Phase II Study of Ex-Vivo Expanded Allogeneic Universal Donor TGFβi NK Cell Infusions in Combination With Temozolomide, Irinotecan, Dinutuximab, and Sargramostim in Patients With Relapsed or Refractory Neuroblastoma The STING (Sequential Temozolomide, Irinotecan, NK Cells and GD2 mAb) Trial

This is a phase II study looking at patient response to treatment with the combination dinutuximab, temozolomide, irinotecan, and GM-CSF.

开始日期2024-12-16

申办/合作机构

United Therapeutics Corp.

[+1]

NCT06172296 / Recruiting临床3期IIT

A Phase 3 Study of Dinutuximab Added to Intensive Multimodal Therapy for Children With Newly Diagnosed High-Risk Neuroblastoma

This phase III trial tests how well the addition of dinutuximab to Induction chemotherapy along with standard of care surgical resection of the primary tumor, radiation, stem cell transplantation, and immunotherapy works for treating children with newly diagnosed high-risk neuroblastoma. Dinutuximab is a monoclonal antibody that binds to a molecule called GD2, which is found on the surface of neuroblastoma cells, but is not present on many healthy or normal cells in the body. When dinutuximab binds to the neuroblastoma cells, it helps signal the immune system to kill the tumor cells. This helps the cells of the immune system kill the cancer cells, this is a type of immunotherapy. When chemotherapy and immunotherapy are given together, during the same treatment cycle, it is called chemoimmunotherapy. This clinical trial randomly assigns patients to receive either standard chemotherapy and surgery or chemoimmunotherapy (chemotherapy plus dinutuximab) and surgery during Induction therapy. Chemotherapy drugs administered during Induction include, cyclophosphamide, topotecan, cisplatin, etoposide, vincristine, and doxorubicin. These drugs work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing or by stopping them from spreading. Upon completion of 5 cycles of Induction therapy, a disease evaluation is completed to determine how well the treatment worked. If the tumor responds to therapy, patients receive a tandem transplantation with stem cell rescue. If the tumor has little improvement or worsens, patients receive chemoimmunotherapy on Extended Induction. During Extended Induction, dinutuximab is given with irinotecan, temozolomide. Patients with a good response to therapy move on to Consolidation therapy, when very high doses of chemotherapy are given at two separate points to kill any remaining cancer cells. Following, transplant, radiation therapy is given to the site where the cancer originated (primary site) and to any other areas that are still active at the end of Induction. The final stage of therapy is Post-Consolidation. During Post-Consolidation, dinutuximab is given with isotretinoin, with the goal of maintaining the response achieved with the previous therapy. Adding dinutuximab to Induction chemotherapy along with standard of care surgical resection of the primary tumor, radiation, stem cell transplantation, and immunotherapy may be better at treating children with newly diagnosed high-risk neuroblastoma.

开始日期2024-04-19

申办/合作机构

National Cancer Institute

NCT05400603 / Recruiting临床1期IIT

A Phase I Study of Allogeneic Ex Vivo Expanded Gamma Delta (γδ) T Cells in Combination With Dinutuximab, Temozolomide, Irinotecan, and Zoledronate in Children With Refractory/ Relapsed, or Progressive Neuroblastoma or Refractory/ Relapsed Osteosarcoma

The goal of this clinical trial is to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of allogeneic expanded γδ T cells when delivered with Dinutuximab, temozolomide, irinotecan, and zoledronate in children with refractory or recurrent neuroblastoma or refractory/ relapsed osteosarcoma as well as to define the toxicities of allogeneic expanded γδ T cells when delivered with Dinutuximab, temozolomide, irinotecan, and zoledronate

开始日期2023-11-06

申办/合作机构

Emory University

100 项与 Dinutuximab 相关的临床结果

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100 项与 Dinutuximab 相关的转化医学

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100 项与 Dinutuximab 相关的专利（医药）

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238

项与 Dinutuximab 相关的文献（医药）

2024-11-01·Cancer Genomics & Proteomics

GD2 in Breast Cancer: A Potential Biomarker and Therapeutic Target

Review

作者: Mokbel, Kefah ; MOKBEL, KEFAH

Expression of disialoganglioside GD2 in normal tissues is primarily limited to the central nervous system, peripheral sensory nerve fibers, dermal melanocytes, lymphocytes, and mesenchymal stem cells. Its widespread overexpression in various cancer types allows it to be classified as a tumor-associated antigen with potential diagnostic and therapeutic implications. This article reviews the synthesis pathways of GD2 and its role in cancer cell adhesion, proliferation, and metastasis with a focus on breast cancer. GD2 appears to be overexpressed on the outer membrane of most breast cancer cells and breast cancer stem cells (BCSCs) and is closely linked to epithelial-mesenchymal transition (EMT). GD3 synthase (GD3S) is considered to be the rate-determining step in GD2 synthesis. Clinical studies indicate that GD2 expression is increased in 35-70% of breast cancer samples, with higher levels in triple-negative breast cancer (TNBC). This overexpression correlates with more aggressive tumor features and worse prognosis. Therapeutic targeting of GD2 with monoclonal antibodies (moABs) like dinutuximab and naxitamab has demonstrated anti-cancer activity in preclinical cancer models and human clinical trials against high-risk neuroblastoma reducing tumor growth and enhancing survival. GD2-specific chimeric antigen receptor (CAR) T-cell therapy and GD3S inhibition present other promising therapeutic strategies to improve clinical outcomes. Furthermore, GD2-targeted vaccines are currently being investigated in cancer therapy. This narrative review article underscores the critical role of GD2 in breast cancer pathogenesis and highlights the promising therapeutic opportunities it offers. It advocates for the initiation of clinical trials to further explore the potential of GD2-targeted treatment in combination with standard breast cancer therapies.

2024-05-01·Journal for ImmunoTherapy of Cancer

Enhancing IgA-mediated neutrophil cytotoxicity against neuroblastoma by CD47 blockade

Article

作者: Leusen, Jeanette ; van Tetering, Geert ; Jansen, Marco ; Wienke, Judith ; Stip, Marjolein ; Passchier, Elsemieke ; Nederend, Maaike ; van den Ham, Femke ; Chan, Chilam

Background:

Approximately half of the neuroblastoma patients develop high-risk neuroblastoma. Current treatment involves a multimodal strategy, including immunotherapy with dinutuximab (IgG ch14.18) targeting GD2. Despite achieving promising results, the recurrence rate remains high and poor survival persists. The therapeutic efficacy of dinutuximab is compromised by suboptimal activation of neutrophils and severe neuropathic pain, partially induced by complement activation.

Methods:

To enhance neutrophil cytotoxicity, IgG ch14.18 was converted to the IgA isotype, resulting in potent neutrophil-mediated antibody-dependent cell-mediated cytotoxicity (ADCC), without complement activation. However, myeloid checkpoint molecules hamper neutrophil cytotoxicity, for example through CD47 that is overexpressed on neuroblastomas and orchestrates an immunosuppressive environment upon ligation to signal regulatory protein alpha (SIRPα) expressed on neutrophils. In this study, we combined IgA therapy with CD47 blockade.

Results:

In vitro killing assays showed enhanced IgA-mediated ADCC by neutrophils targeting neuroblastoma cell lines and organoids in comparison to IgG. Notably, when combined with CD47 blockade, both IgG and IgA therapy were enhanced, though the combination with IgA resulted in the greatest improvement of ADCC. Furthermore, in a neuroblastoma xenograft model, we systemically blocked CD47 with a SIRPα fusion protein containing an ablated IgG1 Fc, and compared IgA therapy to IgG therapy. Only IgA therapy combined with CD47 blockade increased neutrophil influx to the tumor microenvironment. Moreover, the IgA combination strategy hampered tumor outgrowth most effectively and prolonged tumor-specific survival.

Conclusion:

These promising results highlight the potential to enhance immunotherapy efficacy against high-risk neuroblastoma through improved neutrophil cytotoxicity by combining IgA therapy with CD47 blockade.

