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2025-01-19

申办/合作机构

National Cancer Institute

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2024-12-30

申办/合作机构

City of Hope National Medical Center

[+1]

NCT05989828

/ Recruiting临床1期IIT

Phase Ib Clinical Trial of Autologous Anti-NY-ESO-1 TCR-Engineered T Cells in Patients With Relapsed/Refractory Locally Advanced or Metastatic NY-ESO-1-Expressing Triple Negative Breast Cancer

This phase Ib trial tests the safety, side effects and best dose of anti-HLA-A2/NY-ESO-1 T-cell receptor (TCR)-transduced autologous T lymphocytes (A2-ESO-1 TCR-T cells) in treating patients with NY-ESO-1 overexpression positive triple negative breast cancer (TNBC) that has come back after a period of improvement (relapsed/recurrent) or that does not respond to treatment (refractory), and that may have spread from where it first started (primary site) to nearby tissue, lymph nodes (advanced) or to other places in the body (metastatic). NY-ESO-1 is an antigen found on the surface of many different types of tumor cells including TNBC. Antigens make it possible for immune cells to recognize and kill germ cells that invade the body, however, it is more difficult for immune cells to recognize antigens on tumor cells. T cells are a special type of immune cell in the blood. These T cells may be trained to recognize the NY-ESO-1 antigen on tumor cells, allowing the T cells to attack and kill those tumor cells. The A2-ESO-1 TCR-T cells are T cells that have been removed from the patient's blood through a process called leukapheresis and then changed in the laboratory to recognize NY-ESO-1 on tumor cells. When given back to the patient, these A2-ESO-1 TCR-T cells find and attack tumor cells that express NY-ESO-1. Chemotherapy drugs, such as cyclophosphamide and fludarabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. They are given before the T cells to support optimum activity of the A2-ESO-1 TCR-T cells. IL-2 (aldesleukin) is in a class of drugs known as cytokines. It is a man-made version of a naturally occurring protein that stimulates the body to produce other chemicals which increase the body's ability to fight cancer. A2-ESO-1 TCR-T cells may kill more tumor cells in patients with recurrent or refractory advanced or metastatic TNBC that overexpresses NY-ESO-1.

开始日期2024-12-17

申办/合作机构

University of Southern California

[+1]

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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3,036

项与阿地白介素相关的文献（医药）

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 ; Richter, Kirsten ; Huber, Christoph ; 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

Revival of recombinant IL-2 therapy – approaches from the past until today

Review

作者: Sakellariou, Christina ; Ortega Iannazzo, Samira ; Roser, Luise A. ; Gogesch, Patricia ; Sommer, Charline ; Waibler, Zoe

Interleukin-2 (IL-2) was one of the first cytokines discovered and its central role in T cell function soon led to the notion that the cytokine could specifically activate immune cells to combat cancer cells. Recombinant human IL-2 (recIL-2) belonged to the first anti-cancer immunotherapeutics that received marketing authorization and while it mediated anti-tumor effects in some cancer entities, treatment was associated with severe and systemic side effects. RecIL-2 holds an exceptional therapeutic potential, which can either lead to stimulation of the immune system - favorable during cancer treatment - or immunosuppression - used for treatment of inflammatory diseases such as autoimmunity. Due to these pleiotropic immune effects, recIL-2 therapy is still a hot topic in research and modified recIL-2 drug candidates show ameliorated efficacy and safety in pre-clinical and clinical studies. The Immune Safety Avatar (imSAVAR) consortium aims to systemically assess mechanisms leading to adverse events provoked by recIL-2 immunotherapy as a use case in order to aid safety evaluation of future recIL-2-based therapies. Here, we summarize the historical use of recIL-2 therapy, associated side effects, and describe the molecular basis of the dual role of IL-2. Finally, an overview of new recIL-2 compounds and delivery systems, which are currently being developed, will be given, highlighting a possible comeback of recIL-2 therapy.

2024-11-01·Rheumatology (Oxford, England)

Where are we now in biologic drugs for myositis?

