更新于：2024-05-01

Hepatocellular Carcinoma

肝细胞癌

更新于：2024-05-01

基本信息

别名

Adult Liver Cancer、Adult Liver Cancers、CARCINOMA LIVER

+ [94]

简介

A primary malignant neoplasm of epithelial liver cells. It ranges from a well-differentiated tumor with EPITHELIAL CELLS indistinguishable from normal HEPATOCYTES to a poorly differentiated neoplasm. The cells may be uniform or markedly pleomorphic, or form GIANT CELLS. Several classification schemes have been suggested.

关联

582

项与肝细胞癌相关的药物

Inbakicept

因奇西普

靶点

IL-15

作用机制

IL-15激动剂 [+1]

在研机构

National Cancer Institute [+7]

原研机构

Altor BioScience Corp.

在研适应症

非肌层浸润性膀胱肿瘤 [+24]

非在研适应症

急性淋巴细胞白血病 [+27]

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期2024-04-22

Vebreltinib

伯瑞替尼

靶点

c-Met

作用机制

c-Met抑制剂

在研机构

Apollomics, Inc. (United States) [+1]

原研机构

浙江冠科美博生物科技有限公司

在研适应症

IDH突变星形细胞瘤 [+15]

非在研适应症

c-Met阳性非小细胞肺癌 [+4]

最高研发阶段批准上市

首次获批国家/地区

中国

首次获批日期2023-11-14

Bevacizumab biosimilar(Sinocelltech Group)

贝伐珠单抗生物类似药(神州细胞工程)

靶点

VEGF-A

作用机制

VEGF-A抑制剂 [+1]

在研机构

原研机构

在研适应症

非在研适应症

最高研发阶段批准上市

首次获批国家/地区

中国

首次获批日期2023-06-27

5,016

项与肝细胞癌相关的临床试验

NCT06198296 / Not yet recruiting临床1期IIT

Immunotherapy For Adults With GPC3-Positive Solid Tumors Using Interleukin-15 And -21 Armored Glypican-3-Specific Chimeric Antigen Receptor Expressing Autologous T Cells

The body has different ways of fighting infection and disease. No single way seems perfect for fighting cancers. This research study combines two different ways of fighting cancer: antibodies and T cells.
Antibodies are types of proteins that protect the body from infectious diseases and possibly cancer. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including cells infected with viruses and tumor cells. Both antibodies and T cells have been used to treat patients with cancers. They have shown promise but have not been strong enough to cure most patients.
In order to get them to kill cancers more effectively, in the laboratory, the study team inserted a new gene called a chimeric antigen receptor (CAR) into T cells that makes them recognize cancer cells and kill them. When inserted, this new CAR T cell can specifically recognize a protein found on solid tumors, called glypican-3 (GPC3). To make this GPC3-CAR more effective, the study team also added two genes called IL15 and IL21 that help CAR T cells grow better and stay in the blood longer so that they may kill tumors better. When the study team did this in the laboratory, they found that this mixture of GPC3-CAR,IL15 and IL21 killed tumor cells better when compared with CAR T cells that did not have IL15 plus IL21 in the laboratory. This study will use those cells, which are called 21.15.GPC3-CAR T cells, to treat patients with solid tumors that have GPC3 on their surface.
The study team also wanted to make sure that they could stop the 21.15.GPC3-CAR T cells from growing in the blood should there be any bad side effects. In order to do so, they inserted a gene called iCasp9 into the FAST-CAR T cells. This allows us the elimination of 21.15.GPC3-CAR T cells in the blood when the gene comes into contact with a medication called AP1903. The drug (AP1903) is an experimental drug that has been tested in humans with no bad side-effects. This drug will only be used to kill the T cells if necessary due to side effects .
The study team has treated patients with T cells that include GPC3. Patients have also been treated with IL-21 and with IL-15. Patients have not been treated with a combination of T cells that contain GPC3, IL-21 and IL-15. To summarize, this study will test the effect of 21.15.GPC3-CAR T cells in patients with solid tumors that express GPC3 on their surface.
The 21.15.GPC3-CAR T cells are an investigational product not yet approved by the Food and Drug Administration.

开始日期2026-01-01

申办/合作机构

Baylor College of Medicine

[+1]

NCT05293158 / Not yet recruitingN/AIIT

Impact of Hepatitis B Immunoglobulins in Patients With Chronic Hepatitis B on Hepatocellular Carcinoma