2024-04-15·International journal of cancer

GM‐CSF, G‐CSF or no cytokine therapy with anti‐GD2 immunotherapy for high‐risk neuroblastoma

Review

作者: Ragsdale, Carolyn E ; Kinsey, Joyce ; Mora, Jaume ; Modak, Shakeel ; Lazarus, Hillard M

Abstract:

Colony‐stimulating factors have been shown to improve anti‐disialoganglioside 2 (anti‐GD2) monoclonal antibody response in high‐risk neuroblastoma by enhancing antibody‐dependent cell‐mediated cytotoxicity (ADCC). A substantial amount of research has focused on recombinant human granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) as an adjuvant to anti‐GD2 monoclonal antibodies. There may be a disparity in care among patients as access to GM‐CSF therapy and anti‐GD2 monoclonal antibodies is not uniform. Only select countries have approved these agents for use, and even with regulatory approvals, access to these agents can be complex and cost prohibitive. This comprehensive review summarizes clinical data regarding efficacy and safety of GM‐CSF, recombinant human granulocyte colony‐stimulating factor (G‐CSF) or no cytokine in combination with anti‐GD2 monoclonal antibodies (ie, dinutuximab, dinutuximab beta or naxitamab) for immunotherapy of patients with high‐risk neuroblastoma. A substantial body of clinical data support the immunotherapy combination of anti‐GD2 monoclonal antibodies and GM‐CSF. In contrast, clinical data supporting the use of G‐CSF are limited. No formal comparison between GM‐CSF, G‐CSF and no cytokine has been identified. The treatment of high‐risk neuroblastoma with anti‐GD2 therapy plus GM‐CSF is well established. Suboptimal efficacy outcomes with G‐CSF raise concerns about its suitability as an alternative to GM‐CSF as an adjuvant in immunotherapy for patients with high‐risk neuroblastoma. While programs exist to facilitate obtaining GM‐CSF and anti‐GD2 monoclonal antibodies in regions where they are not commercially available, continued work is needed to ensure equitable therapeutic options are available globally.