Review

作者: Isenberg, David A ; Neves, Ana ; Viveiros, Luísa ; Venturelli, Veronica

Abstract:

Idiopathic inflammatory myopathies (IIMs) are a rare and heterogeneous group of chronic autoimmune disorders. Up to 40% of IIM patients have long-term sequelae and significant functional disability. Its management can be challenging and new therapies are badly needed. The small number of cases with diverse presentations and different diagnostic criteria significantly affect clinical trial results. Only IVIG has been internationally approved for IIM patients. Most clinical trials of new biologic therapies have failed to meet their primary endpoints in IIM, with only one biologic drug recommended for refractory IIM treatment (rituximab), although not approved. We review several new emerging biologic drugs, including B cell depletion therapies, abatacept, Janus kinase inhibitors, and aldesleukin. Encouragingly, some phase II randomized controlled trials have evaluated the efficacy and safety of new biologics in IIM, demonstrating an improvement in clinical and laboratory measures.

123

项与阿地白介素相关的新闻（医药）

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

2024-12-13

·GlobeNewswire-Health Care

Medicenna Presents Preclinical Data on MDNA11 as First Step to Shrink Tumors Before Surgery and Prevent Metastasis at the 2024 San Antonio Breast Cancer Symposium (SABCS)

Single-agent MDNA11 was more effective than a combination of immune checkpoint inhibitors (anti-mPD1 and anti-mCTLA4) in preventing metastasis and achieving long-term survival in an aggressive mouse model of triple negative breast cancer (TNBC) Mice treated with MDNA11 prior to surgery were able to mount powerful immune and memory response to subsequent tumor rechallenges, demonstrating potential to prevent new tumor growth TORONTO and HOUSTON, Dec. 13, 2024 (GLOBE NEWSWIRE) -- Medicenna Therapeutics Corp. (“Medicenna” or the “Company”) (TSX: MDNA, OTCQX: MDNAF), a clinical-stage immunotherapy company focused on the development of Superkines, announced that new preclinical data on MDNA11 was presented at the 2024 San Antonio Breast Cancer Symposium (SABCS), the world’s largest breast cancer conference, taking place from December 10-13, 2024, in San Antonio, Texas. Metastasis is the leading cause of cancer-related deaths worldwide. 1 in 8 women will be diagnosed with breast cancer in the US and 1 in 3 of those will become metastatic resulting in approximately 42,000 breast cancer deaths every year. Of those deaths, it is estimated that 97-99% of those will be from metastatic breast cancer.1 Among breast cancer subtypes, triple-negative breast cancer (TNBC) is particularly aggressive, spreading more rapidly and representing a significant unmet medical need. Neoadjuvant immunotherapy offers a promising treatment strategy in which patients with advanced but resectable cancer receive immunotherapy before surgery. This approach aims to shrink tumors, making them easier to remove, delay or prevent metastasis, while also targeting cancerous tissue that may not yet be detectable. Additionally, immunotherapy can prime the immune system against tumor antigens, promoting the development of long-lasting anti-cancer T cells. These T cells may help protect against residual tumor cells that could re-emerge and drive metastatic disease. The presentation at 2024 SABCS highlighted the potential of MDNA11, a long-acting ‘β-enhanced not-α’ IL-2 Superkine, to improve treatment outcomes when administered prior to surgery. New findings demonstrated that a single low dose of MDNA11 as a neoadjuvant therapy significantly prevented metastasis, extended survival, and enabled a memory immune response that protects against tumor rechallenges in a TNBC model. “We are impressed by MDNA11’s remarkable capability, in the on-going ABILITY-1 clinical trial, to durably control cancer in patients with advanced late-stage metastatic disease in immunotherapy resistant tumors. This naturally encourages us to evaluate the potential of MDNA11 to tackle cancer head-on at the earlier stages of the disease and reverse cancer from a death sentence to a chronic manageable condition,” said Fahar Merchant, PhD, President and CEO of Medicenna. “Our findings show that MDNA11 alone not only prevents metastasis in an aggressive preclinical breast cancer model when administered as a single pre-treatment prior to surgery, but also delivers superior long-term survival by preventing metastasis when compared to combinations of the leading checkpoint inhibitors, such as anti-CTLA4 and anti-PD-1. These data illustrate MDNA11’s potential to redefine traditional immunotherapy by attacking cancer at its earliest stages and efficiently leverage the patient’s healthier immune status to dramatically improve patient outcomes.” Key findings from presentation of MDNA11 pre-treatment prior to surgery in the aggressive TNBC model included: Metastasis Prevention: A single dose of neoadjuvant MDNA11 prevented the spread of tumors, with vast majority of treated mice (7/8 at high-dose of 5 mg MDNA11/kg and 6/7 at low-dose of 2 mg MDNA11/kg) surviving to study end (>4 months) without signs of metastasis despite tumor rechallenges. By contrast, all mice in the control group developed multiple metastasis and died within ~2 months even after tumor resection surgery.Superior to Checkpoint Inhibitors: MDNA11 alone, even at the lower dose, was more effective than a combination of immune checkpoint inhibitors (anti-mPD1 and anti-mCTLA4) in preventing metastasis and achieving long-term survival.Memory Response Against Tumor Rechallenge: Mice treated with MDNA11 were able to mount strong immune response to subsequent tumor rechallenges by engaging tumor antigen-specific T cells, demonstrating protection against new tumor growth.Immune Cell Activation: MDNA11 promoted the infiltration of CD8+ T cells with potent tumor-killing capacity (GrzB+) into the tumor microenvironment (TME) with no impact on immune-suppressive Treg cells, driving a potent and lasting immune response. A copy of the presentation has