine them together, ideally as a bispecific or maybe one-by-one, but the bispecific from Roche has failed already with chemotherapy versus chemo/pembrolizumab. So, we think maybe the whole concept is not valid. T-cell engagers are completely different. They activate T-cells by binding onto CD3 making the cell proliferate and produce cytokines. It is a switching on of the T-cells. You don’t need a pre-existing immune response. There are some side effects like CRS (cytokine release syndrome) and some ICANS (immune effector cell-associated neurotoxicity syndrome), but it brings wonderful hope for a specifically targeted therapy. Activating T-cells creates an army of immune cells against the tumor. The amount of further developments by the pharmaceutical industry is huge. Across diseases and various phases of clinical trials, we currently have around 200 bispecifics in clinical trials in phase II.关于晚期非小细胞肺癌的免疫治疗，仍存在一些未解之谜。例如，对于伴有致癌驱动基因的晚期非小细胞肺癌治疗，是否应该排除免疫治疗？Dr. Peters：这个问题的核心在于明确免疫检查点抑制剂（ICI）在伴致癌驱动基因晚期非小细胞肺癌（NSCLC）中的有效性。首先，我们应该谨慎地看待已知信息（我们所知最多的是将EGFR和ALK阳性肺癌系统性地排除在免疫治疗之外），而EGFR和ALK两个靶点非常重要。ALK：免疫检查点抑制剂在ALK阳性肺癌中的活性非常低，也没有任何令人信服的疗效数据，我确实不会为这类患者开免疫疗法的处方。RAF1和MEK相比ALK的研究更少，这类肺癌的特点也是免疫原性极低、PD-L1表达低以及肿瘤突变负荷（TMB）低。与ALK家族一样，RAF1和MEK也不适合免疫治疗。EGFR：免疫治疗是否适用于EGFR突变型肺癌，并非非黑即白的问题。来自中国台湾的Gee-Chen Chang教授一直告诉我，免疫疗法对EGFR突变体有一定的治疗活性，可能需要将其留到后线治疗与化疗/抗血管生成药物联用。当免疫疗法与化疗联用不足以产生效果时，联用抗血管生成药物可提升疗效并产生获益（例如IMpower150、ATTLAS和HARMONi-8研究）。因此，当免疫疗法联用其他疗法（抗血管生成药物，未来可能联用双特异性抗体或T细胞衔接器）时，在EGFR突变型肺癌治疗中仍有应用价值。我认为免疫疗法在这类患者中是有发展空间的。其他靶点：KRAS G12C变异对免疫疗法非常敏感。如果患者是吸烟者，且携带BRAF和MET外显子14，患者可能也会对免疫治疗敏感，而非吸烟者则不那么敏感。因此，在伴有EGFR/ALK以外的其他致癌驱动基因时，免疫疗法可能在一线治疗中没有用武之地，但临床医生需要与医疗机构和患者进行知情讨论，因为目前尚不清楚免疫治疗能否产生影响。（上下滑动可查看）Dr. Peters: The question is how much is immunotherapy valid in the oncogenic addiction setting of advanced NSCLC. First of all, I think you need to be very cautious about what we know. What we know the most is the systematic exclusion of EGFR and ALK. These are the two important targets. For ALK, we have seen very little activity and haven’t seen any convincing data that immune checkpoints are valid in ALK-positive disease. I would really not prescribe in this disease setting. Similar to ALK and even less studied, RAF1 and MEK are also diseases with very low immunogenicity, low PD-L1, low mutational burden. We know that with the ALK family, RAF1 and MEK are the same types of tumors, but EGFR is not so black and white. My colleague from Taiwan, Gee-Chen Chang keeps telling me that it has some activity in EGFR mutant, but you probably need to keep it in reserve for late lines in combination with chemo and probably antiangiogenics. When combining with chemo is not sufficient to make a difference, in IMpower150, in ATTLAS, in HARMONi-8, giving an anti-angiogenic gives rise to a benefit. So, there is room for immunotherapy in EGFR when you combine immunotherapy and something else, maybe an anti-angiogenic, or maybe another bispecific in the future, maybe T-cell engagers too. I think there is room in this setting. Remember that KRAS G12C is very sensitive to immunotherapy. When you are a smoker with BRAF and MET exon 14, you might be sensitive too, less for non-smokers. So, in other oncogenic settings, maybe not useful in frontline, but you need to have this informed discussion with your institution and your patient because it is not clear that it has no impact.晚期非小细胞肺癌患者何时可以或应该停止抗PD(L)-1药物治疗？免疫疗法的“最佳疗程”是多久？Dr. Peters：免疫治疗的停止时机仍存在争议。很多国家的患者别无选择，因为大多数晚期肺癌免疫治疗的临床试验通常设定2年为治疗期限，因此医疗报销到时停止，患者只能停药。然而，有些国家不考虑这个问题，可支付持续治疗的费用。KEYNOTE-024和KEYNOTE-189模拟了接受2年免疫治疗后停药的患者与继续治疗患者的长期结局。若肺癌完成2年免疫治疗后停药，病情得到控制，仍有超50%的患者会在后续3年内复发；如果对复发速度进行模拟，免疫停药后可能存在"复发加速"现象，因此疾病进展的风险会增加，这一现象值得临床医生与患者进行讨论。