项与 Dinutuximab 相关的新闻（医药）

2024-11-06

·生物制品圈

实体瘤过继性T细胞治疗：当前格局与未来挑战

摘要：过继性细胞疗法（Adoptive Cell Therapy, ACT）包括多种策略，旨在增强T淋巴细胞和其他效应细胞的活动，这些细胞协调抗肿瘤免疫反应，包括嵌合抗原受体（CAR）T细胞疗法、T细胞受体（TCR）基因修饰的T细胞，以及用肿瘤浸润性淋巴细胞（TILs）进行治疗。CAR-T细胞在某些血液恶性肿瘤中的卓越成果推动了对ACT在难治性实体恶性肿瘤患者中的研究。然而，实体瘤的某些特征，如它们的抗原异质性和免疫抑制微环境，阻碍了针对抗原的治疗的有效性。其他ACT方式，如TIL疗法，已成为有前景的新策略。TIL疗法在某些免疫原性癌症中显示出安全性和有希望的活性，主要是晚期黑色素瘤，并有令人兴奋的理由将其与免疫检查点抑制剂结合使用。然而，TIL疗法在临床实践的实施受到多个生物学、物流和经济挑战的阻碍。在这篇综述中，我们的目标是总结当前的知识、可用的临床结果和未来研究的潜在领域，这些研究涉及T细胞疗法在实体瘤患者中的使用。 1.引言 1.1.T细胞、抗肿瘤反应和免疫逃逸我们的免疫系统的抗肿瘤活性是一个高度复杂的过程，涉及多个调节和负反馈途径。当恶性细胞被巨噬细胞和自然杀伤（NK）细胞——先天免疫的组成部分——识别和攻击时，由累积突变产生的异常蛋白被释放并被树突状细胞和其他抗原呈递细胞（APC）吞噬。在周围淋巴结中，这些肿瘤相关抗原（TAA）通过主要组织相容性复合体I型（MHC-I）分子向原始CD8+ T细胞的T细胞受体（TCR）展示，导致它们的激活。为了使这种“免疫突触”成功，T细胞膜上的其他共刺激受体（如B7）也应该被激活。同时，MHC II型（MHC-II）分子与CD4+ T辅助淋巴细胞的TCR之间的相互作用导致B细胞的激活和随后产生抗肿瘤抗体，并引发额外的机制，包括树突状细胞许可和细胞因子产生，以促进CD8+ T细胞的功能和分化。一旦CD8+ T细胞被激活，它们就会迁移到肿瘤部位，并识别恶性细胞表面由MHC-II分子呈现的TAA，引发适应性免疫的效应阶段，最终导致肿瘤细胞死亡。这些肿瘤浸润性淋巴细胞（TILs）的数量和表型与几乎所有实体癌症亚型的生物学行为、预后和对抗癌治疗的反应广泛相关。效应阶段的成功受到肿瘤微环境（TME）中的免疫抑制细胞对T细胞反应的抑制，包括骨髓源性抑制细胞（MDSCs）、肿瘤相关巨噬细胞（TAMs）和调节性T淋巴细胞（T-regs）。肿瘤细胞能够通过激活NF-kB和STAT3信号通路调节它们的功能和分化，诱导释放抑制TILs抗肿瘤活性的免疫抑制细胞因子（IL-6、IL-10、TGF-b）。抗肿瘤反应由被称为“免疫检查点”的分子执行的负反馈机制控制，包括在启动阶段——包括CTLA-4、LAG-3和TIM-3——和效应阶段——主要是程序性细胞死亡蛋白1（PD-1），由肿瘤和TME细胞表达的配体（PD-L1）激活。抗肿瘤反应的机制和潜在免疫生物标志物如图1所示。图1 抗肿瘤反应的机制；(A) 先天免疫；(B) 适应性免疫（启动阶段）；(C) 适应性免疫（效应阶段）。TAA，肿瘤相关抗原；DAMPs，损伤相关分子模式；TCR，T细胞受体；MHC，主要组织相容性复合体；IL-12，白介素-12；IFN，干扰素。逃避免疫系统的能力是恶性细胞的特征。在实体肿瘤中，一些最相关的免疫逃逸机制包括免疫检查点的上调——这为使用免疫检查点抑制剂（ICI）提供了理论基础——，MHC-I或其他在抗原呈递中起关键作用的分子的丢失，导致免疫抑制TME的细胞因子（IL-6、IL-10、TGF-b）的产生，以及激活促进T-regs浸润的致癌途径——如色氨酸2,3-双加氧酶（IDO）途径——或抑制CD8+ T细胞向肿瘤部位的迁移——如Wnt/b-catenin途径——。最近的数据显示，从恶性细胞到健康细胞的生物分子货物的远程转移，通过外泌体介导，也可能在误导抗原识别机制中发挥关键作用，从而促进免疫肿瘤逃逸。自2011年和2015年FDA分别批准抗CTLA4和抗PD1疗法用于晚期黑色素瘤以来，ICI单独或与其他疗法结合已改变了几乎所有实体肿瘤的治疗格局。然而，还有几种其他新兴策略可以增强免疫抗肿瘤反应，其中一些在ICI难治性肿瘤中显示出有希望的结果，这肯定会在未来几年增加免疫疗法在癌症治疗中的重要性。 1.2.采用性细胞疗法的基础采用性细胞疗法（ACT）包括几种技术，这些技术使用T淋巴细胞本身，在经过人工修饰或基因工程后，以提高它们的抗肿瘤活性。这意味着从患者身上提取自体T淋巴细胞，并在体外进行操作和扩增。同时，患者接受淋巴细胞耗竭化疗（CT）——通常是氟达拉滨加环磷酰胺——以消灭无效和免疫抑制的淋巴细胞。在此过程之后，改进的细胞产品被重新输回患者体内。不同ACT方式之间的差异在于体外T细胞修饰的特点：CAR-T和TCR基因修饰的T细胞被基因工程化，以整合对选定肿瘤抗原具有高亲和力的修饰膜受体。然而，与血液恶性肿瘤相比，实体瘤由多克隆细胞群体组成，具有巨大的抗原异质性，这阻碍了针对抗原的疗法的有效性。TIL疗法基于从肿瘤本身提取的浸润T细胞的激活和扩增，这些T细胞本质上对肿瘤抗原有反应，为对抗实体癌症不断变化和异质性的细胞群体提供了一个有趣的理论基础。 2.CAR-T细胞在实体瘤中的作用？ 2.1.引言 CAR-T细胞是经过基因修饰的淋巴细胞，它们整合了一个由三部分组成的嵌合抗原受体（CAR）：一个带有单链片段变量（scFv）的细胞外域，允许抗原识别，一个跨膜域——通过一个间隔区与细胞外部分相连——以及一个细胞内域。这包括一个CD3复合体——激活下游信号通路——和几个共刺激域（通常是CD28和/或4-1BB），这些域加强了T细胞因抗原识别而释放的细胞质活性。近年来，CAR-T细胞结构和制造的创新导致了它们临床疗效的显著改善，特别是第四代CAR-T细胞的发展。第五代CAR配备了三个共刺激域，并且能够分泌针对B细胞成熟抗原（BCMA）的抗PDL1 scFv阻断分子，已显示出在多发性骨髓瘤患者中增强的抗肿瘤效果和减少T细胞耗竭。纳米抗体或单域抗体（VHH）最近被用作scFv的替代品，用于T细胞表面的抗原靶向域，基于它们的多种优势，包括它们的小尺寸、高亲和力、特异性和稳定性。基于VHH的CD19重定向CAR-T细胞在扩增率、细胞毒性和抗肿瘤反应方面显示出与基于scFv的对应物相似的效果。由于它们的分子结构，CAR-T细胞只识别细胞外抗原，当它们的scFv对目标蛋白有高亲和力——并且由肿瘤细胞均匀表达——时，它们特别有效。这解释了CAR-T细胞在白血病和淋巴瘤患者中的疗效，这些疾病由克隆细胞群体组成，它们在膜上均匀表达某些抗原——如CD19——。自2018年以来，tisagenlecleucel和axicabtagene-citoleucel已获得EMA批准，用于治疗B细胞LLA和难治性非霍奇金淋巴瘤，而在2020年，brexucabtagene-autoleucel获得EMA批准用于治疗曼特尔淋巴瘤，在重度预处理患者中实现了超过50%的完全缓解率。CAR-T细胞在血液恶性肿瘤中的卓越成果促使人们研究它们在实体瘤中的应用，主要使用过度表达的上皮抗原作为靶标。上皮生长因子受体（EGFR）、HER2、癌胚抗原（CEA）、间皮素和可溶性抗原GD2一直是CAR-T疗法的常见靶标，尽管许多其他抗原已成为临床前研究的对象。 2.2.临床结果已有近500项评估实体瘤中CAR-T细胞的临床试验被注册，其中大多数在亚洲人群中进行，许多仍在进行中。大多数已完成的研究是I/II期试验，报告了适度的结果，只有偶尔和通常短暂的临床反应。关于CAR-T细胞的临床研究主要集中在胶质母细胞瘤（GBM）、肉瘤、神经母细胞瘤和胃肠道癌。 2016年，Brown等人报告了一例GBM患者在IL13靶向CAR-T疗法后8个月完全缓解（CR），尽管进一步的研究未能证实这些结果。Her2可能是GBM中CAR-T细胞的另一个有趣靶标；在一项涉及17名患者的临床试验中，报告了1个部分反应（PR）（持续9个月）和7例病情稳定（SD）（从2到29个月不等）。针对EGFR的CAR-T细胞已在两项临床试验中被评估用于GBM，结果为阴性。针对Her2的CAR-T细胞也已在肉瘤患者中进行测试。在一项包括19名Her2+复发或难治性肉瘤患者的I/II期研究中，观察到4例SD[3例骨肉瘤和1例小圆形细胞性肿瘤]。在神经母细胞瘤中，至少有三项临床试验评估了针对GD2的CAR-T细胞的疗效——基于针对GD2的单克隆抗体如dinutuximab的疗效，显示出有希望的结果（19名患者中有3个CR，8名患者中有4个PR，11名患者中有5个SD]。至于胃肠道（GI）癌，已评估了几个作为CAR-T疗法潜在靶标的抗原。在一项包括23名患有多种GI肿瘤的患者的治疗中，使用针对CD133的CAR-T细胞，观察到3个PR（2个胰腺和1个肝细胞癌[HCC]）和14个SD。Zhan等人评估了针对Claudin 18.2（CLDN 18.2）的CAR-T疗法在11名CLDN 18.2阳性的胃或胰腺癌患者中的效果，报告了1个CR，3个PR和5个SD。针对EGFR的CAR-T疗法主要在胆胰肿瘤中被评估，显示出有希望的结果。Liu等人进行了一项包括14名难治性晚期胰腺癌患者的I期研究，报告了4个PR和8个SD；在Guo等人的I期研究中，包括19名患者（14名胆管癌，5名胆囊癌），观察到1个CR和10个SD。针对Glypican-3（GPC3）的CAR-T细胞和针对CEA的CAR-T细胞分别在HCC和结直肠癌中显示出适度的活性。