been posted on the “Scientific Presentations” page of Medicenna’s website. About MDNA11 MDNA11 is an intravenously administered, long-acting, ‘beta-enhanced not-alpha’ IL-2 Superkine specifically engineered to overcome the shortcomings of aldesleukin and other next generation IL-2 variants by preferentially activating immune effector cells (CD8+ T and NK cells) responsible for killing cancer cells, with minimal or no stimulation of immunosuppressive Tregs. These unique proprietary features of the IL-2 Superkine have been achieved by incorporating seven specific mutations and genetically fusing it to a recombinant human albumin scaffold to improve the pharmacokinetic (PK) profile and pharmacological activity of MDNA11 due to albumin’s natural propensity to accumulate in highly vascularized sites, in particular tumor and tumor draining lymph nodes. MDNA11 is currently being evaluated in the Phase 1/2 ABILITY-1 study as both monotherapy and in combination with pembrolizumab. About Medicenna Therapeutics Medicenna is a clinical-stage immunotherapy company focused on developing novel, highly selective versions of IL-2, IL-4 and IL-13 Superkines and first-in-class Empowered Superkines. Medicenna’s long-acting IL-2 Superkine, MDNA11, is a next-generation IL-2 with superior affinity toward CD122 (IL-2 receptor beta) and no CD25 (IL-2 receptor alpha) binding, thereby preferentially stimulating cancer-killing effector T cells and NK cells. MDNA11 is being evaluated in the Phase 1/2 ABILITY-1 Study (NCT05086692) as a monotherapy and in combination with pembrolizumab. Medicenna’s IL-4 Empowered Superkine, bizaxofusp (formerly MDNA55), has been studied in 5 clinical trials enrolling over 130 patients, including a Phase 2b trial for recurrent GBM, the most common and uniformly fatal form of brain cancer. Bizaxofusp has obtained FastTrack and Orphan Drug status from the FDA and FDA/EMA, respectively. Medicenna’s early-stage high-affinity IL-2β biased IL-2/IL-15 Super-antagonists, from its MDNA209 platform, are being evaluated as potential therapies for autoimmune and graft-versus host diseases. Medicenna’s early-stage BiSKITs™ (Bifunctional SuperKine ImmunoTherapies) and the T-MASK™ (Targeted Metalloprotease Activated SuperKine) programs are designed to enhance the ability of Superkines to treat immunologically “cold” tumors. For more information, please visit www.medicenna.com, and follow us on Twitter and LinkedIn. Forward-Looking Statements This news release may contain forward-looking statements within the meaning of applicable securities laws. Forward-looking statements include, but are not limited to, express or implied statements regarding the future operations of the Company, estimates, plans, strategic ambitions, partnership activities and opportunities, objectives, expectations, opinions, forecasts, projections, guidance, outlook or other statements that are not historical facts, such as statements on the therapeutic treatment potential and safety profile of MDNA11 (both as monotherapy and in combination with pembrolizumab) and the timing and/or release of any additional clinical updates. Drug development and commercialization involve a high degree of risk, and only a small number of research and development programs result in commercialization of a product. Results in early-stage pre-clinical or clinical studies may not be indicative of full results or results from later stage or larger scale clinical studies and do not ensure regulatory approval. You should not place undue reliance on these statements, or the scientific data presented. Forward-looking statements are often identified by terms such as “will”, “may”, “should”, “anticipate”, “expect”, “believe”, “seek”, “potentially” and similar expressions. and are subject to risks and uncertainties. Forward-looking statements are based on a number of assumptions believed by the Company to be reasonable at the date of this news release. Although the Company believes that the expectations reflected in such forward-looking statements are reasonable, there can be no assurance that such statements will prove to be accurate. These statements are subject to certain risks and uncertainties and may be based on assumptions that could cause actual results and future events to differ materially from those anticipated or implied in such statements. Important factors that could cause actual results to differ materially from the Company’s expectations include the risks detailed in the latest annual information form of the Company and in other filings made by the Company with the applicable securities regulators from time to time in Canada. The reader is cautioned that assumptions used in the preparation of any forward-looking information may prove to be incorrect. Events or circumstances may cause actual results to differ materially from those predicted, as a result of numerous known and unknown risks, uncertainties, and other factors, many of which are beyond the control of the Company. The reader is cautioned not to place undue reliance on any forward-looking information. Such information, although considered reasonable by management, may prove to be incorrect and actual results may differ materially from those anticipated or implied in forward-looking statements. Forward-looking statements contained in this news release are expressly qualified by this cautionary statement. The forward-looking statements contained in this news release are made as of the date hereof and except as required by law, we do not intend and do not assume any obligation to update or revise publicly any of the included forward-looking statements. This news release contains hyperlinks to information that is not deemed to be incorporated by reference in this new release. Investor and Company Contact: Christina CameronInvestor Relationsir@medicenna.com(647) 953-0673 Daniel ScarrInvestor Relations & Corporate Developmentdscarr@medicenna.com(647) 220-4509 1 Metastatic breast cancer statistics, METAvivor. https://www.metavivor.org/mbc-prep/metastatic-breast-cancer-statistics