目前尚不清楚持续免疫治疗能否改变这些动力学数据，但可能性很高（50%是很高的概率）。虽然无法确定延长免疫治疗能否阻止上述不利情况，但医患共同决策很重要。基于个人经验，我的大多数患者更倾向持续治疗直到疾病进展，而非主动停药。（上下滑动可查看）Dr. Peters: The time to stop immunotherapy is a matter of debate. Basically, in many countries, you have no choice. Most of the trials stopped at three years, so reimbursement stops at three years. But some countries don’t look at it and can afford to continue. Otherwise, we don’t know. We simulated from the KEYNOTE-24/KEYNOTE-189 what would happen after stopping versus if you continued. If you stop at two years and the patient is controlled, more than 50% will relapse in the next three years. If you simulate the pace of relapse, it looks like an acceleration. When you stop, there is an acceleration in simulations, so an increased risk of progression. This is what you need to discuss with your patient. I don’t know if continuing will change these kinetics, but you need to know that there is a high probability (50% is a high probability). I don’t know that continuing would prevent it, but you can make that decision together. In my experience, most of my patients continue until they experience progression, but most of my patients don’t want to stop.在2025 ELCC报道的胸部肿瘤研究中，您认为哪些研究会对临床实践产生重大影响？Dr. Peters：我非常欣赏此次会议的内容，因为2025 ELCC展示的一系列II期临床试验为解决耐药和探索生物学机制提供了新机遇。2025 ELCC发布了一系列令人惊叹的靶向疗法研究数据，例如在KRAS抑制领域，我们获得了更多关于调节KRAS抑制的信息。2025 ELCC最重要的讨论是对于EGFR突变NSCLC患者，如何通过MARIPOSA方案延长生存期，尽管毒性增加带来挑战。此外，对于发生MET扩增（一种常见耐药机制）的患者，如何使用埃万妥单抗（amivantamab）靶向治疗来解决问题。我认为，EGFR突变NSCLC治疗正在重新定义，这非常重要。在瑞士，EGFR突变阳性肺癌的占比相对较低，但在亚洲这类患者约占一半，因此这一话题具有非常重要的临床意义。2025 ELCC发布的关键信息将重新定义EGFR突变NSCLC治疗，推动共识和指南的更新，进一步优化EGFR突变NSCLC的一线及后线治疗策略。（上下滑动可查看）Dr. Peters: This is a Congress that I like because they present some phase II trials, new opportunities for addressing resistance, of addressing biological questions. I think we have seen today an amazing range of targeted therapies. KRAS inhibition - how you can modulate KRAS inhibition. The most important debate we had at this meeting was how to prolong the life of EGFR mutated patients with the improvement in survival of MARIPOSA, although toxicity is a challenge. MET amplification – this is often encountered, and how to address it with targeted therapy with amivantamab. I think we are redefining these diseases, which is extremely important. I am from Switzerland where it is not so important, but this is half of the patients in Asia, so it is a hugely important topic. I think this meeting has been key in trying to redefine the journey of these patients with EGFR mutants. If I had to pick one key message, with redefinition, we need to work on consensus and guidelines, what to do first, and what to do next in EGFR mutant NSCLC.《肿瘤瞭望》在ELCC现场报道（来源：《肿瘤瞭望》编辑部）声 明凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

The first shards of human data on in vivo CAR-T cell therapy look promising, based on recent separate reports from two biotech companies’ academic-led studies in China. Last week, a Chinese startup called Genocury became the second company to share initial clinical data on a CAR-T treatment that doesn’t require a patient’s cells to be extracted from their body. Genocury said that an advanced large B cell lymphoma patient went into complete remission after one month of in vivo CAR-T therapy, and has remained in remission for over three months. Notably, the in vivo CAR-T therapy does not require lymphodepletion, a course of chemotherapy that conventional CAR-T therapies require before treatment and that comes with toxicities. “This is good news for the field and demonstrates the increasing momentum around in vivo CAR-T approaches,” said University of Pennsylvania CAR-T pioneer