This study is a single arm, phase II pilot design. The study will evaluate the safety and efficacy of intralesional immunotherapy (e.g. IL-2) in early stage TNBC. The overall objective of the research study is to advance our knowledge of novel immunotherapies and routes of administration for the treatment of TNBC
HYPOTHESES: Neoadjuvant treatment of TNBC with intralesional IL-2 is safe and well tolerated and can produce a pathological response.
Aim 1: Examine the safety and possible efficacy of a novel neoadjuvant intralesional intervention (IL-2) for patients with early-stage TNBC.

开始日期2026-01-02

申办/合作机构

Nova Scotia Health Authority

NCT06626256

/ Not yet recruiting临床1期IIT

A Phase 1 Safety and Efficacy Study of STIL101 for Injection in Locally Advanced, Unresectable, or Metastatic Pancreatic Ductal Adenocarcinoma, Colorectal Cancer, Renal Cell Carcinoma, Cervical Cancer, and Melanoma

This phase I trial tests the safety and side effects of STIL101 for injection and how well it works in treating patients with pancreatic cancer, colorectal cancer (CRC), renal cell cancer (RCC), cervical cancer (CC) and melanoma that has spread to nearby tissue or lymph nodes (locally advanced) or to other places in the body (metastatic) or that cannot be removed by surgery (unresectable). STIL101 for injection, an autologous (made from the patients own cells) cellular therapy, is made up of specialized white blood cells called lymphocytes or "T cells" collected from a piece of the patients tumor tissue. The T cells collected from the tumor are then grown in a laboratory to create STIL101 for injection. STIL101 for injection is then given to the patient where it may attack the tumor. Giving chemotherapy, such as cyclophosphamide and fludarabine, helps prepare the body to receive STIL101 for injection in a way that allows the T cells the best opportunity to attack the tumor. Aldesleukin is a form of interleukin-2, a cytokine made by leukocytes. Aldesleukin increases the activity and growth of white blood cells called T lymphocytes and B lymphocytes. Giving STIL101 for injection may be safe, tolerable and/or effective in treating patients with locally advanced, metastatic or unresectable pancreatic cancer, CRC, RCC, CC and melanoma.

开始日期2025-04-30

申办/合作机构

City of Hope National Medical Center

[+1]

NCT06690281

/ Not yet recruiting临床2期IIT

A Phase II Study of Adjuvant Immunotherapy Targeting KRAS G12D, KRAS G12V, or TP53 R175H for Participants With Advanced Gastrointestinal Malignancies

Background:
Gastrointestinal (GI) cancer affects the organs (such as the stomach, large and small intestine, pancreas, colon, liver, and biliary system) of the digestive tract. In some participants who have had surgery for GI cancer, blood tests show that the cancer has spread despite being unable to be identified by scans. Certain gene mutations (changes) in GI cancer (such as KRAS or TP53) can be targeted by T cells, a type of immune cell, in individuals with specific HLA types (genes that help proteins in the body know what is self and non-self). Researchers want to see if they can stop GI cancer from returning or spreading in people with these gene mutations and specific HLA types.
Objective:
To test therapy with modified T-cells to prevent or delay the return of GI cancer after standard treatment. T-cells play a role in the body s immune system.
Eligibility:
People aged 18 to 72 years with GI cancer that was treated with standard therapy and is not seen on imaging scans. They must have specific gene mutations and HLA types. They also must have certain clinical or blood tests showing the cancer is spreading (elevating CA19-9 or detectable ctDNA).
Design:
Participants will be divided into 2 groups. Participants nor the study team can choose what Group to participate in; this is done by randomization , like flipping a coin. Participants will have a 1-to-1 chance of being in Group 1 or Group 2.
Group 1 will receive T-cell therapy. Their own T-cells will be collected. In a lab, the cells will be combined with a virus that carries a protein to target cancer cells.
Group 1 participants will stay in the hospital for 3 weeks or more. They will have chemotherapy, and their modified T-cells will be infused through a tube attached to a needle inserted into a vein.
Group 1 participants will visit the clinic every 3 months for 1 year and then every 6 months for 5 years. Then they will have follow-up visits for another 10 years under a different protocol.
Group 2 participants will not receive treatment with T-cells. They will visit the clinic every 3 months for 1 year and then every 6 months for 5 years.

开始日期2025-02-24

申办/合作机构

National Cancer Institute

100 项与阿地白介素相关的临床结果

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100 项与阿地白介素相关的转化医学

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100 项与阿地白介素相关的专利（医药）

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3,046

项与阿地白介素相关的文献（医药）

2025-01-01·Journal for ImmunoTherapy of Cancer

Art of TIL immunotherapy: SITC’s perspective on demystifying a complex treatment

Review

作者: Marie Svane, Inge ; Rohaan, Maartje W ; Yang, James C ; Creelan, Benjamin ; Donia, Marco ; Lotze, Michael T ; Besser, Michal ; Sondak, Vernon K ; Mullinax, John ; Turcotte, Simon ; Gastman, Brian ; Haanen, John B A G ; Coukos, George ; Goff, Stephanie L ; Brown, Robert

In a first for solid cancers, cellular immunotherapy has entered standard of care in the treatment of patients with metastatic melanoma. The infusion of autologous tumor-infiltrating T lymphocytes (TIL) is capable of mediating durable tumor regression and is now Food and Drug Administration-approved for patients with disease refractory to immune checkpoint inhibitors. Since the advent of chimeric antigen receptor (CAR) T cells for patients with hematological malignancies, a growing network of centers capable of delivering effector T cell products to patients has developed. Administration of TIL can be layered onto that institutional framework, but there are many complex and unique aspects to TIL immunotherapy. The highly multidisciplinary clinical expertise and coordination required to successfully and safely deliver TIL to patients began within the National Cancer Institute Surgery Branch and have been subsequently adopted worldwide. The general steps, most of which require hospital inpatient resources, include a surgical procedure to harvest sufficient tumor for TIL manufacturing, admission for non-myeloablative lymphodepleting chemotherapy followed by TIL, and intravenous interleukin-2 (IL-2, aldesleukin). Here, we provide the principles, practice, and required resources underlying the efficient and safe delivery of TIL immunotherapy derived from the clinical expertise of high-volume centers around the world. This article enhances published clinical practice guidelines by providing underlying clinical rationale and data-driven examples to demystify TIL immunotherapy in order to facilitate uptake and improve patient access to this promising treatment modality in clinical and research settings.