针对间皮素的胸膜内CAR-T细胞已被评估——与ICI联合用于14名恶性间皮瘤和非小细胞肺癌（NSCLC）患者，显示出有希望的结果（2个CR，5个PR和4个SD）。在NSCLC中，一项I期研究显示了针对EGFR的CAR-T细胞的临床活性，11名患者中有2个PR和5个SD，针对ROR1的CAR-T细胞在ROR1+肿瘤中显示出初步的积极结果（6名患者中有4个PR）。针对前列腺特异性膜抗原（PSMA）的CAR-T疗法在转移性去势抵抗性前列腺癌（mCRPC）中取得了适度的结果。关于其他实体瘤中CAR-T疗法的证据更加稀缺，主要来自临床前研究。在实体瘤中评估CAR-T细胞的最相关临床试验的结果总结在图2中。图2 在实体瘤中最具相关性的CAR-T细胞I/II期试验的临床结果。N，表示每项研究中的参与者数量。 3.经过工程化T细胞受体(TCR)改造的T细胞，是否只是更多的相同？ 3.1.引言表达工程化T细胞受体(TCR-T细胞)的T细胞代表了ACT的另一种方式，与CAR T疗法相比具有几个优势（50）。通过使用工程化的TCR而不是CAR，T细胞不仅能识别膜蛋白，还能识别由MHC分子呈递的细胞内抗原，涵盖了更广泛的肿瘤新抗原和治疗靶点。T细胞的内在特性，如高抗原敏感性和使用生理信号传导途径，提高了TCR-T细胞的抗肿瘤功能，并降低了靶向非肿瘤(OTOT)毒性的风险。然而，与CAR-T细胞相比，TCR-T细胞也有一些缺点，例如它们对目标抗原的亲和力较弱，以及它们局限于某些人类白细胞抗原(HLA)单倍型，这限制了可能从每个改造TCR中受益的患者数量。此外，作为针对抗原的改良T淋巴细胞，CAR-T疗法在实体肿瘤中的所有限制——抗原异质性、T细胞迁移的困难以及免疫抑制性TME的有害影响——也适用于TCR-T细胞。 3.2.临床结果 2006年，Morgan等人发表了首个针对实体肿瘤的TCR-T细胞试验结果，针对17名转移性黑色素瘤患者中的MART-1（其中2名PR）。从那时起，至少还有三项I/II期临床试验评估了针对MART-1的TCR-T细胞在晚期黑色素瘤中的疗效——所有试验都使用逆转录病毒作为载体——并报告了不同的结果，ORR从0%到30%不等。在其中一项试验中，还评估了蛋白gp100作为16名患者的目标，观察到1个持续CR（>14个月）和2个PR（ORR：18.8%）。所有这些研究中TCR-T细胞相关的毒性相似，以皮肤毒性为主（23-94%）和CRS的低发生率（<15%）。纽约食管鳞状细胞癌（NY-ESO）-1抗原在黑色素瘤和某些肉瘤免疫原性亚型中——特别是滑膜肉瘤，80%的患者中NY-ESO-1过表达——是一个有希望的目标。在一项II期试验中，38名黑色素瘤和滑膜肉瘤患者接受了NY-ESO-1 TCR-T细胞治疗，ORR为57.9%，包括5个维持CR和几个长期PR，没有与TCR-T细胞相关的严重毒性。在另外两项I期研究中也获得了类似的结果，其中一项CRS的发生率为10%。另外两项I/II期试验评估了滑膜肉瘤患者中的NY-ESO-1 TCR-T细胞——使用慢病毒作为载体而不是逆转录病毒——获得了类似的结果（ORR 30%至50%），其中一项CRS的发生率为41.7%。NY-ESO-1也被用作TCR-T细胞的目标，在一个小的I期试验中包括3名不同实体肿瘤的患者，结果为阴性。其他癌症-睾丸抗原，如MAGE家族蛋白，已在多肿瘤I/II期试验中作为TCR-T细胞的目标进行了评估。一项I期试验评估了针对MAGE-A3的TCR-T细胞在17名实体肿瘤患者中的疗效，观察到ORR为23.5%（包括1个持续CR）。Morgan等人用MAGE-A3靶向细胞治疗了9名实体肿瘤患者（包括7名滑膜肉瘤），获得了56%的ORR（包括1个持续CR），但毒性严重（3名患者ICANS和2例治疗相关死亡）。在一项38名患者接受MAGE-A4-TCR-T细胞治疗的I期试验中，观察到50%的CRS，另一项MAGE-A3-TCR-T细胞的试验在2例治疗相关死亡后被暂停。与神经系统细胞通常表达的蛋白质——如EPS8L2——的交叉反应被假设为MAGE-TCR-T细胞试验报告的严重神经毒性和毒性死亡的来源。针对MAGE的TCR-T细胞在NSCLC和食管癌中获得了阴性或适度的结果。同样，在针对其他非肿瘤细胞特异性表达的蛋白质的研究中也观察到了显著的毒性。例如，一项评估针对CEA的TCR-T细胞在结直肠癌患者中的I期试验因100%的患者出现严重结肠炎而暂停。治疗病毒相关肿瘤是TCR-T细胞的一个有趣方法，因为针对感染肿瘤细胞但不由正常组织表达的特定病毒抗原，应该可以避免交叉反应和OTOT毒性的问题。事实上，两项试验评估了针对人乳头瘤病毒（HPV）致癌相关蛋白（E6和E7）的TCR-T细胞在HPV+肿瘤中的效果，没有任何相关毒性和有趣的临床结果（ORR分别为16.7%和50%）。Meng等人评估了针对乙型肝炎病毒（HBV）的TCR-T细胞在8名HBV+ HCC患者中的效果，观察到1个持续PR和仅有1例肝毒性。Veatch等人测试了针对Merkel癌多瘤病毒（MCPyV）的TCR-T细胞在5名难治性Merkel细胞癌患者中的效果，报告了1个PR和没有显著不良事件。然而，鉴于病毒相关肿瘤在晚期实体癌中所占比例较小，需要其他策略来克服TCR-T细胞的交叉反应和OTOT毒性。与此相关，一个令人兴奋的假设是使用新抗原——肿瘤体细胞突变的副产品，不在非恶性组织中存在——作为TCR-T细胞的肿瘤限制性和免疫原性靶标。事实上，一些研究表明，对免疫检查点抑制剂的长期反应是由新抗原反应性效应T细胞介导的，为结合TCR-T细胞和ICI提供了理论基础。不幸的是，一项探索个性化新抗原靶向TCR-T细胞在16名晚期实体肿瘤患者中的有效性的I期试验获得了令人失望的结果。在其他肿瘤中也观察到了对TCR-T细胞的偶尔反应。Leidner等人报告了一名晚期胰腺腺癌患者使用针对KRAS G12D的TCR-T细胞获得的部分反应（持续>6个月）。Kim等人报告了一名转移性乳腺癌患者对针对TP53的TCR-T细胞的部分反应。针对实体肿瘤的已发表TCR-T细胞临床试验的结果已在表1中总结。 4.挑战和未来策略 4.1.挑战和未来策略 CAR-T和TCR-T细胞在治疗实体肿瘤患者方面都存在固有的局限性，这可能解释了与CAR-T疗法在血液学恶性肿瘤中获得的临床结果相比，显著较差的临床结果。 4.1.1.抗原异质性与淋巴瘤和白血病的克隆性质不同，实体肿瘤——特别是在转移性疾病的背景下——以获得体细胞突变为特征，导致不同细胞系的多克隆扩展，产生基因组不稳定性与抗原异质性。在同一疾病不同区域的适应性免疫系统中，新表位表达和克隆扩展的显著肿瘤内异质性也在乙型肝炎病毒（HBV）相关的肝癌中得到证实。在Her2+乳腺癌中，空间转录组学研究表明，决定细胞与T淋巴细胞和其他免疫细胞相互作用的基因签名表达在患者内部存在异质性。O’Rourke等人研究了7名胶质母细胞瘤（GBM）患者肿瘤细胞中几种抗原的表达，在单次输注针对EGFR的CAR-T细胞前后，观察到所有患者EGFR表达显著下降，但具有已知免疫抑制功能的几种其他抗原（CD8, GRZMB, CD25, IDO1, PDL1, 和 FoxP3）显著增加。这些结果揭示了针对特定抗原的T细胞疗法可能迅速促进具有免疫抑制活性的耐药细胞亚克隆的选择。提出具有多抗原识别能力的T细胞作为克服这一问题的潜在策略。一些临床前研究表明，具有双特异性适配器的CAR-T细胞可以促进抗原性不同的肿瘤的根除。更进一步，配备合成Notch（synNotch）受体的CAR-T细胞可能只能在识别肿瘤特异性抗原后诱导CAR表达，创建精确的启动和杀伤识别电路。尽管这些是有希望的策略，但它们尚未在临床试验中得到评估，需要进一步的研究来评估其可行性。 4.1.2.靶向非肿瘤毒性大多数在实体肿瘤中被CAR-T或TCR-T细胞靶向的抗原并不特异性于癌细胞，也表达在非恶性组织上，导致潜在的靶向非肿瘤毒性。除了在血液学恶性肿瘤患者中观察到的通常不良事件，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），这些通常可以管理，这些细胞疗法的靶向非肿瘤效应增加了显著的毒性，并且通常是实体肿瘤患者剂量限制性的。T细胞激活后释放的穿孔素和颗粒酶被认为在靶向非肿瘤细胞毒性中起关键作用，尽管T细胞表面促凋亡分子（如FAS配体）的上调也可能有助于组织破坏。急性呼吸窘迫、消化性出血和严重的皮肤粘膜毒性在几项临床试验中被报告为靶向非肿瘤效应，特别是针对Her2、CLDN18.2和EGFR的CAR-T细胞。有趣的是，尽管GD2在健康脑组织中表达，但在患有弥漫中线胶质瘤的患者中没有报告针对GD2的CAR-T细胞的靶向非肿瘤毒性。尽管对抗原识别阈值知之甚少，但这表明在肿瘤和健康细胞之间表达不同水平的抗原的情况下，CAR-T疗法可能是可行的，且没有显著的靶向非肿瘤效应。克服靶向非肿瘤毒性的一些理论策略包括调节scFv亲和力和/或CAR结构、局部给药CAR-T细胞以避免系统效应、开发工程方法以外部控制CAR-T细胞活性，以及设计基于蛋白质的逻辑电路策略以限制CAR-T细胞激活。需要进一步的研究来评估这些方法的临床可行性，并发现严重毒性的预测生物标志物。 4.1.3.T细胞迁移确保CAR-T细胞与肿瘤细胞之间的接触在白血病和淋巴瘤中不是问题，因为恶性细胞集中在血液和淋巴结中；然而，在实体转移性肿瘤中，特别是在浸润免疫特权器官——如中枢神经系统——的情况下，这是一个重大障碍。几项研究表明，与原发性肿瘤相比，实体癌的转移病灶的淋巴细胞浸润明显较低，表明T细胞迁移到肿瘤部位的丧失是免疫逃逸的相关机制，并可能促进肿瘤进展。