Bruce Levine, who isn’t involved in Genocury’s studies but is a scientific founder of another in vivo CAR-T company called Capstan. Last week’s results follow Belgian startup EsoBiotec’s announcement in January that a multiple myeloma patient who received the lowest dose of its in vivo CAR-T therapy had no detectable cancer cells in their bone marrow at one month, without any significant adverse events during treatment. That patient also did not receive prior lymphodepletion. The data from both companies come from investigator-initiated studies in China, which biotech startups have been leveraging more frequently to quickly generate early clinical data on their experimental treatments. EsoBiotec is working with Pregene Biopharma which, like Genocury, is based in Shenzhen. In March, AstraZeneca announced plans to acquire EsoBiotec for $425 million, plus additional payments. At least five groups have begun clinical trials for in vivo CAR cell therapies. Aside from EsoBiotec and Genocury, Myeloid Therapeutics, Interius BioTherapeutics and Umoja Biopharma are all studying experimental in vivo cell therapies in patients. In conventional CAR-T therapy, a patient’s cells are extracted, engineered, and then reinfused — a complex, expensive process that can take weeks to months. The therapy, while transformative for certain blood cancers, comes with safety risks from the lymphodepletion before treatment and immune overreaction (cytokine release syndrome and ICANS) afterwards. And so far, comparatively less complex “off-the-shelf” treatments using donor cells have yet to take off. Makers of in vivo cell therapy hope that their treatments can become a different kind of “off-the-shelf” option. Their therapies deliver genetic material to turn the patient’s immune cells into cancer-fighting ones directly in the body. The companies are using different technologies to deliver their treatments and are also going after a range of diseases. The delivery technologies fall into two camps: viral and non-viral. Researchers have more concerns around the potential risks of a virus-based therapy, including of secondary cancer, but it’s an older and more proven approach. Non-viral delivery is newer and more challenging, and fewer companies have reached clinical studies. It is unclear based on Genocury’s disclosures whether it is using a viral or non-viral approach. A photo on its website mentions both viral and non-viral methods, and the company could not be reached for comment. EsoBiotec is developing a lentiviral-based cell therapy that goes after BCMA, a well-known target for multiple myeloma. Interius, which expects to report clinical data later this year, and Umoja are likewise studying lentiviral-based therapies. Umoja, like Genocury, is developing a CD19-targeted CAR-T therapy for blood cancer, and it plans to study the treatment in autoimmune disease as well. AbbVie has an option to license that therapy, and in January the startup raised $100 million to jumpstart its clinical studies. Interius’ therapy targets another immune cell protein called CD20, and it’s studying its B cell cancer therapy in both Australia and Germany. The Philadelphia biotech’s therapy is meant to make both ​​CAR-T and NK cells directly in the body. On the other hand, Sid Mukherjee’s startup Myeloid is using mRNA delivered non-virally. It uses fatty acid envelopes called lipid nanoparticles — similar to what’s used in the Covid vaccines. However, as its name suggests, it’s targeting a type of immune cell called myeloid cells. It has two programs in the clinic going after solid tumors — an area of cancer that conventional CAR-T therapies have yet to crack.