In the current literature, infection with the hepatitis B virus (HBV) is described as one of the main risk factors for the development of hepatocellular carcinoma (HCC).
According to the current study situation, the Hepatitis B surface antigen (HBsAg) is considered as an important marker, since low levels and sero-clearance of HBsAg are both correlated with a lower risk of HCC development / recurrence.Currently there is no treatment option available that efficiently targets HBsAg. Besides neutralizing infectious HBV virions, Hepatitis B immunoglobulins (HBIG) can directly bind and neutralize extracellular HBsAg/SVPs, and even intracellular HBsAg targeting is reported. In addition, HBIGs can initiate effector-cell attack (via antibody-dependent cellular cytotoxicity, ADCC) towards infected hepatocytes.
The potential benefit of HBIGs in the HCC context is further underlined by recent evidence for the ability of HBIGs to reduce the viability, proliferation, and self-renewal of tumor-initiating cells (TICs) - isolated from HBV-HCC patients - accompanied by downregulation of stemness markers, e.g., OCT-4.According to the current study situation, the use of HBIGs significantly reduces the risk of HBV reinfection after transplantation and improves the results of liver transplantation in patients with chronic HBV infection. The potential benefit of treating HBV-HCC patients on the LTx (liver transplantation) waiting list with hepatitis B immunoglobulin is the possible stop or inhibition of tumor progression while waiting for an LTx. So far there is no clinical evidence of this.
Mechanistically, hepatitis B immunoglobulin could occur through neutralization of circulating HBsAg, which is an important driver of an immunosuppressive environment in HBV patients, and possibly through direct effects against HBV HCC tumor cells (through antibody-dependent cellular cytotoxicity, ADCC). Therefore, the idea behind preoperative HBIG administration before liver transplantation is to reduce the rate of patients in whom a transplantation would no longer have been possible due to tumor progression. Thus, due to tumor progression in HBV-positive HCC-patients there is a monthly drop-out from the waiting list of about 4%.
The basic idea behind the treatment of HBV-HCC patients before tumor resection with hepatitis B immunoglobulin is to potentially stop or positively influence tumor progression through the effects mentioned above, in the time between diagnosis and resection.
Zhou et al. (2015) have shown a connection between HBsAg levels and HCC relapses after resection, although the exact role of HBsAg is still unclear. In no case will the treatment postpone the time of tumor resection, as only patients are considered who, for clinical reasons, can expect a certain time until resection. The present proof of concept study aims to quantify HBsAg reduction due to preoperative administration of HBIGs in HBV-positive HCC-patients and serve as a template for future multicentre clinical trials.

开始日期2024-11-01

申办/合作机构

Medizinische Universität Graz

NCT06217094 / Not yet recruiting临床1期IIT

Phase I Study of NP-101 in Patients With Unresectable Hepatocellular Carcinoma (HCC) Undergoing Y-90 Treatment

Surgical resection and liver transplantation are the primary curative treatments for hepatocellular carcinoma (HCC). However, many patients are ineligible for these treatments due to advanced disease, social factors, or limited availability of liver donors. Therefore, for patients with unresectable HCC, locoregional therapies like transarterial radioembolization (TARE with Y90) are considered the next best non-operative option, especially when the cancer remains confined to the liver. Despite the use of these liver-directed therapies, relapse rates and mortality remain high, underscoring the need for new predictive biomarkers and therapeutic targets, including immune modulation.
The rationale behind NP-101 (TQ formula) stems from its immune modulatory properties as a potent drug derived from a natural substance, black seed or Nigella Sativa. Previous studies have demonstrated its immune modulation and anti-cancer effects, showing promise in preclinical models of HCC. In a randomized phase 2 study conducted in Covid patients, NP-101 exhibited safety and significantly increased T effector cells (CD4+ and CD8+ T lymphocytes), resulting in accelerated recovery. The immune modulation effect of NP-101, observed in the Covid study, and its potential to enhance CD4+ and CD8+ T effector lymphocytes can potentially modify the immune microenvironment and improve outcomes in locally advanced HCC patients undergoing Y90 treatment.
This study will investigate the safety, efficacy and maximum tolerated dose of NP-101 in patients with unresectable hepatocellular carcinoma.
The dosing scheme for NP-101 in this study will follow a Bayesian Optimal Interval design. Based on the target dose-limiting toxicity (DLT) rate of 30% and assuming a 3+3 design, three subjects will be sequentially enrolled at each of the 3 dose levels (beginning with 3g) until at least one DLT occurs.
If no DLTs occur, dosing will be escalated to the next dose level for the next three enrolled subjects. At either of the two dose levels, if 1 DLT occurs, three more subjects will be enrolled at that dose level. If no DLTs occur in these subjects, three more subjects will be enrolled at the next highest dose level. Dosing escalation will be stopped if two or more total DLTs occur at any dose level. The maximum tolerated dose (MTD) will be one dose level below the dose level at which two or more DLTs occurred.

开始日期2024-08-01

申办/合作机构

University of Florida

[+1]

100 项与肝细胞癌相关的临床结果

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100 项与肝细胞癌相关的转化医学

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0 项与肝细胞癌相关的专利（医药）

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146,785

项与肝细胞癌相关的文献（医药）

2024-12-31·Organogenesis

Lipid Nanovesicle Platforms for Hepatocellular Carcinoma Precision Medicine Therapeutics: Progress and Perspectives.

Review

作者: Brandon M Lehrich ; Evan R Delgado

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality globally. HCC is highly heterogenous with diverse etiologies leading to different driver mutations potentiating unique tumor immune microenvironments. Current therapeutic options, including immune checkpoint inhibitors and combinations, have achieved limited objective response rates for the majority of patients. Thus, a precision medicine approach is needed to tailor specific treatment options for molecular subsets of HCC patients. Lipid nanovesicle platforms, either liposome- (synthetic) or extracellular vesicle (natural)-derived present are improved drug delivery vehicles which may be modified to contain specific cargos for targeting specific tumor sites, with a natural affinity for liver with limited toxicity. This mini-review provides updates on the applications of novel lipid nanovesicle-based therapeutics for HCC precision medicine and the challenges associated with translating this therapeutic subclass from preclinical models to the clinic.