在转移性黑色素瘤患者中，Harlin等人表明某些细胞因子（CCL2, CCL3, CCL4, CCL5, CXCL9, 和 CXCL10）在富含TILs的病变中的表达明显高于淋巴细胞浸润不良的病变，表明这些分子在T细胞招募中发挥重要作用。针对肿瘤血管和微环境以调节趋化反应是一个激动人心的研究课题，以改善CAR-T细胞迁移到实体肿瘤。 4.1.4.免疫抑制性TME 除了阻碍T细胞迁移外，TME对浸润肿瘤部位的淋巴细胞具有抑制作用，这是CAR-T细胞功能的障碍。此外，持续暴露于肿瘤抗原和炎症信号被认为会逐渐减轻改良T细胞的功能和增殖，导致CAR-T细胞“耗竭”。针对T细胞内在途径（PD-1/PD-L1轴，TOX/NR4A，TGF-b，CBL-B），使用CRISPR技术调节CAR的表面表达，以及解耦抗原识别与CAR激活信号，是正在研究的激动人心的方法，以克服耗竭并改善CAR-T细胞在实体肿瘤中的临床结果。 5.TIL 疗法，实体瘤中ACT的希望？ 5.1.引言来自不同实体癌症的体外扩增肿瘤浸润性淋巴细胞（TILs）包含一组反应于肿瘤相关抗原异质性的寡克隆效应T细胞。这为TILs在体外（脱离肿瘤微环境的不利影响）进行人工扩增和激活提供了理论基础，随后将它们与刺激细胞因子IL-2一起重新输回体内，以期在化学耗尽免疫抑制细胞后创造一个更有利的环境。由于TIL疗法不是针对特定抗原的治疗，而是使用自然“选择”的肿瘤反应性淋巴细胞，理论上可以克服抗原异质性、肿瘤迁移和靶向肿瘤外毒性等问题，这些问题限制了CAR-T和TCR-T疗法对抗晚期实体瘤的有效性。 5.2.黑色素瘤的临床结果 TIL疗法主要在晚期黑色素瘤中进行了评估。自从Rosenberg进行的首批积极研究以来，几项I/II期试验已经获得了扩展TILs的临床反应——单独或与全身照射结合——在IL2剂量、输注细胞数量和淋巴细胞耗尽强度方面有显著变异性。所有这些研究都是在ICI和靶向疗法大规模扩展成为晚期黑色素瘤的标准治疗之前进行的。在2020年ASCO会议上，Sarnaik等人报告了一项II期试验的结果，评估了冷冻保存的自体TIL疗法lifileucel（LN-144）在对抗PD-1 +/-抗CTLA4疗法（以及BRAF/MEK抑制剂在BRAF突变肿瘤中）进展的转移性黑色素瘤患者中的疗效。在66名可评估的患者中，有2例CR和22例PR（ORR 36.4%），中位反应持续时间在18.7个月时尚未达到。81%的患者观察到肿瘤负担的减少。无论BRAF突变状态、PD-L1表达和肿瘤位置如何，都观察到了反应。在有脑和肝转移、基线大量疾病、乳酸脱氢酶（LDH）水平升高和先前抗PD-1治疗的患者中观察到了客观反应。安全概况与已知的淋巴细胞耗尽和IL-2方案的毒性一致。两年后，Rohaan等人发表了第一项针对实体瘤的ACT III期试验，比较TIL疗法与ipilimumab在IIIC/IV期黑色素瘤患者中的疗效。共有168名患者以1:1的比例随机分配接受TILs（至少5×10^9个细胞，先进行淋巴耗竭CT，随后以高剂量600,000 IU/kg的IL2）或ipilimumab（每组84名患者）。89%的患者曾接受过先前的系统治疗，其中大多数人接受了辅助或一线抗PD-1抗体。中位无进展生存期（mPFS）在TIL组显著更高（7.2对比3.1个月；风险比[HR] 0.50；p<0.001），以及ORR（49%对比21%）。中位总生存期为25.8个月（对比ipilimumab组的18.9个月）。上述所有研究都是在皮肤黑色素瘤患者中进行的。一项II期试验评估了21名转移性葡萄膜黑色素瘤患者的TILs，其中1例持续CR和6例PR（ORR为35%）。有趣的是，这些反应者中有3人（43%）之前接受过抗PD-1和/或抗CTLA4药物的免疫治疗，没有任何临床益处。这些结果表明，TIL疗法值得在非皮肤黑色素瘤中进一步研究，特别是考虑到其对ICI和其他系统治疗的难治性。TIL疗法发表的临床试验结果已在表2中总结。 5.3.其他实体瘤的临床结果尽管TIL疗法尚未在非黑色素瘤肿瘤中取得强有力的结果，但一些I/II期临床试验已在其他免疫原性恶性肿瘤中显示出有希望的数据，如NSCLC、宫颈癌和头颈癌。在一项I/II期试验中，Creelan等人评估了20名在接受nivolumab单药治疗后进展的晚期NSCLC患者中，自体TILs与抗PD-1 nivolumab联合使用的疗效。在13名可评估的患者中，有3例客观反应（2例CR——均持续超过18个月——1例PR，以及8例SD伴肿瘤缩小）。有趣的是，其中一名持续CR的患者是EGFR突变（19号外显子缺失），这是已知的抗PD-1失败预测因子，表明通常对ICI有抗性的NSCLC亚型可能对TIL疗法不具有抗性。需要进一步研究以评估TIL疗法是否对ICI使用具有重新敏感化效果。一项II期试验评估了28名接受过预处理的晚期NSCLC患者的TIL单药疗法（LN-145），在24名可评估的患者中观察到1例CR（>21个月）和5例PR（其中4例>8个月）（ORR 25%）。 TIL疗法在一项II期试验中也显示出有希望的结果，该试验涉及晚期宫颈癌患者，观察到1例CR和11例PR（其中2例未被研究标准确认）（ORR：44%）。另一项研究评估了29名HPV+上皮肿瘤患者（头颈癌、宫颈癌和肛门癌），ORR为24%（包括2例CR，持续时间超过53和67个月）。O'Malley等人进行了一项多肿瘤试验，使用TIL疗法加pembrolizumab治疗31名患者（13名头颈癌，10名宫颈癌和8名黑色素瘤），取得了积极结果（ORR分别为46.2%，50%和87.5%）。这种TIL+ICI组合也在头颈癌和转移性乳腺癌的小规模II期试验中进行了评估，结果令人鼓舞（ORR分别为44%和50%）。有趣的是，第二项研究包括了一名激素受体阳性乳腺癌患者，她实现了持续的CR（超过5年）。然而，这些试验的一个限制是，一些患者，特别是那些对ICI有反应的肿瘤患者，如黑色素瘤和头颈癌，可能对单独的抗PD1阻断有反应，这使得评估TIL疗法的作用变得困难。在不同的实体瘤中评估了ipilimumab、TIL疗法和nivolumab的顺序使用，在25名患者的I/II期试验中，结果适中（2例PR，持续时间为3至7个月）。 5.4.临床实践的挑战尽管TIL疗法在临床试验中取得了有希望的结果，但许多实际和经济挑战限制了其大规模实施。TIL制造始于肿瘤组织的外科切除，最好来自可以通过微创手术获取的转移灶。迄今为止，无论切除的病变部位如何，TILs的生成都同样成功。外科样本的酶消化和/或机械破碎后，将碎片培养在含IL-2的培养基中，这个过程可能需要2-6周。这些最小扩展或“年轻”的TILs使用高剂量的IL-2、抗CD3和辐照的外周血单个核细胞（PBMCs）或“饲养细胞”进行大规模扩展，在一个2周的快速扩展协议（REP）中。扩展的TILs最终被重新输回淋巴耗尽的患者体内，随后进行高剂量IL2。这是一个昂贵且后勤复杂的流程，需要高度专业的设施、规范化的程序和合格的技术人员。这些是TIL疗法广泛应用的重要限制，特别是在发展中国家。几乎所有接受TIL疗法治疗的患者都会出现3-4级不良事件，主要在淋巴耗尽和IL2给药后，也需要高度专业的管理。显著的治疗毒性，加上制造流程的长期性，是TIL疗法在通常快速临床恶化的难治性转移瘤患者中成功应用的重大障碍。迄今为止，TIL疗法已在年轻、健康的患者中进行评估，他们的ECOG表现状态（PS）为0-1。即使在临床试验中选择的人群中，也常常发现只有一小部分筛选的患者最终能接受治疗。例如，在一项晚期乳腺癌的TIL疗法II期试验中，只有46名筛选患者中的6名（13%）接受了TILs输注。切除后无残留或可评估疾病、筛选材料不足、切除样本中淋巴细胞的阴性或弱分离、临床进展、PS恶化和淋巴耗尽相关的严重毒性是治疗失败的常见原因。最后，不仅是经济费用，TIL疗法的个体化特性也与常规商业药物不同，这是TIL疗法监管批准的重要挑战。以往在血液学恶性肿瘤中使用CAR-T细胞的经验无疑将为处理TIL疗法的健康经济方面及其在临床实践中的实施铺平道路。 6.结论在实体瘤中，过继细胞疗法（ACT）的临床结果受到与血液学恶性肿瘤截然不同的生物学因素的制约，如它们的抗原异质性、免疫抑制微环境和免疫逃逸能力。数十项I/II期CAR-T细胞试验只导致了偶尔的、通常是短期的临床反应，尽管多抗原识别、SynNotch受体和通过CRISPR技术调节CAR等新策略是提高其疗效的有希望的方法。尽管抗原靶向治疗存在固有限制，TCR工程化T细胞与CAR-T细胞相比具有几个优势，并在某些肿瘤中显示出有希望的结果，如NY-ESO1过表达的黑色素瘤和滑膜肉瘤。作者认为，HPV+和其他病毒相关恶性肿瘤的治疗，以及使用新抗原作为靶标，是TCR-T细胞研究的激动人心的领域。从概念上讲，与其他ACT方式不同，TIL疗法基于提取、体外扩增和刺激自然反应的肿瘤浸润性淋巴细胞，然后将其重新输回淋巴耗尽的患者体内。TILs在晚期黑色素瘤中显示出积极结果，最近的一项积极的III期试验证明了它们在抗PD1难治性疾病中优于ipilimumab。TIL疗法的疗效，单独或与检查点抑制剂结合，也在其他实体瘤中得到证实，包括NSCLC、宫颈癌和头颈癌。选择性扩增新抗原反应性TILs或通过CRISPR技术对扩增细胞进行基因修饰是提高TIL疗法疗效的激动人心的研究领域，以提高TIL疗法在黑色素瘤患者中的疗效，并将其临床益处扩展到其他恶性肿瘤。然而，目前阻碍其大规模实施的众多临床和实际限制仍需克服。识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