点上方蓝字“ioncology”关注我们，然后点右上角“…”菜单，选择“设为星标”ELCC 2025 微专辑扫描二维码可查看更多内容在2025欧洲肺癌大会（ELCC）上，北爱沙尼亚医疗中心肿瘤内科医生、欧洲肿瘤内科学会（EORTC）肺癌组成员、欧洲肿瘤内科学会（ESMO）科学委员会成员Kersti Oselin作报告《小细胞肺癌的新型疗法和靶向治疗通路》，并接受《肿瘤瞭望》现场专访。Kersti Oselin教授在报告中总结了小细胞肺癌（SCLC）治疗的最新进展，聚焦新型治疗策略与靶点，指出抗体药物偶联物（ADC）、T细胞激活疗法（如BiTE、TriTAC）和抗血管生成药物（VEGF抑制剂）是有望进入临床的疗法。ADC药物的临床试验数据TROP-2靶向：TROPiCS-03试验中，戈沙妥珠单抗（sacituzumab govitecan，SG）二线治疗广泛期小细胞肺癌（ES-SCLC）的客观缓解率（ORR）为41.9%，中位总生存（OS）达13.6个月（WCLC2024，OA04.04）。中国学者研究的TROP-2靶向ADC药物SHR-A1921也在既往经治ES-SCLC患者中显示出令人鼓舞的疗效，中位随访时间5.3个月时，在15例可评估肿瘤反应的患者中，ORR为 33.3%，中位缓解持续时间（DoR）为 4.4 个月。在所有患者中，中位无进展生存（PFS）为 3.8 个月（WCLC 2024, OA04.05）。B7-H3靶向：II期IDeate-Lung01试验中期分析显示，在12mg/kg和8mg/kg剂量组中，ifinatamab deruxtecan（I-DXd）治疗复发性转移性ES-SCLC患者的ORR分别为54.8%和26.1%，中位OS分别为11.8个月和9.4个月（WCLC 2024，OA04.03）。在I期ARTEMIS-001研究中，靶向B7-H3的ADC药物HS-20093采用8.0mg/kg剂量的ORR为61.3%，采用10.0mg/kg剂量的中位PFS为7.3个月（WCLC 2024，OA04.06）。SEZ6靶向：I期首次人体研究显示，ABBV-011用于复发/难治性SCLC患者在1mg/kg剂量扩增阶段（n=40）的ORR为25%（Morgensztern et al. Clin Cancer Res 2024;30:5042–52）。经治广泛期小细胞肺癌的ADC治疗数据挑战：当前研究多为小样本、非对照试验，缺乏可以筛选患者的生物标志物，未能明确靶点表达水平与疗效的关联。T细胞激活疗法（DLL3靶向）Delta样配体3（DLL3）是一种在小细胞肺癌中高表达的蛋白质，是T细胞介导最有前景的靶点。Rovalpituzumab tesirine（Rova-T）是最早进入临床的DLL3靶向药物，这种ADC的临床研发已终止。其他靶向DLL3的新型药物包括双特异性T细胞接合剂（BiTE）和三特异性T细胞活化蛋白构建体（Tri-Tac）。DLL3也是CAR-T细胞治疗的主要靶点。BiTE药物：Tarlatamab是一种靶向SCLC细胞上DLL3的BiTE药物。Ib期DeLLphi-303研究中，Tarlatamab联合PD-L1抑制剂作为ES-SCLC一线维持治疗的中位PFS为5.6个月，9个月OS率88.9%（WCLC 2024, OA10.04）。Obrixtamig（BI764532）是另一款靶向DLL3的BiTE药物，目前处于临床开发阶段。TriTAC药物：目前在SCLC治疗展现前景的药物包括HPN328（MK-6070）等。小结：多种靶向DLL3的BiTE疗法正在临床开发中。细胞因子释放综合征是50%患者的主要治疗相关不良事件（TRAE），大多为1-2级且可控。抗血管生成治疗（VEGF抑制剂）III期BEAT-SC试验中，化疗+阿替利珠单抗基础上加用贝伐珠单抗未显著改善ES-SCLC患者的OS（Ohe Y, et al. J Clin Oncol 2024;42(suppl):Abstr 8001）。III期ETER701试验中，安罗替尼+贝莫苏拜单抗（PD-L1单抗）+依托泊苷/卡铂（EC）一线治疗ES-SCLC的中位OS达19.3个月，相比对照组（安慰剂+依托泊苷/卡铂）延长了7.4个月，显著降低死亡风险39%（Cheng Y et al. Nature Medicine 2024;2967）。Ib期试验结果显示，依沃西单抗联合EC化疗一线治疗ES-SCLC的ORR为80%（JTO February 2025, P233-239）。总结ES-SCLC一线维持治疗：EP化疗+PD-(L)1抑制剂+研究药物方案展现前景，在ETER701试验中，安罗替尼+贝莫苏拜单抗的中位OS达19.3个月；经治ES-SCLC：Tarlatamab基于II期非对照DeLLphi-301试验结果已获FDA批准，中位OS为17.5个月；经治复发/难治ES-SCLC：小型非对照I-II期研究中，新型药物的ORR为30%-60%，中位PFS为4-7个月（靶点为TROP2、B3-H7、SEZ6、DLL3）。哪些新型药物和疗法在小细胞肺癌治疗中最有前景，有望进入临床治疗？Dr. Oselin：我们对小细胞肺癌的研究进展感到兴奋。在历经诸多治疗失败后，我们终于看到了隧道尽头的曙光。