2024-12-31·mAbs

Discovery and development of ANV419, an IL-2/anti-IL-2 antibody fusion protein with potent CD8+ T and natural killer cell-stimulating capacity for cancer immunotherapy

Article

作者: Regnier, Catherine ; Rondeau, Jean-Michel ; Popp, Simone ; Katopodis, Andreas ; Egli, Nicole ; Huber, Christoph ; Richter, Kirsten ; Murer, Patrizia ; Petersen, Laetitia ; Brannetti, Barbara

Novel engineered IL-2 agonists strive to increase the therapeutic window of aldesleukin (human IL-2) by increasing selectivity toward effector over regulatory T cells and reducing dose-limiting toxicities. Here we describe ANV419, an IL-2/anti-IL2 antibody fusion protein designed for selective IL-2 receptor βγ (IL-2 Rβγ) activation by sterically hindering IL-2 from binding to IL-2 Rα. The fusion protein has an IL-2 connected to the light chain complementarity-determining region (CDR) domain of a humanized antibody that binds to IL-2 at the same epitope as IL-2 Rα. Optimization of the selectivity and pharmacological properties led to the selection of ANV419. ANV419 preferentially expands CD8⁺ T cells and natural killer (NK) cells over T_regs and can be safely administered at doses that elicit strong pharmacodynamic effects and efficacy in mouse tumor models. Its anti-tumor efficacy was enhanced when combined with programmed cell death protein 1 (PD-1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) checkpoint inhibitors. ANV419 also enhances the NK cell killing capacity and increases tumor growth inhibition when used alongside trastuzumab in a Her-2⁺ xenograft mouse model. In cynomolgus monkeys, the estimated half-life of ANV419 is 24 h, and doses that induced sustained expansion of effector cells were well tolerated without the severe toxicities typically observed with high-dose IL-2. These data support the clinical development of ANV419 in solid tumors and hematological malignancies as monotherapy and in combination with checkpoint inhibitors or agents that induce antibody-dependent cellular cytotoxicity. ANV419 is currently in Phase 1/2 clinical development and may provide cancer patients with a wider therapeutic window than aldesleukin.

2024-12-09·Journal of Immunotoxicology

Type 2 responses determine skin rash during recombinant interleukin-2 therapy

Review

作者: Dehmel, Susann ; Gogesch, Patricia ; Neuhaus, Vanessa ; Sommer, Charline ; Flandre, Thierry ; Sewald, Katherina

The skin is the organ most often affected by adverse drug reactions. Although these cutaneous adverse drug reactions (CADRs) often are mild, they represent a major burden for patients. One of the drugs inducing CADRs is aldesleukin, a recombinant interleukin-2 (recIL-2) originally approved to treat malignant melanoma and metastatic renal cell carcinoma which frequently led to skin rashes when applied in high doses for anti-cancer therapy. Skin rashes and other side effects, together with poor efficacy led to a drawback of the therapeutic, but modified recIL-2 molecules are on the rise to treat both cancer and inflammatory diseases such as autoimmunity. Still, pathophysiological mechanisms of recIL-2-induced skin rashes are not understood. In the study reported here, a hypothetical literature-based immune-related adverse outcome pathway (irAOP) was developed to identify possible key cells and molecules in recIL-2-induced skin rash. Using this approach, a hypothesis was formed that the induced immune response predominantly is Type 2-driven by T-helper and innate lymphoid cells, leading to the occurrence of cutaneous side effects during recIL-2 therapy. This paper further discusses mechanisms beyond the proposed irAOP which might add to the pathology but currently are less-studied. Together, this hypothetic irAOP forms a basis to clarify possible cellular and molecular interactions leading to recIL-2-induced skin rash. This might be used to adapt existing or develop new test systems to help predict and prevent cutaneous side effects in future IL-2-based or similar therapies.