细胞疗法免疫疗法

2024-10-30

·ir.unither.com

United Therapeutics Corporation Reports Third Quarter 2024 Financial Results

Three Months Ended September 30, Dollar Change Percentage Change 2024 2023 Total revenues $ 748.9 $ 609.4 $ 139.5 23 % Net income $ 309.1 $ 267.6 $ 41.5 16 % Net income, per basic share $ 6.93 $ 5.71 $ 1.22 21 % Net income, per diluted share $ 6.39 $ 5.38 $ 1.01 19 % Three Months Ended September 30, Dollar Change Percentage Change 2024 2023 Net product sales: Tyvaso DPI®(1) $ 274.6 $ 205.1 $ 69.5 34 % Nebulized Tyvaso®(1) 159.2 120.7 38.5 32 % Total Tyvaso 433.8 325.8 108.0 33 % Remodulin®(2) 128.3 131.1 (2.8 ) (2) % Orenitram® 113.2 92.0 21.2 23 % Unituxin® 61.1 51.3 9.8 19 % Adcirca® 7.0 7.3 (0.3 ) (4) % Other 5.5 1.9 3.6 189 % Total revenues $ 748.9 $ 609.4 $ 139.5 23 % (1) Net product sales include both the drug product and the respective inhalation device. (2) Net product sales include sales of infusion devices, including the Remunity® Pump. Three Months Ended September 30, 2024 2023 U.S. ROW Total U.S. ROW Total Net product sales: Tyvaso DPI(1) $ 274.6 $ — $ 274.6 $ 205.1 $ — $ 205.1 Nebulized Tyvaso(1) 145.2 14.0 159.2 118.1 2.6 120.7 Total Tyvaso 419.8 14.0 433.8 323.2 2.6 325.8 Remodulin(2) 115.4 12.9 128.3 111.6 19.5 131.1 Orenitram 113.2 — 113.2 92.0 — 92.0 Unituxin 57.6 3.5 61.1 48.8 2.5 51.3 Adcirca 7.0 — 7.0 7.3 — 7.3 Other 4.3 1.2 5.5 1.7 0.2 1.9 Total revenues $ 717.3 $ 31.6 $ 748.9 $ 584.6 $ 24.8 $ 609.4 (1) Net product sales include both the drug product and the respective inhalation device. (2) Net product sales include sales of infusion devices, including the Remunity Pump. Three Months Ended September 30, Dollar Change Percentage Change 2024 2023 Category: Cost of sales $ 81.8 $ 69.1 $ 12.7 18 % Share-based compensation expense(1) 1.3 1.0 0.3 30 % Total cost of sales $ 83.1 $ 70.1 $ 13.0 19 % (1) See Share-based compensation below. Three Months Ended September 30, Dollar Change Percentage Change 2024 2023 Category: External research and development(1) $ 51.7 $ 47.2 $ 4.5 10 % Internal research and development(2) 43.9 34.3 9.6 28 % Share-based compensation expense(3) 7.4 3.6 3.8 106 % Other(4) 0.5 (0.4 ) 0.9 225 % Total research and development expense $ 103.5 $ 84.7 $ 18.8 22 % (1) External research and development primarily includes fees paid to third parties (such as clinical trial sites, contract research organizations, and contract laboratories) for preclinical and clinical studies and payments to third-party contract manufacturers before FDA approval of the relevant product. (2) Internal research and development primarily includes salary-related expenses for research and development functions, internal costs to manufacture product candidates before FDA approval, and internal facilities-related expenses, including depreciation, related to research and development activities. (3) See Share-based compensation below. (4) Other primarily includes upfront fees and milestone payments to third parties under license agreements related to development-stage products and adjustments to the fair value of our contingent consideration obligations. Three Months Ended September 30, Dollar Change Percentage Change 2024 2023 Category: General and administrative(1) $ 100.4 $ 90.4 $ 10.0 11 % Litigation accrual 65.1 — 65.1 NM(2) Sales and marketing 20.7 20.7 — — % Share-based compensation expense(3) 33.0 16.5 16.5 100 % Total selling, general, and administrative expense $ 219.2 $ 127.6 $ 91.6 72 % (1) Excluding litigation accrual. See Litigation accrual section below. (2) Calculation is not meaningful. (3) See Share-based compensation below. Three Months Ended September 30, Dollar Change Percentage Change 2024 2023 Category: Stock options $ 8.0 $ 6.0 $ 2.0 33 % Restricted stock units 27.2 12.5 14.7 118 % Share tracking awards plan 5.9 2.1 3.8 181 % Employee stock purchase plan 0.6 0.5 0.1 20 % Total share-based compensation expense $ 41.7 $ 21.1 $ 20.6 98 % UNITED THERAPEUTICS CORPORATION CONSOLIDATED STATEMENTS OF OPERATIONS (In millions, except per share data) Three Months Ended September 30, 2024 2023 (Unaudited) Total revenues $ 748.9 $ 609.4 Operating expenses: Cost of sales 83.1 70.1 Research and development 103.5 84.7 Selling, general, and administrative 219.2 127.6 Total operating expenses 405.8 282.4 Operating income 343.1 327.0 Interest income 49.8 45.3 Interest expense (10.1 ) (15.6 ) Other income (expense), net 5.8 (4.9 ) Total other income, net 45.5 24.8 Income before income taxes 388.6 351.8 Income tax expense (79.5 ) (84.2 ) Net income $ 309.1 $ 267.6 Net income per common share: Basic $ 6.93 $ 5.71 Diluted $ 6.39 $ 5.38 Weighted average number of common shares outstanding: Basic 44.6 46.9 Diluted 48.4 49.7 SELECTED CONSOLIDATED BALANCE SHEET DATA (Unaudited, in millions) September 30, 2024 Cash, cash equivalents, and marketable investments $ 4,605.9 Total assets 7,123.1 Total liabilities 1,022.2 Total stockholders’ equity 6,100.9