2024-12-31·Cancer biology & therapy

The role of liver cancer stem cells in hepatocellular carcinoma metastasis.

Review

作者: Qinghui Niu ; Susu Ye ; Liu Zhao ; Yanzhi Qian ; Fengchao Liu

Metastasis accounts for the vast majority of cancer deaths; however, this complex process has yet to be fully explained. To form metastases, cancer cells must undergo a series of steps, known as the "Metastatic cascade", each of which requires a specific functional transformation. Cancer stem cells (CSCs) play a vital role in tumor metastasis, but their dynamic behavior and regulatory mechanisms have not been fully elucidated. Based on the "Metastatic cascade" theory, this review summarizes the effect of liver CSCs on the metastatic biological programs that underlie the dissemination and metastatic growth of cancer cells. Liver CSCs have the capacity to initiate distant organ metastasis via EMT, and the microenvironment transformation that supports the ability of these cells to disseminate, evade immune surveillance, dormancy, and regenerate metastasis. Understanding the heterogeneity and traits of liver CSCs in these processes is critical for developing strategies to prevent and treat metastasis of advanced hepatocellular carcinoma (HCC).

2024-12-01·Journal of enzyme inhibition and medicinal chemistry

Anti-cancer activity and cellular uptake of 7,3',4'- and 7,8,4'-trihydroxyisoflavone in HepG2 cells under hypoxic conditions.

Article

作者: Wen-Sheng Tzeng ; Wei-Lin Teng ; Pao-Hsien Huang ; Feng-Lin Yen ; Yow-Ling Shiue

Transarterial chemoembolisation (TACE) is used for unresectable hepatocellular carcinoma (HCC) treatment, but TACE-induced hypoxia leads to poor prognosis. The anti-cancer effects of soybean isoflavones daidzein derivatives 7,3',4'-trihydroxyisoflavone (734THIF) and 7,8,4'-trihydroxyisoflavone (784THIF) were evaluated under hypoxic microenvironments. Molecular docking of these isomers with cyclooxygenase-2 (COX-2) and vascular endothelial growth factor receptor 2 (VEGFR2) was assessed. About 40 μM of 734THIF and 784THIF have the best effect on inhibiting the proliferation of HepG2 cells under hypoxic conditions. At a concentration of 40 μM, 784THIF significantly inhibits COX-2 expression in pre-hypoxia conditions compared to 734THIF, with an inhibition rate of 67.73%. Additionally, 40 μM 784THIF downregulates the expression of hypoxic, inflammatory, and metastatic-related proteins, regulates oxidative stress, and inhibits the expression of anti-apoptotic proteins. The uptake by HepG2 confirmed higher 784THIF level and slower degradation characteristics under post- or pre-hypoxic conditions. In conclusion, our results showed that 784THIF had better anti-cancer effects and cellular uptake than 734THIF.