117

项与阿地白介素相关的新闻（医药）

2025-01-23

·药事纵横

头对头K药，信达生物剑指药王

1月22日，信达生物在CDE药物临床试验登记与信息公示平台网站上，登记了一项与K药头对头比较的II期临床试验CTR20250280。该项临床旨在评估IBI363单药对比帕博利珠单抗在晚期黑色素瘤患者中的有效性和安全性，预计入组人数180例。 IBI363为信达开发的全球首创PD-1/IL-2α双特异性抗体融合蛋白，目前在非小细胞肺癌和黑色素瘤治疗上均显示了不俗的治疗结果。IL-2作为免疫刺激和免疫抑制双重机制靶点，在肿瘤的治疗中潜力巨大。（一）IL-2靶点简介 IL-2是免疫系统的关键调控因子，其在免疫刺激和免疫抑制过程中均发挥重要作用。IL-2主要由抗原活化的CD4+ T细胞分泌，其他免疫细胞，如CD8+ T细胞、自然杀伤（natural killer, NK）细胞以及活化的树突状细胞也可分泌IL-2分子。IL-2与IL-2Rβγc或IL-2Rαβγc结合后，启动信号转导。其信号转导过程主要通过3条通路完成：(1) Janus kinase (JAK)/STAT；(2) phosphoinositide 3-kinase (PI3K)/AKT；(3) MAPK信号通路。图：IL-2信号转导通路数据来源：生物工程学报 IL-2分子对免疫系统刺激具有两面性，一方面它能促进效应T细胞的增殖，驱动增强T细胞的抗癌活性；但另一方面，IL-2也同时促进调节性T细胞（Tregs）的生长，该T细胞可在一定程度上协助肿瘤细胞逃避效应性T细胞的攻击，且在大剂量使用IL-2时，会引发致命的⾎管渗漏综合征和其它副作用。实际上，早在上世纪，Chiron Corporation公司的阿地白介素（aldesleukin）已被FDA批准上市，用于转移性肾癌及黑色素瘤的治疗，但其剂量限制性毒性(包括⾎管渗漏综合征)限制了其广泛应用。近年来，随着一批IL-2药物陆续被收购，IL-2的关注度空前提高。（二）IL-2领域的重磅收购近年来，IL-2领域屡现重磅收购。早在2017年，礼来便与Nektar Therapeutics就NKTR-358达成4亿美元的交易，获得NKTR-358的全球权益。此外，礼来愿意分摊75%该产品II期SLE适应症开发的费用并承诺承担其商业化的全部成本。 2018年，百时美施贵宝（BMS）与Nektar Therapeutics宣布为Nektar领先的免疫肿瘤学项目NKTR-214进行全球战略开发和商业化合作。在这次合作下，两家公司将共同开发和推广NKTR-214与百时美施贵宝的Opdivo（nivolumab）和Opdivo＋Yervoy（ipilimumab）在9种肿瘤类型20多种适应症中的联合应用，以及与来自这两家公司或第三方的其它抗癌药物的组合。根据协议条款，百时美施贵宝将支付18.5亿美元的预付款，Nektar将有资格额外获得17.8亿美元的里程碑付款。 2019年，赛诺菲宣布以25亿美元现金收购Synthorx，以加强其免疫肿瘤产品组合。Synthorx的主要免疫肿瘤学产品THOR-707是白介素2（IL-2）的改良版，作为单物或与免疫检查点抑制剂联用，用于治疗多种实体瘤。 2022年9月，Good Therapeutics宣布，已经与罗氏（Roche）达成交易协议。根据双方的协议约定，罗氏将获得Good Therapeutics公司的创新、条件性活化、由PD-1调节的IL-2项目，以及通过公司平台技术开发PD-1调节的IL-2受体激动剂疗法的专属权利。根据协议条款，罗氏将支付2.5亿美元的预付款，并将根据预定的开发、监管和商业里程碑的实现情况进行额外支付。表：IL-2领域的重磅收购数据来源：药智网（三）IL-2领域药物研发受阻但IL-2的研发进展并不顺利，礼来已退回NKTR-358的全部开发权益。2023年2月23日，Nektar宣布NKTR-358治疗系统性红斑狼疮（SLE）患者的II期ISLAND研究未达到主要终点。对于该研究失败的结果，礼来表示将放弃推进NKTR-358治疗SLE的III期临床开发计划并寄希望于即将推进至IIb期的特应性皮炎适应症。同年4月，Nektar Therapeutics在SEC文件中披露礼来已决定退回IL-2疗法Rezpegaldesleukin（NKTR-358）的全部开发权益。 BMS和Nektar已终止推进IL-2的研发。经过四年研发后，在2022ESMO上，Opdivo联合NKTR-214折戟于多项适应症，包括肾癌、黑色素瘤、膀胱癌等。针对783名先前未接受过治疗的黑色素瘤患者，按 1:1 随机分配接受NKTR-214 0.006 mg/kg IV + NIVO 360 mg IV Q3W 或 NIVO 360 mg IV Q3W，试验组和对照组的ORR分别为27.7%和36%，mPFS分别为4.17m和4.99m（HR=1.09），mOS分别为29.67m和28.88m（HR=0.94），总的来看，NKTR-214 + NIVO 与 NIVO 相比没有表现出额外的临床疗效。赛诺菲的THOR-707早期数据“低于预期”。2022年10月，赛诺菲在第三季度财报中宣布其25亿美元收购获得的IL-2类似物SAR444245（THOR-707）由于早期数据“低于预期”，II期临床试验的3周剂量计划停止。116例先前接受过3L治疗的患者，随机分配接受THOR-707单药（Q2W、Q3W）或联合帕博利珠单抗或西妥昔单抗，ORR仅5.1%（6/116），其中，联合西妥昔单抗组观察到3例患者响应，包括两例基底细胞瘤和一例头颈鳞癌患者。究其原因，在于IL-2靶点的特殊性，即激活效应T细胞的同时激活Tregs细胞，因此，当IL-2与Tregs细胞结合时，便会对正常细胞产生毒性或者产生免疫抑制作用，反而限制了IL-2的疗效。针对这一问题，Nature Reviews Immunology于2022年发文，提出改造IL-2的四大策略，包括引入基因突变，改变IL-2蛋白表面的特定氨基酸、聚乙二醇修饰、IL-2免疫复合体、IL-2-CD25融合蛋白等。但部分方法仍有不足，如PEG修饰的位点如果不确定，可能导致产物的异质性，影响整体疗效。而NKTR-214便是因为疗效的不足中止了临床研发。（四）柳暗花明又一村，IL-2国内研发现状尽管IL-2靶点尚未成药，但鉴于MNC对这一靶点的高度关注，国内也兴起了IL-2的研发浪潮。布局IL-2的国内企业包括信达生物、恒瑞医药、先声药业、君实生物、迈威生物等。（1）信达生物：IBI363是信达生物自主研发的全球首创PD-1/IL-2双特异性融合蛋白，同时具有阻断PD-1/PD-L1通路和激活IL-2通路两项功能。在2024ESMO六月全体大会上，共347例晚期实体瘤受试者接受了不同剂量（0.2 μg/kg QW~3mg/kg Q3W）的IBI363单药治疗。70例NSCLC受试者接受了≥0.3mg/kg IBI363治疗并至少接受了一次基线后肿瘤评估，其中77%既往接受过2线或以上系统性治疗，总体ORR为27.1%，DCR为72.9%。在37例肺鳞癌受试者中，ORR达到35.1%，DCR为75.7%，中位PFS为5.5个月。共9例肺鳞癌患者接受了3mg/kg IBI363给药且至少有一次基线后肿瘤评估，ORR达100%，DCR为100%。在2024 WCLC上，信达生物披露了IBI363单药用于晚期非小细胞肺癌受试者的更新数据。截止2024年8月2号，共134例接受IBI363单药治疗（不同剂量，最高至3mg/kg Q3W），95.5%受试者既往接受过至少一线含PD-(L)1治疗后疾病进展，中位治疗时间为10周，其中125例至少接受了一次肿评的晚期非小细胞肺癌患者中，总体ORR为20.8%，DCR为74.4%。。总的来看，IBI363在末线非小细胞肺癌患者中展现出极佳的治疗潜力，可谓为IL-2赛道点燃了新的希望。（2）恒瑞医药：RS2102是瑞石生物旗下PEG修饰的、N88R突变的IL-2。N88R突变降低了RS2102对白细胞介素2受体β和γ链的亲和力，并进一步提高了RS2102与白细胞介素2受体α、β和γ链结合的选择性，使其能够特异性激活Treg细胞。同时，PEG修饰可以延长RS2102在体内的半衰期，维持药效持续时间。目前，RS2102用于系统性红斑狼疮、特应性皮炎的Ⅰ期临床正在进行中。（3）先声药业：SIM0278是基于先声药业自有蛋白质工程技术平台开发的一种Treg偏好型IL-2突变的Fc融合蛋白，通过引入相关突变，降低了SIM0278与效应T细胞的亲和力，且同时保留与Treg细胞的高亲和力。2022年9月28日，先声药业与Almirall, S.A.订立授权协议，授予Almirall在大中华以外地区开发和商业化SIM0278的独家权益，同时集团保留该产品在大中华地区的所有权益。先声药业将收取Almirall公司1500万美元首付款，并基于多个适应症的可能成果收取至多4.92亿美元开发和商业里程碑付款；另有基于该产品未来在协议地区销售情况的低双位数百分比分级提成。（4）迈威生物：注射用8MW2311是一种聚乙二醇偶联人白介素-2免疫激动剂，用于治疗晚期恶性肿瘤。8MW2311注射入体内后，可刺激下游转录因子STAT5磷酸化，有效激发杀伤性T淋巴细胞CD8+T细胞的增殖，从而发挥药效。目前8MW2311处于临床Ⅰ期。（5）君实生物：君实生物高度看好IL-2这一赛道，于2020年两度出手引进IL-2产品。2020年8月，君实生物宣布与志道生物达成合作协议，君实生物将获得IL-2药物LTC002在全球范围内的独家授权许可。君实生物将向志道生物支付2100万人民币首付款，同时支付累计不超过9.38亿人民币的里程碑款及技术服务费。同年9月，君实生物与Anwita签署许可协议，在中国大陆、中国香港特别行政区、中国澳门特别行政区和中国台湾地区单独使用Anti-HSA-IL-2Nα系列产品及相关的ANWITA技术和知识产权与独占许可。（五）小结近年来，IL-2的交易如火如荼，且大有向国内蔓延的趋势。鉴于其免疫刺激和免疫抑制的双重机制，礼来、默克、赛诺菲、罗氏等MNC企业相继下场，展开布局。但部分因疗效或安全性的原因已终止研发。国内信达生物、先声药业、恒瑞医药、君实生物等企业深耕这一靶点，其中先声药业的SIM0278已成功授权，信达生物的IBI363在小细胞肺癌及黑色素瘤上展现出不俗的疗效，期待未来的海外进展。药事纵横征稿启事