财报引进/卖出ASH会议

2024-07-31

·Business Wire

United Therapeutics Corporation Reports Second Quarter 2024 Financial Results

SILVER SPRING, Md. & RESEARCH TRIANGLE PARK, N.C.--( BUSINESS WIRE )--United Therapeutics Corporation (Nasdaq: UTHR ), a public benefit corporation, today announced its financial results for the quarter ended June 30, 2024. Total revenues in the second quarter of 2024 grew 20 percent year-over-year to $714.9 million, compared to $596.5 million in the second quarter of 2023. “This quarter we drove record revenue from our foundational commercial business. Next year we expect data from our innovative clinical pipeline. All this while we march forward with our revolutionary organ manufacturing programs,” said Martine Rothblatt, Ph.D. , Chairperson and Chief Executive Officer of United Therapeutics. “We believe there is no other biotech with our combination of relentless focus, near-term commercial growth, and clinical potential.” Michael Benkowitz , President and Chief Operating Officer of United Therapeutics, added, “Our fifth straight quarter of record revenue was driven by continued traction for Tyvaso in pulmonary hypertension associated with interstitial lung disease, along with strong fundamentals for our other products in pulmonary arterial hypertension and neuroblastoma.” Second Quarter 2024 Financial Results Key financial highlights include (dollars in millions, except per share data): Three Months Ended June 30, Dollar Change Percentage Change 2024 2023 Total revenues $ 714.9 $ 596.5 $ 118.4 20 % Net income $ 278.1 $ 259.2 $ 18.9 7 % Net income, per basic share $ 6.26 $ 5.53 $ 0.73 13 % Net income, per diluted share $ 5.85 $ 5.24 $ 0.61 12 % Revenues The table below presents the components of total revenues (dollars in millions): Three Months Ended June 30, Dollar Change Percentage Change 2024 2023 Net product sales: Tyvaso DPI ®(1) $ 258.3 $ 193.6 $ 64.7 33 % Nebulized Tyvaso ®(1) 139.9 125.3 14.6 12 % Total Tyvaso 398.2 318.9 79.3 25 % Remodulin ®(2) 147.3 127.2 20.1 16 % Orenitram ® 107.1 95.1 12.0 13 % Unituxin ® 51.7 44.3 7.4 17 % Adcirca ® 5.7 7.5 (1.8 ) (24 )% Other 4.9 3.5 1.4 40 % Total revenues $ 714.9 $ 596.5 $ 118.4 20 % (1) Net product sales include both the drug product and the respective inhalation device. (2) Net product sales include sales of infusion devices, including the Remunity ® Pump. Total Tyvaso revenues grew by 25 percent to $398.2 million in the second quarter of 2024, compared to $318.9 million in the second quarter of 2023. This growth was primarily due to an increase in quantities sold, driven by the commercial launch of Tyvaso DPI in June 2022 and continued growth in commercial utilization by patients with pulmonary hypertension associated with interstitial lung disease and, to a lesser extent, price increases. The growth in Tyvaso DPI revenues resulted primarily from an increase in quantities sold and, to a lesser extent, price increases. The increase in Tyvaso DPI quantities sold was due to continued growth in the number of patients following the product’s launch and, to a lesser extent, increased commercial utilization following the implementation of the Part D redesign under the Inflation Reduction Act ( IRA ). The growth in Remodulin revenues resulted primarily from an increase in U.S. Remodulin revenues, driven by an increase in quantities sold and, to a lesser extent, lower Medicaid rebates. The growth in Orenitram revenues resulted primarily from an increase in quantities sold and, to a lesser extent, a price increase. The increase in quantities sold was driven, at least in part, by increased commercial utilization following the implementation of the Part D redesign under the IRA. The growth in Unituxin revenues resulted from a price increase and an increase in quantities sold. The table below presents the breakdown of total revenues between the United States and rest-of-world ( ROW ) (in millions): Three Months Ended June 30, 2024 2023 U.S. ROW Total U.S. ROW Total Net product sales: Tyvaso DPI (1) $ 258.3 $ — $ 258.3 $ 193.6 $ — $ 193.6 Nebulized Tyvaso (1) 130.2 9.7 139.9 119.6 5.7 125.3 Total Tyvaso 388.5 9.7 398.2 313.2 5.7 318.9 Remodulin (2) 122.5 24.8 147.3 103.5 23.7 127.2 Orenitram 107.1 — 107.1 95.1 — 95.1 Unituxin 46.8 4.9 51.7 39.5 4.8 44.3 Adcirca 5.7 — 5.7 7.5 — 7.5 Other 4.6 0.3 4.9 3.2 0.3 3.5 Total revenues $ 675.2 $ 39.7 $ 714.9 $ 562.0 $ 34.5 $ 596.5 (1) Net product sales include both the drug product and the respective inhalation device. (2) Net product sales include sales of infusion devices, including the Remunity Pump. Expenses Cost of sales. The table below summarizes cost of sales by major category (dollars in millions): Three Months Ended June 30, Dollar Change Percentage Change 2024 2023 Category: Cost of sales $ 75.9 $ 63.2 $ 12.7 20 % Share-based compensation expense (1) 1.9 0.9 1.0 111 % Total cost of sales $ 77.8 $ 64.1 $ 13.7 21 % (1) See Share-based compensation below. Cost of sales, excluding share-based compensation. Cost of sales for the three months ended June 30, 2024 increased as compared to the same period in 2023, primarily due to an increase in Tyvaso DPI royalty expense. Research and development. The table below summarizes the nature of research and development expense by major expense category (dollars in millions): Three Months Ended June 30, Dollar Change Percentage Change 2024 2023 Category: External research and development (1) $ 49.4 $ 49.3 $ 0.1 — % Internal research and development (2) 44.5 34.7 9.8 28 % Share-based compensation expense (3) 8.6 5.0 3.6 72 % Impairments (4) — — — — % Other (5) 37.1 — 37.1 NM (6) Total research and development expense $ 139.6 $ 89.0 $ 50.6 57 % (1) External research and development primarily includes fees paid to third parties (such as clinical trial sites, contract research organizations, and contract laboratories) for preclinical and clinical studies and payments to third-party contract manufacturers before FDA approval of the relevant product. (2) Internal research and development primarily includes salary-related expenses for research and development functions, internal costs to manufacture product candidates before FDA approval, and internal facilities-related expenses, including depreciation, related to research and development activities. (3) See Share-based compensation below. (4) Impairments primarily includes impairment charges to write down the carrying value of in-process research and development and of certain property, plant, and equipment as a result of research and development activities. There were no impairment charges during the three months ended June 30, 2024 and June 30, 2023. (5) Other primarily includes upfront fees and milestone payments to third parties under license agreements related to development-stage products and adjustments to the fair value of our contingent consideration obligations. (6) Calculation is not meaningful. Research and development, excluding share-based compensation. Research and development expense for the three months ended June 30, 2024 increased as compared to the same period in 2023, primarily due to increased expenditures related to upfront non-refundable licensing payments for drug delivery devices and increased expenditures related to organ manufacturing projects. Selling, general, and administrative. The table below summarizes selling, general, and administrative expense by major category (dollars in millions): Three Months Ended June 30, Dollar Change Percentage Change 2024 2023 Category: General and administrative $ 113.0 $ 102.0 $ 11.0 11 % Sales and marketing 25.4 20.1 5.3 26 % Share-based compensation expense (1) 39.2 7.9 31.3 396 % Total selling, general, and administrative expense $ 177.6 $ 130.0 $ 47.6 37 % (1) See Share-based compensation below. General and administrative, excluding share-based compensation . General and administrative expense for the three months ended June 30, 2024 increased as compared to the same period in 2023, primarily due to an increase in legal expenses related to litigation matters and an increase in personnel expense due to growth in headcount. Share-based compensation. The table below summarizes share-based compensation expense by major category (dollars in millions): Three Months Ended June 30, Dollar Change Percentage Change 2024 2023 Category: Stock options $ 8.1 $ 1.6 $ 6.5 406 % Restricted stock units 19.2 13.6 5.6 41 % Share tracking awards plan ( STAP ) 21.9 (1.9 ) 23.8 NM (1) Employee stock purchase plan 0.5 0.5 — — % Total share-based compensation expense $ 49.7 $ 13.8 $ 35.9 260 % (1) Calculation is not meaningful. The increase in share-based compensation expense for the three months ended June 30, 2024, as compared to the same period in 2023, was primarily due to an increase in STAP expense driven by a 39 percent increase in our stock price for the three months ended June 30, 2024, as compared to a one percent decrease in our stock price for the same period in 2023. Income tax expense. Income tax expense for the three months ended June 30, 2024 and 2023 was $77.2 million and $76.0 million, respectively. Our effective income tax rate ( ETR ) for the three months ended June 30, 2024 and 2023 was 22 percent and 23 percent, respectively. Our ETR for the three months ended June 30, 2024 decreased compared to our ETR for the three months ended June 30, 2023 primarily due to a lower amount of uncertain tax positions recorded. Share repurchase. In March 2024, we entered into an accelerated share repurchase agreement (the ASR agreement ) with Citibank, N.A. ( Citi ). Under the ASR agreement, we made an aggregate upfront payment of $1.0 billion to Citi and received an aggregate initial delivery of 3,275,199 shares of our common stock on March 27, 2024, representing approximately 80 percent of the total shares that would be repurchased under the ASR agreement measured based on the closing price of our common stock on March 25, 2024. The share purchase under the ASR agreement was divided into two tranches, resulting in upfront payments of $300 million and $700 million, respectively. The final settlement of the $300 million tranche occurred in June 2024, and we received an additional 181,772 shares of our common stock upon settlement. At the final settlement of the $700 million second tranche, which we expect to occur in the third quarter of 2024, we may be entitled to receive additional shares of common stock, or, under certain limited circumstances, be required to make a cash payment to Citi or, if we so elect, deliver shares of common stock to Citi. The final number of shares that we will ultimately repurchase pursuant to the ASR agreement will be based on the average of the daily volume-weighted average price per share of our common stock during the repurchase period, less a discount and subject to adjustments pursuant to the terms and conditions of the ASR agreement. Webcast We will host a webcast to discuss our second quarter 2024 financial results on Wednesday, July 31, 2024, at 9:00 a.m. Eastern Time. The webcast can be accessed live via our website at https://ir.unither.com/events-and-presentations . A replay of the webcast will also be available at the same location on our website. United Therapeutics: Enabling Inspiration At United Therapeutics, our vision and mission are one. We use our enthusiasm, creativity, and persistence to innovate for the unmet medical needs of our patients and to benefit our other stakeholders. We are bold and unconventional. We have fun; we do good. We are the first publicly-traded biotech or pharmaceutical company to take the form of a public benefit corporation ( PBC ). Our public benefit purpose is to provide a brighter future for patients through (a) the development of novel pharmaceutical therapies; and (b) technologies that expand the availability of transplantable organs . You can learn more about what it means to be a PBC here: unither.com/pbc . Forward-Looking Statements Statements included in this press release that are not historical in nature are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements include, among others, statements related to our anticipated near-term commercial growth; the anticipated progress of our organ manufacturing programs; our clinical potential, including anticipated clinical trial data next year; our unique position in the biotech industry; and our goals of innovating for the unmet medical needs of our patients and to benefit our other stakeholders, furthering our public benefit purpose of developing novel pharmaceutical therapies and technologies that expand the availability of transplantable organs. These forward-looking statements are subject to certain risks and uncertainties, such as those described in our periodic reports filed with the Securities and Exchange Commission, that could cause actual results to differ materially from anticipated results. Consequently, such forward-looking statements are qualified by the cautionary statements, cautionary language and risk factors set forth in our periodic reports and documents filed with the Securities and Exchange Commission, including our most recent Annual Report on Form 10-K, Quarterly Reports on Form 10-Q, and Current Reports on Form 8-K. We claim the protection of the safe harbor contained in the Private Securities Litigation Reform Act of 1995 for forward-looking statements. We are providing this information as of July 31, 2024, and assume no obligation to update or revise the information contained in this press release whether as a result of new information, future events, or any other reason. ORENITRAM, REMODULIN, REMUNITY, TYVASO, TYVASO DPI, and UNITUXIN are registered trademarks of United Therapeutics Corporation and/or its subsidiaries. ADCIRCA is a registered trademark of Eli Lilly and Company. UNITED THERAPEUTICS CORPORATION CONSOLIDATED STATEMENTS OF OPERATIONS (In millions, except per share data) Three Months Ended June 30, 2024 2023 (Unaudited) Total revenues $ 714.9 $ 596.5 Operating expenses: Cost of sales 77.8 64.1 Research and development 139.6 89.0 Selling, general, and administrative 177.6 130.0 Total operating expenses 395.0 283.1 Operating income 319.9 313.4 Interest income 46.2 37.2 Interest expense (11.6 ) (14.8 ) Other income (expense), net 0.8 (0.6 ) Total other income, net 35.4 21.8 Income before income taxes 355.3 335.2 Income tax expense (77.2 ) (76.0 ) Net income $ 278.1 $ 259.2 Net income per common share: Basic $ 6.26 $ 5.53 Diluted $ 5.85 $ 5.24 Weighted average number of common shares outstanding: Basic 44.4 46.9 Diluted 47.5 49.5 SELECTED CONSOLIDATED BALANCE SHEET DATA (Unaudited, in millions) June 30, 2024 Cash, cash equivalents, and marketable investments $ 4,301.9 Total assets 6,723.2 Total liabilities 1,026.0 Total stockholders’ equity 5,697.2 Category: Earnings