免疫疗法孤儿药临床2期临床结果

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

10 条最早获批的记录,

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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

未上市

10 条进展最快的记录,

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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

分期

评价

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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


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)	積繭齋膚製窪醖壓襯鬱(鏇築顧鏇網鹽積鏇廠願) = 遞製築夢壓顧艱遞艱鏇築艱簾蓋網憲憲鬱憲壓 (壓鹽壓夢廠蓋鑰膚選選, 鹹構積夢蓋窪觸鹽獵鏇 ~ 膚積顧簾齋鬱選淵簾鏇) 更多	-	2024-11-07
				IL-2+Cyclophosphamide (Dose Level 2)	積繭齋膚製窪醖壓襯鬱(鏇築顧鏇網鹽積鏇廠願) = 齋餘鹹觸顧範醖齋廠淵築艱簾蓋網憲憲鬱憲壓 (壓鹽壓夢廠蓋鑰膚選選, 遞簾糧膚積願選網鹹獵 ~ 醖壓夢齋廠蓋壓顧簾淵) 更多
NCT05267626 (SITC2024) 人工标引	临床1/2期	晚期恶性实体瘤	-	AU-007	遞築廠艱製觸製鏇餘憲(夢壓餘遞齋餘鹽選衊獵) = None 選鏇顧範範憲築壓艱鑰 (獵淵衊蓋鑰顧憲齋膚窪 ) 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)	壓願蓋蓋願觸顧願齋壓(廠膚觸遞廠觸襯醖壓積) = 積膚蓋繭蓋膚憲選顧糧鹹範製鏇觸網淵鏇窪衊 (艱憲網觸簾壓鑰選憲襯, 餘膚選鏇餘醖艱蓋構鑰 ~ 廠壓鏇衊範選襯衊淵範) 更多	-	2024-10-26
				infiltrating lymphocytes+Fludara+Cyclophosphamide+proleukin (Treated Participants)	獵憲積簾淵鹽膚鑰築網(鹹網淵製鬱鹹構鏇鹽選) = 廠夢襯鹽襯鹽繭蓋膚構壓齋積鬱簾糧遞製鹽艱 (構製艱襯遞觸範觸廠網, 餘築蓋醖願積衊鬱鹽遞 ~ 顧夢築糧繭壓選壓鹹構) 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	衊窪壓蓋選網襯製構繭(積繭鹹蓋築憲繭選鑰餘) = 製醖範簾餘鑰窪遞壓繭艱網廠鏇醖夢壓醖憲襯 (衊壓獵顧積獵觸鹽壓鹹, 襯鑰廠鹹觸襯膚遞鬱繭 ~ 齋顧鑰積繭廠鹽遞鏇獵) 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)	壓壓鑰夢淵壓顧顧淵膚(鑰衊構壓鬱壓齋構築遞) = 構製襯構醖蓋積製糧顧積願壓獵繭繭簾餘艱淵 (糧夢範獵鬱夢簾製衊糧, 夢壓鑰積鏇衊願獵鑰窪 ~ 壓衊憲窪鹹鏇選襯範壓) 更多	-	2024-07-24