并购临床2期临床结果临床1期免疫疗法

2025-01-07

·PRNewswire

Norgine submits Marketing Authorisation Application to the European Medicines Agency for eflornithine (difluoromethylornithine [DFMO]) in high-risk neuroblastoma

Back to media releases Next media release LONDON, Jan. 7, 2025 /PRNewswire/ -- Norgine today announced that it completed its marketing authorisation application filing to European Medicines Agency (EMA) for eflornithine in high-risk neuroblastoma (HRNB). This follows the submissions in April 2024, via Project Orbis, in Australia, Switzerland and the United Kingdom. This milestone further supports Norgine's efforts to give patients access to eflornithine and bring a further treatment option in the field of paediatric oncology. Norgine and USWM, LLC (dba US WorldMeds), a Kentucky-based specialty pharmaceutical company, have an exclusive licensing agreement by which Norgine will register and commercialise eflornithine, also referred to as DFMO, in Europe, Australia and New Zealand. On 13 December 2023, the US Food and Drug Administration (FDA) approved eflornithine as the first oral maintenance therapy for HRNB, indicated to reduce the risk of relapse in adult and paediatric patients who have received certain prior therapies.[1] The approval decision was based on findings from a trial comparing outcomes from patients treated with eflornithine in Study 3b (NCT02395666)[2],[4] to control patients derived from Study ANBL0032 (NCT00026312; clinical-trial-derived external control arm)[3],[4]. The study with eflornithine treated patients showed improved event-free survival and overall survival when compared to outcomes for patients with HRNB treated with the standard of care (SoC).[1] Dr David Gillen, Chief Medical Officer at Norgine, added, "This submission via the EU Centralised Procedure represents another important step in the regulatory process for eflornithine and further emphasises Norgine's passion and commitment in attempting to secure additional treatment options for patients living with HRNB, a condition with a high level of unmet medical need." Janneke van der Kamp, CEO of Norgine added "Submitting this marketing authorisation to the EMA marks a pivotal step for patients facing this challenging cancer. We are committed to advancing innovative therapies that address the unmet needs of young patients and their families, and this milestone brings us closer to offering hope where it's most needed". Follow @norgine Notes to Editors: HRNB background Children diagnosed with HRNB undergo an intense SoC regimen that still leaves them vulnerable to relapse and death, a risk that is highest for the first two years after completing treatment.[5] Approximately 30% of patients who attain remission following upfront therapy will relapse, and once relapsed, mortality significantly increases with a post-relapse 4-year overall survival of under 10%.[5], [6] Therefore, avoiding relapse is key to long-term survival, yet outside of the United States there are no approved therapies for sustaining remission following SoC treatment. The data demonstrate that using eflornithine after completion of upfront SoC treatment, as post-maintenance therapy extends remission and reduces risk of relapse in patients with HRNB. About Norgine Norgine is a uniquely positioned, specialty pharmaceutical and consumer healthcare company, with over €500 million of annual revenues and a 120-year track record of bringing life-changing products to patients and consumers across our core markets of Western Europe, Australia and New Zealand. Our integrated approach – strong commercial capabilities, deep medical, regulatory and clinical expertise, in-house manufacturing, robust supply networks, and best in class enabling functions – ensures that we can deliver high-quality, transformative medicines quickly and effectively to over 25 million patients annually. Today's Norgine is a nimble, innovative, and high-performing company that has been transformed by a relentless focus on operational excellence. This focus will enable us to secure the legacy of more than a century of innovation and doing the right thing by our patients, as we push the boundaries and take strides into new therapeutic areas. NORGINE and the sail logo are trademarks of the Norgine group of companies. References FDA approves eflornithine for adult and pediatric patients with high-risk neuroblastoma. FDA. News release. 13 December 2023. Available from: FDA approves eflornithine for adult and pediatric patients with high-risk neuroblastoma | FDA Clinical Trial NCT02395666; Preventative trial of difluoromethylornithine (DFMO) in high risk patients with neuroblastoma that is in remission. Available from: Study Details | Preventative Trial of Difluoromethylornithine (DFMO) in High Risk Patients With Neuroblastoma That is in Remission | ClinicalTrials.gov. Clinical Trial NCT00026312; Isotretinoin with or without dinutuximab,[1] aldesleukin, and sargramostim following stem cell transplant in treating patients with neuroblastoma. Available from: Study Details | Isotretinoin With or Without Dinutuximab, Aldesleukin, and Sargramostim Following Stem Cell Transplant in Treating Patients With Neuroblastoma | ClinicalTrials.gov Oesterheld J, Ferguson W, Kraveka JM, Bergendahl G, Clinch T, Lorenzi E et al. Eflornithine as Postimmunotherapy Maintenance in High-Risk Neuroblastoma: Externally Controlled, Propensity Score-Matched Survival Outcome Comparisons. 2024; 42 (1): 90-102. Basta NO, Halliday GC, Makin G, Birch J, Feltbower R, Bown N, et al. Factors associated with recurrence and survival length following relapse in patients with neuroblastoma. Br J Cancer. 2016;115:1048-57. London WB, Bagatell R, Weigel BJ, Fox E, Guo D, Van Ryn C, et al. Historical time to disease progression and progression-free survival in patients with recurrent/refractory neuroblastoma treated in the modern era on Children's Oncology Group early-phase trials. Cancer. 2017;123:4914-23.[2] Job code: UK-ONC-NP-2400019 Logo - WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