3,306

项与肝细胞癌相关的新闻（医药）

2024-04-07

·药明康德

开辟mRNA新应用的蛋白替代疗法；使截肢率降低6倍的糖尿病辅助治疗…… | 一周盘点

▎药明康德内容团队编辑本期看点1. Moderna公司公布了其开发的mRNA蛋白替代疗法mRNA-3927的首个临床试验结果，将mRNA的应用范围扩展到疫苗之外。2. 中度或重度糖尿病足溃疡感染的外用辅助治疗pravibismane在早期临床试验中能够加速缩小溃疡面积，同时使患者与糖尿病溃疡相关的下肢截肢发生率降低了约6倍。药明康德内容团队整理mRNA-3927：公布1/2期临床试验数据Moderna公司在《自然》杂志上发表了其用于治疗丙酸血症（PA）的在研mRNA疗法mRNA-3927的积极早期临床数据。PA是由丙酰辅酶A羧化酶（PCC）的α或β亚基（分别由PCCA和PCCB基因编码）的致病变异引起的，这些变异会导致PCC缺乏，并使有毒的代谢物积累。该病的特点是反复出现的危及生命的代谢失代偿事件（MDE）和多系统并发症。目前，没有针对PA的根本原因的有效治疗方法。mRNA-3927是一种通过静脉给药、由脂质纳米颗粒（LNP）包裹的双mRNA疗法，该疗法编码PCCA和PCCB亚基蛋白以恢复肝脏中功能性PCC酶活性。通过编码细胞内蛋白，mRNA疗法可能在预防和治疗急性代谢失代偿中起作用。此次公布的中期分析显示，mRNA-3927表现出良好的安全性和耐受性，接受mRNA-3927治疗的患者的发病风险降低了70%。研究人员指出，这是首个在罕见疾病患者中，使用mRNA表达细胞内蛋白，作为蛋白替代疗法的临床试验。▲mRNA-3927降低患者出现危及生命的代谢失代偿事件的次数（图片来源：参考资料[16]）Pravibismane：公布1b期临床试验数据Microbion公司公布了其外用候选疗法pravibismane作为中度或重度糖尿病足溃疡感染的辅助治疗的1b期研究结果。Pravibismane具有独特的三重新型作用模式，包括强效广谱抗感染性、抗生物膜活性和免疫调节活性。此次公布的结果显示，pravibismane的耐受性良好，全身吸收率极低，没有出现任何治疗引发的不良反应或严重不良事件。与安慰剂组相比，接受pravibismane治疗的受试者溃疡面积缩小了约3倍（85%对比30%），与糖尿病溃疡相关的下肢截肢发生率降低了约6倍（2.6%对比15.4%）。这些结果表明，局部使用pravibismane有望满足糖尿病溃疡患者的未竟药物需求，这种新疗法可以同时治疗细菌生物膜相关感染并加速缩小溃疡面积，并有可能导致伤口完全再上皮化和闭合，同时降低患者再感染和截肢的风险。Deltacel（KB-GDT-01）：公布1期临床试验中第三例患者的数据Kiromic BioPharma公司公布了其在研γ-δ T细胞（GDT）疗法Deltacel（KB-GDT-01）用于治疗IV期转移性非小细胞肺癌（NSCLC）患者的1期临床试验的积极早期疗效数据。Deltacel是一种同种异体细胞治疗产品，由未经修饰的供体来源GDT组成。Deltacel旨在利用GDT的天然效力靶向实体瘤，最初的临床开发重点是NSCLC（约占肺癌病例的80%至85%）。两项临床前研究的数据表明，Deltacel与低剂量放射治疗相结合具有良好的安全性和有效性。从治疗开始六周后获得的初步结果显示，Deltacel在控制肿瘤生长方面具有有效性，以及良好的安全性和耐受性。此前公布的首例患者在治疗前三天被确诊为病情进展活跃。接受Deltacel治疗六周后，计算机断层扫描（CT）扫描证实了此患者的病情稳定，初步的无进展生存期为一个半月。第二例患者在治疗开始前进行了核磁共振（MRI）扫描，发现了新的转移灶，这些新病灶在治疗后第六周的MRI复查中被发现已完全消退。此次公布的第三例患者在入组时疾病处于活动期，接受治疗后的第六周时，PET/CT、诊断CT和MRI扫描结果均显示患者的疾病正趋于稳定，没有出现新的转移性疾病。cNeT：公布1/2a期临床试验的中期数据Achilles Therapeutics公司公布了关于克隆性新抗原反应性T细胞（cNeT）在晚期不可切除或转移性NSCLC患者中、以及在复发性或转移性恶性黑色素瘤患者中的早期临床试验的中期数据。此次公布的数据显示，25%（3/12）的高剂量组患者达到疾病稳定（SD）状态，肿瘤体积有所缩小。而因为与IL-2相关的毒性更少，cNeT的安全性和耐受性与标准的肿瘤浸润淋巴细胞疗法相比更有优势。FG-3246：公布1期临床试验数据FibroGen公布了其与Fortis Therapeutics联合开发的潜在“first-in-class”抗体偶联药物（ADC）FG-3246（亦称FOR46）在1期临床试验中获得积极顶线数据。FG-3246旨在治疗转移性去势抵抗性前列腺癌和其他肿瘤类型，其靶向的CD46是一种细胞受体靶点，在前列腺癌和其他肿瘤类型中高度表达，并在大多数正常组织中表达非常有限。FG-3246由抗CD46抗体与抗有丝分裂剂MMAE连接而成，MMAE是一种已经过临床验证的ADC有效载荷。此次公布的结果显示，36%可评估前列腺特异性抗原（PSA）的患者被观察到PSA减少超过50%（PSA50）。对于可根据RECIST评估的患者，20%达到部分缓解（PR），定义为肿瘤缩小超过30%，中位缓解持续时间为7.5个月。在这批接受大量前期治疗的患者中，中位放射学无进展生存期（rPFS）为8.7个月。最常见的不良事件与其他包含细胞毒性药物MMAE作为载荷的ADCs一致，包括输液相关反应、疲劳、体重减轻、中性粒细胞减少和周围神经病变。Itolizumab：公布1b期临床试验数据Equillium公司公布了其在研单克隆抗体itolizumab治疗狼疮性肾炎的1b期临床试验的积极顶线数据。Itolizumab是一种潜在“first-in-class”的CD6靶向单克隆抗体，可选择性靶向CD6-ALCAM信号通路，选择性抑制致病性效应T细胞，同时保留对维持平衡免疫反应至关重要的调节T细胞。T细胞可驱动多种免疫炎症疾病，该通路在调节T细胞的活性和运输方面发挥着核心作用。此次公布的结果显示，当itolizumab联合吗替麦考酚酯/霉酚酸（MMF/MPA）和皮质类固醇使用时，与标准治疗方法相比，患者达成完全缓解（CR）和PR的比例更高，且尿蛋白肌酐比值（UPCR）的降低更为迅速和显著。大多数治疗伴发不良反应（TEAE）的严重程度被评估为轻度（1级）或中度（2级），其中两种最常见的TEAE是淋巴细胞减少和外周水肿。CONV01-α：公布1/2期临床试验数据Convergent Therapeutics的主打在研疗法CONV01-α是一种与锕-225（Ac-225）结合的单克隆抗体，靶向前列腺特异性膜抗原（PSMA）。锕-225是一种放射性α粒子发射器。CONV01-α的一个关键功能特性是，一旦与PSMA结合，它就会被内化，将其强大的放射性有效成分直接送入前列腺癌细胞，同时将对周围健康组织的损害降至最低。新闻稿指出，CONV01-α有望成为首个获批用于前列腺癌治疗的Ac-225放射性抗体。在一项针对晚期前列腺癌患者的多剂量、剂量递增研究中，患者对CONV01-α的耐受性良好，67%的患者达到了PSA50，27%的患者被观察到PSA减少超过90%（PSA90）。正在进行的研究表明，CONV01-α在单独使用或与其他癌症疗法联合使用时可能非常有效。TPST-1120：公布1期临床试验数据Tempest Therapeutics公司公布了其在研疗法TPST-1120单药或联用纳武利尤单抗治疗晚期实体瘤的1期试验的积极结果。