				Saline (Saline Injection)	壓壓鑰夢淵壓顧顧淵膚(鑰衊構壓鬱壓齋構築遞) = 獵醖廠淵廠襯鹽蓋鏇願積願壓獵繭繭簾餘艱淵 (糧夢範獵鬱夢簾製衊糧, 築鏇繭壓糧醖顧醖顧襯 ~ 淵鏇襯醖壓網鹽衊膚鹹) 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))	簾範構築糧顧網糧壓網(選鏇淵範壓製積壓夢簾) = 願網鏇鹽簾選範遞壓窪鑰餘醖壓積築壓鬱顧壓 (鏇窪鬱廠憲齋艱獵鏇糧, 壓構觸夢製鹽蓋窪壓鹽 ~ 積鏇鑰簾觸遞積鹹窪網) 更多	-	2024-04-08
				ECP (Overall Study)	壓餘齋糧窪蓋窪齋選獵(遞鏇壓衊憲餘獵遞鹽選) = 遞構壓餘衊糧構構窪夢廠積鹽淵醖範製築鬱鏇 (繭鹹獵築選窪廠衊鏇製, 積衊憲觸選構蓋艱鏇艱 ~ 繭蓋餘膚壓齋範網繭鬱) 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)	窪簾鹹顧齋獵夢醖夢膚(鑰齋鏇簾膚廠鹹蓋醖餘) = 蓋鹽遞鏇壓鏇襯觸糧壓淵窪糧廠襯簾積簾餘積 (醖窪衊製範鹹獵構選繭, 廠糧鏇醖築衊壓憲廠廠 ~ 壓顧夢艱構築選鬱夢築)	-	2023-12-05
				ipilimumab+High Dose Interleukin-2 (Treatment Arm 2)	窪簾鹹顧齋獵夢醖夢膚(鑰齋鏇簾膚廠鹹蓋醖餘) = 顧夢醖齋憲鬱顧選繭顧淵窪糧廠襯簾積簾餘積 (醖窪衊製範鹹獵構選繭, 繭製糧遞蓋鬱糧選餘選 ~ 製鬱膚獵膚獵範選遞觸)
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	繭壓窪憲顧觸齋艱觸遞(鹹餘鏇齋獵積範積選艱) = 鏇衊遞憲觸範製鏇遞簾糧襯餘獵夢觸夢製範範 (蓋夢憲齋廠鏇製製築窪, 淵憲醖夢顧醖觸繭窪簾 ~ 衊糧積築築鏇淵繭遞蓋) 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	艱壓簾範憲鑰繭醖鬱範(鹹鏇鹽鹹獵鬱獵遞構鹹) = 襯鑰鹽顧遞廠遞獵簾願醖選壓醖遞遞夢襯願憲 (餘選鏇製願壓夢醖衊醖, 築壓願廠鏇蓋淵糧壓願 ~ 衊獵觸夢齋窪膚窪觸鏇) 更多	-	2023-02-09
Tandem Meetings ASTCT and CIBMTR2023	N/A	类固醇难治性移植物抗宿主病	15	Low Dose Interleukin-2 (LD IL-2)	鏇壓鹹簾餘選鏇積構壓(淵網醖鬱淵衊製齋衊夢) = Two deaths occurred; one patient with advanced hepatic dysfunction due to cGVHD and one patient with poor graft function at the time of IL-2 start 觸夢範獵選觸艱築窪顧 (淵觸鬱鑰淵鏇襯網鏇鹽 ) 更多	积极	2023-02-01