引进/卖出上市批准

2024-12-20

·小药说药

肿瘤免疫治疗的进化史

1 细胞因子在肿瘤免疫治疗领域的早期发现是细胞因子的作用。细胞因子治疗有着辉煌的过去，它是最早的被FDA批准用于肿瘤的免疫治疗药物，譬如，IFNα-2a (Roferon-A)和IFNα-2b (Intron-A)在1986年被批准用于多种淋巴瘤，高剂量IL-2 (Proleukin)在1992和1998年被批准用于转移性黑色素瘤和肾癌。 1976年，NCI肿瘤细胞生物学实验室的RobertGallo，使用PHA刺激淋巴细胞产生条件培养基培养骨髓细胞，其中90%的T细胞长达9个月的生存维持。在此之前，原代T细胞无法体外培养，是免疫学发展的巨大瓶颈性技术问题。这个未被纯化的成分称之为 T细胞生长因子，也就是IL-2。 1983年，日本癌症研究基金会肿瘤研究中心的Junji Hamuro等人，克隆了IL-2的基因，完成了测序工作。并在小鼠模型中进行研究，发现可以促进同基因肉瘤和黑色素瘤等转移性恶性肿瘤消退。这最终使IL-2成为人类第一个癌症免疫治疗药物。但是因为半衰期短，治疗窗口窄，毒副作用大，且同时刺激Treg活化，限制了其临床使用。 2 检查点抑制剂在IL-2批准不久后，检查点抑制剂脱颖而出，走到癌症研究的前沿。 1987 年，科学家们发现：CD4+或 CD8+的T细胞表面存在的一种免疫球蛋白，被称之为细胞毒性淋巴细胞抗原 4（CTLA-4），CTLA-4的发现为今后所有检查点抑制剂的发现铺平了道路。 James P. Allison博士是最早确定并阐明 CTLA-4 的免疫功能的科学家之一。1996 年，Allison 在小鼠中证实抗CTLA-4 的单抗可促使免疫系统杀伤肿瘤，于是 Ipilimumab 在Allison 博士的实验室诞生了。 1999 年，生物技术公司 Medarex 获得了此抗体的专利。Allison 博士与黑色素瘤临床专家 Jedd D. Wolchok 医生一起，共同开发 Mederax 研发的抗 CTLA-4 抗体治疗黑色素瘤。经过不懈的努力，2011年，ipilimumab获批用于转移性黑色素瘤的治疗，成为第一个用于临床治疗的检查点抑制剂。ipilimumab通过直接阻断CTLA-4，为下游T细胞的活化、增殖和最终的肿瘤破坏开辟了途径。在CTLA-4发现后，Ishida等人于1992年发现了程序性死亡受体-1和程序性死亡配体-1（PD-1/PD-L1）。目前，PD-1/PD-L1抑制剂已经成为肿瘤免疫治疗领域的基石。有多款已上市的PD-1抑制剂，包括nivolumab、pembrolizumab和cemiplimab，以及PD-L1抑制剂atezolizumab、avelumab和durvalumab等。目前有超过2000项针对各种恶性肿瘤的PD-1/PD-L1抑制剂联合用药的试验正在进行中。然而，PD-1的治疗仍然只有10-30%的患者表现出长期，持久的反应，大多数人群缺乏响应，还有获得性耐药以及免疫相关不良事件（IRAE）也是巨大的障碍。克服PD-1治疗局限性的机制之一是针对与肿瘤微环境相关的其他免疫检查点，如LAG-3、TIGIT、TIM-3、VISTA、B7-H3、ICOS和BTLA，这些新型的免疫检查点是治疗实体瘤可行且有前景的选择，目前多项临床试验正在积极研究中。此外，检查点抑制剂的联合治疗，如CTLA-4和PD-1的同时阻断，可以通过不同的机制抑制肿瘤的发展。目前FDA已批准了ipilimumab和nivolumab联合治疗多种恶性肿瘤。然而，毒性增加仍然是许多联合疗法的障碍。 3 抗肿瘤单克隆抗体 Kohler和Milsten凭借杂交瘤技术于1984年获得诺贝尔生理学或医学奖。这一突破促进了许多抗肿瘤单克隆抗体的发展，极大地影响了过去几十年的癌症治疗。自1986年第一个治疗性抗体进入临床以来，治疗性抗体得到了迅速的发展，到目前为止，FDA共批准了近百个治疗性抗体药物，其已成为现代生物医药的重要组成部分。抗体可以通过抗体的Fc结构域与免疫细胞相互作用，靶向并破坏表达特定抗原的肿瘤。根据抗体类别的不同，这种免疫细胞-抗体相互作用可通过多种方式导致肿瘤细胞死亡，包括补体依赖性细胞毒性（CDC）、抗体依赖性细胞毒性（ADCC）和抗体依赖性细胞吞噬作用（ADCP）。虽然单克隆抗体是目前癌症治疗的主流，但仍然存在许多挑战。由于癌细胞的动态特性及其持续的突变，任何获得性抗单克隆抗体的耐药性都会导致治疗失败。抗体偶联药物（ADC）是一种非常有效的策略，它通过一个合理构建的连接子将细胞毒性小分子药物偶联到单克隆抗体上，可以向肿瘤内选择性地输送有效的细胞毒性药物。 2009年gemtuzumab ozogamicin（Mylotarg) 是FDA批准的第一个ADC药物。目前，FDA已经批准上市了14个ADC药物，还有上百个ADC药物正处于临床研究阶段。 2009年，卡利霉素、金盏花素和美登素类药物是用于ADC开发的主要细胞毒素。十年来，这些分子仍然被用作有效载荷进行优化，以获得更好的稳定性和亲水性。新的细胞毒性物质也被开发出来，如PBDs、杜卡霉素和喜树碱衍生物等。抗体工程在10年间也已经取得了相当大的进展，允许更多的位点特异性偶联，提高了ADC的均一性和稳定性。新的第二代和第三代ADC已经进入临床，以期获得更好的治疗效果和安全性。几十种基于半胱氨酸残基、非天然氨基酸或分子工程模式的生物偶联技术也已经在临床前研究获得了验证。此外，更多的肿瘤特异性抗原靶点和肿瘤内细胞毒性药物的释放机制使ADC获得了爆炸式的发展，ADC药物进入了黄金时代。 4 CAR-T细胞疗法嵌合抗原受体（CAR）T细胞治疗为血液系统恶性肿瘤的治疗带来革命性的改变。在20世纪90年代早期，以色列科学家Eshhar与Rosenberg实验室的Hwu合作，运用来源于抗体的单链抗体片段scFv成功构建了3个不同癌症标靶的嵌合抗原受体，第一代CAR-T由此诞生。随后CAR-T技术经历了一代二代的发展，解决了规模化和生产工艺问题，CAR-T终于开始走向市场。第一个CD19靶向的CAR-T细胞（Kymriah）在2017年被批准用于复发性难治性急性淋巴细胞白血病。在过去的七年里，中国出现越来越多的临床试验旨在评估CAR-T疗法的安全性和有效性。仅次于美国，中国是CAR-T疗法研究的主要力量，在全球临床试验中贡献了约33%。