TPST-1120是一种口服、选择性PPARα小分子拮抗剂。临床前数据显示，TPST-1120可直接杀死肿瘤细胞，并靶向肿瘤微环境中的抑制性免疫通路。这两种类型中的靶向细胞皆依赖脂肪酸代谢，该代谢过程由PPARα转录因子调节。在一项针对接受过多次治疗的晚期实体瘤患者的1期临床试验中，TPST-1120单药治疗和与PD-1抑制剂纳武利尤单抗联合应用均导致肿瘤缩小及生物标志物的变化。此次公布的临床数据显示，TPST-1120单药或联用纳武利尤单抗的耐受性良好，最大耐受剂量尚未确定。在接受单药治疗的患者中，53%（10/19）可评估患者的最佳缓解是SD，其中5名患者的治疗时间超过5个月。21%的患者（4例）在接受治疗后靶病灶缩小，另有3例患者的最佳缓解是靶病灶无生长。在此前接受过多线治疗的胆管癌（CCA）、肝细胞癌（HCC）和肾细胞癌（RCC）患者的联合治疗队列中，所有剂量水平的客观缓解率（ORR）为23%（3/13，均为PR）。在曾接受过抗PD-1治疗并疾病进展的RCC和CCA患者中，ORR为50%（2/4）。全血标本分析显示，PPARα相关免疫基因的表达与TPST-1120的剂量水平有关。其中一些变化仅在部分获得缓解的患者中观察到，这说明TPST-1120的生物活性与患者的临床结局有关。SZN-043：公布1a期临床试验数据Surrozen公司公布了SZN-043在健康受试者和肝硬化患者中进行的1a期临床试验的最新进展。SZN-043是采用Surrozen的SWEETS技术开发的首个候选药物，旨在治疗严重肝病。在这项研究中，SZN-043在所有受试者中均表现出了可接受的安全性和耐受性。在有肝病史的肝硬化患者中，SZN-043能够呈剂量依赖性地激活Wnt信号转导，并改善患者的肝功能。ELI-002：公布1期临床试验的新数据Elicio Therapeutics公司公布了其在研治疗性癌症免疫疗法ELI-002治疗具高复发风险胰腺癌和结直肠癌患者的新临床试验数据，这些患者携带KRAS G12D和G12R突变。ELI-002由AMP修饰的KRAS突变体（mKRAS）肽段，和一种AMP修饰的免疫刺激寡核苷酸佐剂ELI-004组成，经皮下给药靶向淋巴结。它能产生RAS特异性杀伤性T细胞，以攻击术后残留肿瘤细胞，有望延长癌症患者缓解并可预防未来复发。此次公布的结果显示，68%接受ELI-002治疗的患者产生了细胞毒性mKRAS特异性CD4+T细胞；84%的患者产生了细胞毒性mKRAS特异性CD8+T细胞；大多数接受ELI-002治疗的患者都出现了抗原扩散，诱导的T细胞靶向mKRAS以外的其他患者特异性肿瘤突变；在大多数接受ELI-002加强剂量治疗的患者中观察到持久的mKRAS特异性T细胞应答，记忆T细胞表型增加。大家都在看药明康德为全球生物医药行业提供一体化、端到端的新药研发和生产服务，服务范围涵盖化学药研发和生产、生物学研究、临床前测试和临床试验研发、细胞及基因疗法研发、测试和生产等领域。如您有相关业务需求，欢迎点击下方图片填写具体信息。▲如您有任何业务需求，请长按扫描上方二维码，或点击文末“阅读原文/Read more”，即可访问业务对接平台，填写业务需求信息▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料（可上下滑动查看）[1] Hanmi Pharm submits IND to US FDA for obesity drug HM15275 phase 1 trial. Retrieved April 7, 2024, from https://www.koreabiomed.com/news/articleView.html?idxno=23719[2] Equillium Announces Positive Topline Data from the Type B Portion of the Phase 1b EQUALISE Study of Itolizumab in Lupus Nephritis. Retrieved April 7, 2024, from https://www.businesswire.com/news/home/20240401373328/en[3] Context Therapeutics Submits IND Application to Evaluate CTIM-76 in Claudin 6-Positive Cancers. Retrieved April 7, 2024, from https://www.globenewswire.com/news-release/2024/04/01/2855097/0/en/Context-Therapeutics-Submits-IND-Application-to-Evaluate-CTIM-76-in-Claudin-6-Positive-Cancers.html[4] FibroGen Announces Topline Results from Phase 1 Monotherapy Study of FG-3246 in Patients with Metastatic Castration-Resistant Prostate Cancer. Retrieved April 7, 2024, from https://www.globenewswire.com/news-release/2024/04/02/2856521/33525/en/FibroGen-Announces-Topline-Results-from-Phase-1-Monotherapy-Study-of-FG-3246-in-Patients-with-Metastatic-Castration-Resistant-Prostate-Cancer.html[5] Convergent Therapeutics Announces FDA Clearance of IND Application for CONV01-α, a Best-in-Class Radioantibody Targeting Prostate-Specific Membrane Antigen. Retrieved April 7, 2024, from https://www.prnewswire.com/news-releases/convergent-therapeutics-announces-fda-clearance-of-ind-application-for-conv01--a-best-in-class-radioantibody-targeting-prostate-specific-membrane-antigen-302106271.html[6] Caribou Biosciences Expands Clinical Development of CB-010 with FDA Clearance of IND in Lupus. Retrieved April 7, 2024, from https://www.globenewswire.com/news-release/2024/04/04/2858178/0/en/Caribou-Biosciences-Expands-Clinical-Development-of-CB-010-with-FDA-Clearance-of-IND-in-Lupus.html[7] iECURE Announces FDA Clearance of Investigational