在我的报告中，我重点梳理了去年及今年初发表的研究结果和演讲报告。我讨论的主要治疗类别是抗体药物偶联物（ADCs）、各类T细胞活化机制以及血管内皮生长因子受体（VEGFR）相关疗法。当然，这三类疗法并非小细胞肺癌独有，在非小细胞肺癌领域也有相关研究，但两种疾病的靶点选择存在差异。 （上下滑动可查看）Dr. Oselin: I am Kersti Oselin. I am a medical oncologist from North Estonia Medical Center in Tallinn, Estonia. I have been a member of the EORTC Lung Cancer Group, and also a member of ESMO for over ten years. It is my great pleasure to be part of the ESMO Scientific Committee and to contribute to the European Lung Cancer Conference.I think everyone is a bit excited at the moment. After so many failures in the treatment of small cell lung cancer, there seems to be light at the end of the tunnel. In my presentation, I tried to focus on the latest publications and presentations from last year and earlier this year. I think the main therapeutic classes we are discussing are ADCs, various mechanisms of T-cell activation and maybe the VEGFRs. These are three main therapeutic classes. Of course, they are not unique to small cell lung cancer. We can talk about the same classes for non-small cell lung cancer, but for SCLC, we have slightly different targets.请谈一谈广泛期小细胞肺癌治疗的未来研究方向。Dr. Oselin：当ES-SCLC患者一线治疗进展后，疾病基因组的异质性会加剧，治疗难度也会更大。因此，如果必须做出选择，我认为ES-SCLC的未来治疗方向是强化一线治疗——无论是一线采用化疗-免疫联合治疗后接续免疫联合维持治疗，还是替换现有疗效欠佳的一线免疫方案。 为了显著改善疗效，我们必须聚焦一线治疗。铂类化疗的问题不在于患者对药物没有反应（多数患者反应良好），而在于复发后疾病性质改变，进而导致治疗难度加大。我将希望寄托于强化一线治疗方案以提升疗效。（上下滑动可查看）Dr. Oselin: Once patients have already progressed on first-line treatment, the disease is even more genomically heterogenous, and likely very difficult to treat. So, if I needed to choose, I think the way forward is to intensify first-line treatment, whether it is in combination with chemo-IO followed by IO combinations in the maintenance setting, or replacing the current already less effective IO upfront. To significantly improve outcomes, we need to focus on first-line. The problem with platinum-based chemotherapy is not that the patients don’t respond (the majority respond very well), but when they relapse, it is a different disease and more difficult to treat. I would rather put my hopes on intensifying and improving outcomes in the first-line setting.（来源：《肿瘤瞭望》编辑部）声 明凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。