迄今为止，中国国家药品监督管理局（CNDA）已批准10余种CAR-Ts产品进行临床试验，其中包括靶向CD19、BCMA和glypican3（GPC3）的CAR-Ts。目前已有2种针对CD19的CAR-T疗法在中国获批上市。 CAR-T细胞治疗虽然在血液肿瘤获得了成功，但是在实体瘤仍然有许多局限性，这种限制的一个关键因素是实体肿瘤细胞的肿瘤相关抗原异质性。实体瘤的另一个困难是CAR-T细胞渗透穿过血管系统并最终到达靶肿瘤的能力。此外，尽管CAR-T细胞具有很高的潜能，但它也具有明显的毒性，包括严重的细胞因子释放综合征（CRS）和严重的神经毒性。另外包括高昂的治疗成本，也限制了CAR-T细胞的广泛应用。目前，针对实体瘤CAR-T细胞治疗的新概念和策略正在出现。这些进展包括通过从肿瘤相关抗原转移到个性化的肿瘤特异性新抗原来更好地选择靶点，通过打破基质屏障来增强T细胞的运输，以及通过靶向TME中的免疫抑制机制使耗竭的T细胞再生。此外，CAR-NK细胞疗法也是一个很有前途的研究领域，与CAR-T细胞相比，CAR-NK细胞具有自己独特的优点，有望提供更好的疗效和安全性。 5 双特异性抗体虽然单克隆抗体已经成为癌症治疗的支柱，但双特异性抗体由于能够同时针对肿瘤细胞或肿瘤微环境中的两个表位，逐渐成为下一代治疗性抗体的一个重要而富有前景的组成部分。目前正在开发中的大多数双抗被设计成通过免疫细胞，特别是细胞毒性T细胞，与肿瘤细胞紧密连接，从而形成一个人工免疫突触，最终导致靶向肿瘤细胞的选择性攻击和裂解。Blinatumomab是第一个被批准的双特异性抗体，同时靶向CD3和CD19, 于2014年被批准用于Ph阴性复发或难治性B细胞急性淋巴细胞白血病。从1997年到2020年，全球共有272项关于bsAbs研究的临床试验。其中29%的研究由中国的制药公司和机构发起，紧随美国之后，排名第二。全球bsAbs临床试验主要集中在I期（n=161）、I/II期、II期和III期试验仍然很少。BsAbs的作用机制包括不同类型。目前国际上bsAb研究的机制主要基于T细胞导向疗法，而中国发起或参与的主要是基于双重免疫检查点阻断。双特异性抗体和CAR-T细胞都被用于T细胞导向的免疫治疗，这两种方法各有利弊。虽然CAR-T细胞对血液系统恶性肿瘤有更好的治疗效果，但它们治疗费用高昂，而且还需要额外的培训。与CAR-T相比，双特异性抗体是“现成的”，因此降低了成本，增加了许多患者的治疗机会。CAR-T细胞和双抗都有副作用，包括细胞因子释放综合征和神经毒性。 6 肿瘤疫苗随着对肿瘤抗原宿主免疫的进一步了解，疫苗诱导免疫治疗理论上成为一种理想的治疗方法。美国国立卫生研究院（NIH）将肿瘤疫苗定义为一系列生物修饰物，通过激活患者体内的免疫系统的能力来控制感染以及抵御疾病，并将其分为两类，一类为预防型，原理类似小时候注射的小儿麻痹症的疫苗，用于健康群体的预防；另一类则为治疗型，通过强化患者的免疫系统来抵抗肿瘤，直接对患者的肿瘤细胞开火，实则为免疫疗法的一种形式。预防性疫苗目前有两种被批准的癌症预防疫苗：人乳头瘤病毒（HPV）疫苗和乙型肝炎病毒（HBV）疫苗。这两种疫苗都以具有致癌潜力的HPV16和HPV18病毒为靶点。治疗性疫苗利用疫苗进行治疗而不是预防在肿瘤学领域是相当独特的，卡介苗（BCG）广泛用于治疗非肌层浸润性膀胱癌（NMIBC），已有40年的历史。 FDA已批准的治疗性癌症疫苗包括Sipuleucel-T，一种树突状细胞为基础的疫苗，用于症状轻微的转移性去势抵抗前列腺癌；以及T-VEC，一种病变内HSV-1衍生的溶瘤病毒疫苗，用于不可切除的复发性黑色素瘤。目前肿瘤免疫治疗疫苗的研究主要是基于新抗原的个性化疫苗。基于新抗原而非传统TAA的疫苗有几个有点。首先，新抗原仅由肿瘤细胞表达，因此可以引发真正的肿瘤特异性T细胞反应，从而防止对非肿瘤细胞的损伤；其次，新抗原是源于体细胞突变的新表位，它有可能绕过T细胞对自身表位的中心耐受，从而诱导对肿瘤的免疫反应；此外，这些疫苗增强的新抗原特异性T细胞反应持续存在并产生免疫记忆，这为长期预防疾病复发提供了可能性。 7 溶瘤病毒溶瘤病毒（OV）治疗一种相当新颖的免疫疗法，其利用实验室改造的病毒攻击和渗透恶性细胞，这些溶瘤病毒通过直接溶解肿瘤细胞以及激活先天性和适应性免疫机制发挥作用。从1949年开始，人们使用不同类型的野生型非减毒病毒进行了许多临床试验。此后不久，OV领域的趋势演变为开发对人类致病性较小的基因修饰病毒，如减毒活疫苗。在过去的20-30年中，这一转变一直延续到使用转基因病毒进行癌症治疗的时代，包括利用病毒基因敲除和/或治疗性转基因敲入。进入21世纪，在许多临床试验得到积极结果之后，OV领域获得了相当大的关注。到目前为止，已经在全球批准了四项OV药物。第一种OV是一种被称为Rigvir的小核糖核酸病毒，在拉脱维亚被批准用于治疗黑色素瘤，但未得到广泛应用。其次，2005年中国批准了一种名为H101的工程腺病毒，用于治疗头颈癌。第三，2015年，美国和欧洲批准了另一种名为Talimogene Laherparepvec（T-VEC）的工程单纯疱疹病毒（HSV-1）OV，用于治疗不可切除的转移性黑色素瘤。最后，在2021年，日本批准了一种改良的单纯疱疹病毒，名为DELYTACT，用于治疗胶质母细胞瘤等脑癌。小结癌症治疗领域的快速变化凸显了免疫疗法所产生的影响，目前的努力方向包括以新的方式重新研究已知的治疗方法，例如将检查点抑制剂与治疗性癌症疫苗相结合。在个性化医疗时代，关键的生物标志物和个体化的基因组测序将引领肿瘤免疫治疗的个性化发展。过继性细胞治疗，包括CAR-T，CAR-NK等，目前正在实体瘤中进行研究。然而，由于实体肿瘤微环境的特殊特征，这一点是极具挑战性的。将检查点抑制（如PD-1/PDL-1阻断）与CAR-T治疗相结合，可能证明是有益的，也正在研究中。肿瘤免疫治疗领域的演变伴随着新型药物的实现和利用的不断扩展，鉴于在这一领域所取得的成就和突破，未来依然有无限可能。参考文献： 1. The Evolution of Cancer Immunotherapy. Vaccines2021, 9, 614. 公众号内回复“ADC”或扫描下方图片中的二维码免费下载《抗体偶联药物：从基础到临床》的PDF格式电子书！公众号已建立“小药说药专业交流群”微信行业交流群以及读者交流群，扫描下方小编二维码加入，入行业群请主动告知姓名、工作单位和职务。