New Drug Application for ECUR-506 to Initiate OTC-HOPE Trial for Treatment of Neonatal Onset Ornithine Transcarbamylase Deficiency in the U.S. Retrieved April 7, 2024, from https://www.businesswire.com/news/home/20240404289854/en[8] Tempest Announces Publication of Positive Data from Phase 1 Trial of TPST-1120 in Patients with Advanced Solid Tumors in Journal of Cancer Research Communications. Retrieved April 7, 2024, from https://www.globenewswire.com/news-release/2024/04/04/2857718/0/en/Tempest-Announces-Publication-of-Positive-Data-from-Phase-1-Trial-of-TPST-1120-in-Patients-with-Advanced-Solid-Tumors-in-Journal-of-Cancer-Research-Communications.html[9] Verismo Therapeutics Announces Submission of IND Application to the FDA for SynKIR™-310 in Relapsed/Refractory B-cell NHL. Retrieved April 7, 2024, from https://www.prnewswire.com/news-releases/verismo-therapeutics-announces-submission-of-ind-application-to-the-fda-for-synkir-310-in-relapsedrefractory-b-cell-nhl-302106584.html[10] EILEAN THERAPEUTICS RECEIVES CLEARANCE TO INITIATE R/R AML TRIAL WITH LOMONITINIB, A SELECTIVE PAN-FLT3/IRAK4 INHIBITOR. Retrieved April 7, 2024, from https://www.prnewswire.com/news-releases/eilean-therapeutics-receives-clearance-to-initiate-rr-aml-trial-with-lomonitinib-a-selective-pan-flt3irak4-inhibitor-302108790.html[11] Microbion's Topical Pravibismane Phase 1b Moderate or Severe Diabetic Foot Ulcer Infection Study is Published in International Wound Journal. Retrieved April 7, 2024, from https://www.prnewswire.com/news-releases/microbions-topical-pravibismane-phase-1b-moderate-or-severe-diabetic-foot-ulcer-infection-study-is-published-in-international-wound-journal-302107893.html[12] Elicio Therapeutics to Present Updated Clinical T Cell and Antigen Spreading Response Data from the Ongoing AMPLIFY-201 Phase 1 Study of ELI-002 and Preclinical Data on ELI-007 and ELI-008 at the AACR Annual Meeting. Retrieved April 7, 2024, from https://elicio.com/press_releases/elicio-therapeutics-to-present-updated-clinical-t-cell-and-antigen-spreading-response-data-from-the-ongoing-amplify-201-phase-1-study-of-eli-002-and-preclinical-data-on-eli-007-and-eli-008-at-the-aacr/[13] Achilles Therapeutics Provides Interim Phase I/IIa Update on Clonal Neoantigen Reactive T Cells in Advanced NSCLC and Melanoma Including First Patients Dosed with Enhanced Host Conditioning. Retrieved April 7, 2024, from https://ir.achillestx.com/news-releases/news-release-details/achilles-therapeutics-provides-interim-phase-iiia-update-clonal[14] Kiromic BioPharma Reports Favorable Safety, Tolerability, and Early Efficacy from Third Patient in Deltacel-01 Clinical Trial. Retrieved April 7, 2024, from https://www.businesswire.com/news/home/20240402903280/en[15] Surrozen Announces Safety, Pharmacodynamic and Liver Function Data for SZN-043. Retrieved April 7, 2024, from https://investors.surrozen.com/news-releases/news-release-details/surrozen-announces-safety-pharmacodynamic-and-liver-function[16] Koeberl et al., (2024). Interim analyses of a first-in-human phase 1/2 mRNA trial for propionic acidaemia. Nature, https://doi-org.libproxy1.nus.edu.sg/10.1038/s41586-024-07266-7免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