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100 项与 Dinutuximab 相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
D10559	Dinutuximab	L01XC	DB09077

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适应症	国家/地区	公司	日期
神经母细胞瘤	美国	United Therapeutics Corp.	2015-03-10

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适应症	最高研发状态	国家/地区	公司	日期
神经节成神经细胞瘤	临床3期	美国	National Cancer Institute	2024-04-19
神经节成神经细胞瘤	临床3期	澳大利亚	National Cancer Institute	2024-04-19
神经节成神经细胞瘤	临床3期	加拿大	National Cancer Institute	2024-04-19
神经节成神经细胞瘤	临床3期	新西兰	National Cancer Institute	2024-04-19
复发性小细胞肺癌	临床3期	美国	United Therapeutics Corp.	2017-06-01
复发性小细胞肺癌	临床3期	澳大利亚	United Therapeutics Corp.	2017-06-01
复发性小细胞肺癌	临床3期	保加利亚	United Therapeutics Corp.	2017-06-01
复发性小细胞肺癌	临床3期	加拿大	United Therapeutics Corp.	2017-06-01
复发性小细胞肺癌	临床3期	法国	United Therapeutics Corp.	2017-06-01
复发性小细胞肺癌	临床3期	格鲁吉亚	United Therapeutics Corp.	2017-06-01

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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


NCT04385277 (ANBL19P1, CTgov)	临床2期	神经节成神经细胞瘤	41	FDG-Positron Emission Tomography+Dinutuximab+Temozolomide+Isotretinoin+Sargramostim+Irinotecan	觸簾鬱衊窪艱淵築壓蓋(獵襯蓋蓋願鹹積醖壓顧) = 蓋壓廠繭壓窪築窪憲製選構繭襯鹹衊構構築選 (構範繭鹹範餘壓糧構廠, 襯衊鬱積選觸蓋獵繭壓 ~ 選鏇艱製鏇鹹鬱窪鏇蓋) 更多	-	2024-08-14
ASCO2024 人工标引	N/A	高风险神经母细胞瘤	1,393	Dinutuximab	蓋艱遞鏇觸網選鑰構壓(構顧選襯鏇選蓋鑰簾廠): RR = 0.41 (95% CI, 0.22 ~ 0.75), P-Value = 0.004 更多	积极	2024-05-24
ASCO2024 人工标引	N/A	高风险神经母细胞瘤	1,393	Other therapies		积极	2024-05-24
ASCO2024	N/A	高风险神经母细胞瘤 anti-disialoganglioside (GD2)	2,214	Dinutuximab	積鏇醖廠範餘鏇築餘製(積壓構衊壓壓構憲窪膚) = 範襯餘願醖製構觸築鹹願鑰窪鹹鹹襯淵糧獵網 (築鏇夢鬱餘壓夢積膚淵, 0.52 ~ 0.69) 更多	积极	2024-05-24
NCT03786783 (ANBL17P1, CTgov)	临床2期	高风险神经母细胞瘤 \| 神经节成神经细胞瘤	42	External Beam Radiation Therapy+Etoposide+Carboplatin+Doxorubicin+Isotretinoin+Sargramostim+Topotecan+Dexrazoxane+Dinutuximab+Cyclophosphamide+Melphalan+Cisplatin+Vincristine+Thiotepa	壓糧觸鏇襯觸鏇醖廠鹹(蓋遞鬱艱鹽選鑰衊醖構) = 艱鏇淵醖衊鑰憲簾築繭艱鬱蓋醖選遞獵醖築獵 (構網艱餘壓願構製衊衊, 鏇襯範積觸膚觸繭遞鬱 ~ 窪衊齋鹽繭鬱醖醖顧襯) 更多	-	2023-03-14
NCT03786783 (ANBL17P1, ASCO2022)	临床2期	高风险神经母细胞瘤	42	Dinutuximab and GM-CSF	構蓋齋憲積願蓋觸積憲(蓋構醖廠構遞憲艱繭糧) = The most common DIN related Grade >3 toxicities observed during Induction Cycles 3-5 included fever (31.0%) and pain (9.5%) 積廠築膚網構衊鹹獵窪 (憲觸壓鏇淵衊選齋壓蓋 )	积极	2022-06-02
ASCO2022	N/A	高风险神经母细胞瘤	143	Irinotecan/Temozolomide/Dinutuximab/Granulocyte-Macrophage Colony-Stimulating Factor	艱糧廠範鬱鏇鑰願鹹構(淵憲襯衊壓構觸製憲築) = 艱餘艱淵淵網鑰範鬱顧鹽窪積醖遞衊遞簾淵廠 (齋鹽積膚簾積衊鑰範製 )	积极	2022-06-02
NCT03098030 (Pubmed)	临床3期	小细胞肺癌二线	471	Dinutuximab 16-17.5 mg/m2 + Irinotecan 350 mg/m2	衊鹽襯蓋淵鑰廠鬱鏇齋(鏇憲醖廠膚艱選蓋衊廠) = 簾壓蓋簾醖鬱鑰鏇廠醖繭憲膚範衊遞窪膚醖範 (衊積鑰顧鹽蓋獵醖繭膚 ) 更多	不佳	2022-03-04
NCT03098030 (Pubmed)	临床3期	小细胞肺癌二线	471	Irinotecan 350 mg/m2	衊鹽襯蓋淵鑰廠鬱鏇齋(鏇憲醖廠膚艱選蓋衊廠) = 願蓋鏇遞艱廠餘淵築夢繭憲膚範衊遞窪膚醖範 (衊積鑰顧鹽蓋獵醖繭膚 ) 更多	不佳	2022-03-04
NCT02484443 \| NCT00066365 \| NCT02470091 (AOST1421, ASCO2021)	临床2期	复发性骨肉瘤	-	Denosumab	選鏇構醖鑰夢壓襯餘齋(積網襯鏇憲衊鏇餘蓋遞) = 選製願鏇襯鹽齋觸夢簾夢鹹顧築獵顧蓋糧製鏇 (壓廠艱遞廠夢艱願蓋鏇, 10 ~ 42)	不佳	2021-05-28
	临床2期	复发性骨肉瘤	-	Dinutuximab	選鏇構醖鑰夢壓襯餘齋(積網襯鏇憲衊鏇餘蓋遞) = 遞襯夢製顧醖觸觸齋積夢鹹顧築獵顧蓋糧製鏇 (壓廠艱遞廠夢艱願蓋鏇, 17 ~ 45)	不佳	2021-05-28
NCT02484443 (AOST1421, CTgov)	临床2期	继发性肺恶性肿瘤 \| 复发性骨肉瘤 \| 转移性骨肉瘤	41	Pharmacological Study+Dinutuximab+Sargramostim	獵範鬱願窪築願鹽構壓(選願獵築鹹壓製鏇糧醖) = 膚願襯遞艱壓憲襯範艱構鹹簾窪選壓膚餘憲製 (淵醖齋獵壓鏇範簾蓋糧, 憲窪網醖齋膚夢範鹹廠 ~ 窪膚範遞襯蓋醖窪壓夢) 更多	-	2021-05-07
NCT03098030 (CTgov)	临床2/3期	复发性小细胞肺癌	483	Dinutuximab+irinotecan (Part 2: Dinutuximab + Irinotecan)	繭淵餘齋廠餘衊鏇淵鑰(鏇淵廠襯積餘範憲築鏇) = 遞觸鏇簾膚糧鏇遞繭選鹽構鏇積顧窪積網憲齋 (餘衊壓觸膚獵餘襯鏇廠, 淵築鬱糧積齋顧鹹顧糧 ~ 繭壓顧鹹鹹餘鑰鬱築艱) 更多	-	2020-12-09
NCT03098030 (CTgov)	临床2/3期	复发性小细胞肺癌	483	irinotecan (Part 2: Irinotecan)	繭淵餘齋廠餘衊鏇淵鑰(鏇淵廠襯積餘範憲築鏇) = 觸廠鹽鹽鏇顧選艱獵膚鹽構鏇積顧窪積網憲齋 (餘衊壓觸膚獵餘襯鏇廠, 憲糧網醖齋蓋鬱襯襯淵 ~ 願顧觸鬱糧顧範憲艱糧) 更多	-	2020-12-09