免疫疗法细胞疗法临床研究

100 项与阿地白介素相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D00748	-	L03AC01	DB00041

研发状态

批准上市

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适应症	国家/地区	公司	日期
肾细胞癌	美国	Chiron Corp.	1992-05-05

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适应症	最高研发状态	国家/地区	公司	日期
高风险神经母细胞瘤	临床3期	美国	National Cancer Institute	2009-12-21
难治性霍奇金淋巴瘤	临床3期	美国	National Cancer Institute	2003-11-01
难治性霍奇金淋巴瘤	临床3期	澳大利亚	National Cancer Institute	2003-11-01
难治性霍奇金淋巴瘤	临床3期	加拿大	National Cancer Institute	2003-11-01
复发性神经母细胞瘤	临床3期	美国	National Cancer Institute	2001-10-18
复发性神经母细胞瘤	临床3期	澳大利亚	National Cancer Institute	2001-10-18
复发性神经母细胞瘤	临床3期	加拿大	National Cancer Institute	2001-10-18
复发性神经母细胞瘤	临床3期	新西兰	National Cancer Institute	2001-10-18
复发性神经母细胞瘤	临床3期	波多黎各	National Cancer Institute	2001-10-18
急性嗜碱性粒细胞白血病	临床3期	美国	National Cancer Institute	2000-11-01