信使RNA临床结果临床2期临床1期疫苗

2024-04-07

·PRNewswire

Geneos Therapeutics Announces Positive Phase 1/2 Data for GT-30 Trial of Personalized Therapeutic Cancer Vaccine

Trial has met primary endpoints of safety and immunogenicity and secondary endpoint for efficacy based on response rate Trial data published today in Nature Medicine Selected clinical trial data also presented at the 2024 AACR Annual Meeting PHILADELPHIA, April 7, 2024 /PRNewswire/ -- Geneos Therapeutics, a clinical stage biotherapeutics company focused on the development of personalized therapeutic cancer vaccines (PTCVs), today announced the publication of positive safety, immunogenicity, and efficacy data from the full cohort of patients enrolled in its GT-30 clinical trial in Nature Medicine. The paper, titled, "Personalized Neoantigen Vaccine and Pembrolizumab in Advanced Hepatocellular Carcinoma: A phase 1/2 trial," details the GT-30 clinical trial, a 36-patient, single-arm, open-label, multi-center Phase 1/2 study of GNOS-PV02, a DNA plasmid encoded PTCV in combination with DNA plasmid encoded IL-12 (a cytokine adjuvant), and pembrolizumab (a PD-1 inhibitor) in second-line (2L) patients with advanced hepatocellular carcinoma (HCC) previously treated with a multi-tyrosine kinase inhibitor. The study met its primary endpoints of safety and immunogenicity and its secondary endpoint of efficacy based on observed response rate (ORR). PTCV-related adverse events were all limited to Grades 1 and 2 with no dose-limiting toxicities or grade > 3 adverse events observed. The most common adverse events were injection site reactions observed in 41.6% (15/36) of patients. This is in contrast to typical immuno-oncology combination regimens, including those approved for first-line use in advanced HCC, wherein adding a second agent may lead to markedly increased toxicity; here, the addition of a PTCV to a PD-1 inhibitor was not observed to lead to any significant decrease in patient safety and tolerability. The ORR for GT-30 is currently at 30.6% (11/36), including three complete responses (CR) and eight partial responses. This response is statistically significant based on pre-specified criteria at a one-sided p-value = 0.031 (1-sided 90% CI 20.4%-100%) versus a pre-specified historical control of 16.9% for pembrolizumab monotherapy. This historical comparator response rate was modeled on Phase 3 KN-240 data presented at ASCO 2019 and is also consistent with the prior Phase 2 KN-224 study. As an overall class, anti-PD1 monotherapy for 2L advanced HCC has shown response rates of 11%-18% in seven Phase 2 and Phase 3 clinical studies enrolling over 1400 patients. Additionally, the GT-30 CR rate of 8.3% (3/36) compares with a historical anti-PD-1 monotherapy CR rate in 2L of 0% - 3% in the prior studies. As of the data cutoff, the median OS (mOS) in GT-30 was 19.9 months compared to a mOS range of 12.9 – 15.1 months reported for the prior 2L studies of pembrolizumab and other anti-PD-1 monotherapy. 11 of 36 patients remain on treatment and, in total, 17 patients continue to be followed for overall survival (OS). "Other recent industry trials have tested personalized cancer vaccines in patients with highly immune-sensitive tumor phenotypes and no measurable disease. In marked contrast, the GT-30 trial assesses PTCVs in HCC, a cancer with very low tumor mutational burden and an immune-excluded phenotype, and in patients with significant late-stage unresectable and metastatic disease," said Niranjan Sardesai, PhD, CEO and president of Geneos. "Despite the small size of this study, our results are important for the advancement of the field. We have not only met endpoints for safety, immunogenicity, and clinical efficacy based on ORR in this difficult to treat setting, but our mechanism of action data trace and confirm every step, from vaccination to tumor reduction, required to explain the immunological basis for the observed clinical responses." Immunological analyses confirm the induction of new T cell responses to vaccine-encoded neoantigens in 14 of 14 (100%) evaluated patients and the expansion of this TCR repertoire both in the peripheral blood and tumors of PTCV-treated patients. Single cell sequencing analyses show the vast majority of these T cell clones to be CD8 T effector memory cells, a key requirement to induce anti-tumor cytotoxicity. In contrast, while anti-PD-1 monotherapy has been observed to reverse T cell dysfunction in existing neoantigen-specific T cell clones, it is not known to induce any new neoantigen-specific T cell clones. Today Geneos also presented selected GT-30 clinical trial data and updated longitudinal circulating tumor DNA (ctDNA) biomarker data from the trial at the 2024 American Association for Cancer Research (AACR) Annual Meeting in San Diego. Reductions of at least 50% versus baseline in patient ctDNA, an exploratory endpoint, were seen in 40.7% of patients (11 of 27 patients for whom the full data set are available). All such responses correlate with ongoing survival. "To our knowledge, the GT-30 clinical study provides the first definitive demonstration of a personalized cancer vaccine enhancing clinical response to anti-PD-1 therapy by inducing new, neoantigen-specific T cells which traffic to the tumor," said Ildiko Csiki, MD, PhD, chief medical officer of Geneos. "The fact that the PTCV regimen has produced this important result in a form of cancer as immunologically 'cold' as HCC, leading to multiple complete responses and a doubling of objective response versus PD-1, is incredibly promising and shows the therapeutic potential of personalized cancer vaccines for cancer patients." DNA-based PTCVs may include up to 40 neoantigens. The majority of patients in the GT-30 study were administered PTCVs which included all of their targetable neoantigens across a broad range of predicted MHC binding affinity. A correlation was seen in GT-30 between the number of vaccine epitopes and the number of reactive epitopes post-vaccination, suggesting that having more neoantigens in the vaccine increased the effectiveness of tumor control. Other personalized vaccine platforms, especially those not based on DNA, have historically had to target a more limited selection of neoantigens, which may limit their efficacy. About Geneos Therapeutics Geneos Therapeutics, a clinical stage biotherapeutics company, is developing personalized therapeutic cancer vaccines (PTCVs) that may serve an important role in new immunotherapeutic paradigms for cancer. The company's approach, using its proprietary GT-EPIC™ platform, is to target neoantigens (abnormal mutations produced by cancer cells) from individual patient tumors to develop novel and uniquely personalized treatments for cancer. Planning is underway for a potentially registrational clinical trial in advanced hepatocellular carcinoma. For more information, please visit . This press release contains certain forward-looking statements relating to our business, including our plans regarding the development of personalized therapeutic cancer vaccines and the therapeutic potential and clinical benefits of our product candidates. Actual events or results may differ from the expectations set forth herein. There can be no assurance that any product candidate in Geneos' pipeline will be successfully developed, manufactured or commercialized, that final results of clinical trials will be supportive of regulatory approvals required to market licensed products, or that any of the forward-looking information provided herein will be proven accurate. Forward-looking statements speak only as of the date of this release, and Geneos undertakes no obligation to update or revise these statements, except as may be required by law. This press release does not constitute an offer to sell or the solicitation of an offer to buy any securities. SOURCE Geneos Therapeutics, Inc.