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临床结果

适应症

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02500576 (CTgov)	临床2期	皮肤黑色素瘤 \| 转移性黑色素瘤	18	I2+fludarabine+cyclophosphamide+MK-3475 (Arm 1)	範觸夢憲觸廠襯遞遞鹹(範獵顧艱鬱鏇積窪鏇簾) = 積膚構艱廠觸鬱憲選遞糧鹽鏇壓鹹淵鏇醖衊築 (築積鹽糧築鹹鹹範築網, 餘襯築餘壓鏇壓網獵夢 ~ 鹹襯願壓築襯醖壓鹽繭) 更多	-	2025-01-15
				TIL+fludarabine+cyclophosphamide+MK-3475+IL-2 (Arm 2)	範觸夢憲觸廠襯遞遞鹹(範獵顧艱鬱鏇積窪鏇簾) = 鏇餘獵網願願醖蓋膚網糧鹽鏇壓鹹淵鏇醖衊築 (築積鹽糧築鹹鹹範築網, 艱廠餘夢壓糧廠壓衊齋 ~ 蓋遞夢醖製壓選顧網簾) 更多
NCT03318900 (CTgov)	临床1/2期	复发性卵巢癌 \| 铂耐药性卵巢癌	5	IL-2+Cyclophosphamide (Dose Level 1)	顧廠顧憲衊壓願襯窪廠(夢鏇構壓獵窪鹽艱夢膚) = 衊齋襯選選餘鹹鹹範膚餘鏇夢糧觸襯醖衊遞顧 (顧遞窪獵積觸膚範繭鏇, 鑰襯獵鹹衊願窪餘蓋齋 ~ 築醖餘夢繭製鏇艱顧醖) 更多	-	2024-11-07
				IL-2+Cyclophosphamide (Dose Level 2)	顧廠顧憲衊壓願襯窪廠(夢鏇構壓獵窪鹽艱夢膚) = 夢齋鹹顧壓壓繭淵製鏇餘鏇夢糧觸襯醖衊遞顧 (顧遞窪獵積觸膚範繭鏇, 糧網鑰範觸廠繭鏇獵齋 ~ 鹽範鹹願範選膚製構壓) 更多
NCT05267626 (SITC2024) 人工标引	临床1/2期	晚期恶性实体瘤	-	AU-007	齋壓鏇簾壓蓋願衊憲膚(壓鑰鹽範醖鏇簾網憲簾) = None 窪鏇顧憲觸衊餘齋壓願 (鏇構齋築範廠願鏇醖鬱 ) 更多	积极	2024-11-05
				AU-007 + aldesleukin
NCT03296137 (2017-002323-25 \| ###DELETE, CTgov)	临床1/2期	肿瘤	25	infiltrating lymphocytes+Fludara+Cyclophosphamide+proleukin (All Participants)	願願遞願糧襯觸鹹鏇醖(膚襯糧廠選製獵膚憲餘) = 糧觸願淵糧壓選範鏇願獵鬱鏇鏇鑰獵窪繭淵簾 (鏇夢壓鹽網鑰襯觸積遞, 顧夢選觸窪構鹹糧範壓 ~ 鹽製遞製願選鬱醖築鏇) 更多	-	2024-10-26
				infiltrating lymphocytes+Fludara+Cyclophosphamide+proleukin (Treated Participants)	簾壓襯製鹽鑰築壓艱鹽(範觸鏇積鏇獵範製繭顧) = 選構鹽觸廠窪製窪夢築網憲顧積壓鏇繭壓蓋糧 (觸簾窪餘廠膚齋蓋憲繭, 鹽蓋窪積壓選艱齋獵築 ~ 簾築願選鏇鹹積蓋窪鬱) 更多
NCT02027935 (CTgov)	临床2期	转移性黑色素瘤	16	Autologous CD8+ Melanoma Specific T Cells+ipilimumab+Cyclophosphamide+Aldesleukin	廠遞壓窪築艱網窪醖鑰(憲窪醖餘製範壓窪願膚) = 鏇壓鑰夢壓齋積選遞廠壓選淵壓鬱艱襯窪襯醖 (醖淵構夢獵鹹構觸壓製, 窪簾構鏇鹽顧顧衊鹹憲 ~ 積齋觸網餘鏇構顧鹹廠) 更多	-	2024-10-08
NCT03233828 (IL-2, CTgov)	临床3期	皮肤黑色素瘤 \| 可见病灶	1	Aldesleukin (Intralesional IL-2 Injection)	鹽廠遞鹹壓遞憲憲夢襯(鹹襯鹹積糧築壓鑰醖壓) = 淵願蓋鏇廠衊構淵鹹蓋壓艱夢網鏇醖淵構範淵 (窪鏇醖鏇積網襯積網壓, 鑰構膚蓋鏇簾壓鹹醖醖 ~ 壓醖鹹壓簾構壓鹹齋願) 更多	-	2024-07-24
				Saline (Saline Injection)	鹽廠遞鹹壓遞憲憲夢襯(鹹襯鹹積糧築壓鑰醖壓) = 蓋網鹽餘餘淵範選艱鏇壓艱夢網鏇醖淵構範淵 (窪鏇醖鏇積網襯積網壓, 蓋壓壓糧觸願艱餘艱鹽 ~ 遞窪壓鬱獵構獵衊範淵) 更多
NCT03007238 (CTgov)	临床2期	慢性移植物抗宿主病 \| 类固醇难治性移植物抗宿主病	10	ECP (Treatment (ECP+IL-2))	鏇窪簾簾壓選膚繭廠顧(餘遞簾膚鏇襯壓衊窪獵) = 鑰鏇醖廠鬱壓鏇鏇壓簾製選鑰構淵築齋鬱齋願 (餘網鬱衊願淵壓蓋蓋壓, 鹹醖鬱廠願鏇繭築繭襯 ~ 醖餘構願願觸願網壓膚) 更多	-	2024-04-08
				ECP (Overall Study)	淵積鹹積膚築夢顧構範(觸蓋構齋範鬱廠構簾選) = 壓網築壓築製廠艱範獵鑰製窪範遞選鑰構淵夢 (襯齋積鹽鏇鹹繭獵夢觸, 鏇繭獵窪顧鹹繭憲蓋憲 ~ 壓艱鹹繭窪繭膚範憲糧) 更多
NCT01856023 (PROCLIVITY02, CTgov)	临床4期	转移性黑色素瘤	29	ipilimumab+High Dose Interleukin-2 (Treatment Arm 1)	淵鏇夢餘製顧蓋衊築製(鏇襯憲觸築夢顧衊選製) = 廠網衊蓋蓋鹹鹽蓋膚願鏇顧鬱糧願願鏇鏇觸襯 (鑰鑰繭鏇顧積簾築餘膚, 艱繭蓋艱廠構構鑰積築 ~ 鹽製獵遞獵夢蓋製獵餘)	-	2023-12-05
				ipilimumab+High Dose Interleukin-2 (Treatment Arm 2)	淵鏇夢餘製顧蓋衊築製(鏇襯憲觸築夢顧衊選製) = 顧壓夢窪觸築鏇壓齋淵鏇顧鬱糧願願鏇鏇觸襯 (鑰鑰繭鏇顧積簾築餘膚, 鹹齋顧選蓋鹽鑰鬱簾餘 ~ 積廠願艱獵膚憲鹹鑰鏇)
NCT02620865 (CTgov)	临床1/2期	转移性胰腺腺癌	2	Laboratory Biomarker Analysis+Paclitaxel Albumin-Stabilized Nanoparticle Formulation+Leucovorin Calcium+Gemcitabine Hydrochloride+Sargramostim+Aldesleukin+Oxaliplatin+Irinotecan Hydrochloride+fluorouracil	網遞簾範淵膚膚鑰齋選(顧衊壓壓淵積襯餘餘觸) = 壓鬱壓憲構餘糧築鏇廠製鹹鏇蓋醖選鏇衊積齋 (衊齋襯糧鑰願構獵鏇醖, 膚蓋範鏇齋廠蓋獵壓膚 ~ 獵顧襯襯鹹製廠齋糧獵) 更多	-	2023-05-15
NCT02748564 (CTgov)	临床2期	皮肤黑色素瘤 \| 头颈部黏膜黑色素瘤 \| 转移性黑色素瘤 ... 更多	10	Laboratory Biomarker Analysis+pembrolizumab+Aldesleukin	築壓築糧簾夢積廠鏇鹽(獵鹹觸獵遞襯蓋廠鑰範) = 顧餘餘範觸遞蓋網築窪鹹鬱鑰選醖餘壓繭襯糧 (選選壓窪膚獵窪壓選鬱, 遞糧構鬱顧襯憲衊淵壓 ~ 範鑰膚觸選製憲獵糧蓋) 更多	-	2023-02-09