临床结果疫苗AACR会议免疫疗法临床2期

2024-04-05

·CPHI制药在线

攻克gBRCA突变/HER2-乳腺癌，PARP抑制剂有望再出新组合

关注并星标CPHI制药在线日前，恒瑞医药的「氟唑帕利胶囊」和「甲磺酸阿帕替尼片」被CDE拟纳入突破性治疗品种，适应症为：两者联合治疗gBRCA突变的HER2阴性乳腺癌。氟唑帕利（艾瑞颐®）是恒瑞医药自主研发的一款PARP抑制剂，已在国内获批两项适应症：既往经二线及以上化疗的伴有胚系BRCA突变(gBRCAm)的铂敏感复发性卵巢癌、输卵管癌或原发性腹膜癌（2020.12）；铂敏感的复发性上皮性卵巢癌、输卵管癌或原发性腹膜癌成人患者在含铂化疗达到完全缓解或部分缓解后的维持治疗（2021.06）。此外，氟唑帕利单药或联合阿帕替尼用于晚期上皮性卵巢癌、输卵管癌或原发性腹膜癌患者在一线含铂化疗达到完全缓解或部分缓解后的维持治疗的上市申请正在国内接受审查（相关受理号为：CXHS2300070）。甲磺酸阿帕替尼（艾坦®）是恒瑞自主研发的小分子抗血管生成靶向药（作用靶点为VEGFR-2），目前已在国内获批三项适应症：既往至少接受过2种系统化疗后进展或复发的晚期胃腺癌或胃-食管结合部腺癌（2014.10）；既往接受过至少一线系统性治疗后失败或不可耐受的晚期肝细胞癌（HCC）（2020.12）；联合PD-1抑制剂卡瑞利珠单抗一线治疗晚期肝细胞癌（2023.01）。氟唑帕利联合阿帕替尼被开发用于治疗gBRCA突变、HER2-乳腺癌是有理论和临床研究支持的。研究发现，抗血管生成药物可以引起肿瘤微环境缺氧，导致遗传不稳定性和BRCA1/2的下调，从而增强对PARP抑制剂的敏感性。既往研究也表明PARP抑制剂来联合抗血管生成药物可改善患者PFS。《BMC Medicine》上发表的氟唑帕利联合阿帕替尼治疗晚期卵巢癌和三阴性乳腺癌的1期研究结果显示：最高剂量下，即氟唑帕利100mg联合阿帕替尼500mg治疗组的客观缓解率（ORR）为50%，其中gBRCA突变的患者ORR和中位无进展生存期（PFS）均优于gBRCA野生型患者。而且，氟唑帕利联合阿帕替尼治疗晚期卵巢癌或三阴性乳腺癌患者安全性良好。期待氟唑帕利联合阿帕替尼可以早日攻克gBRCA突变、HER2-乳腺癌。 gBRCA突变、HER2-乳腺癌治疗现状据WHO最新数据，乳腺癌已取代肺癌成为全球第一大恶性肿瘤，2020年全球新增病例达226万。BRCA1/2基因是目前已知最主要的乳腺癌易感基因，约5%-10%的乳腺癌患者携带BRCA基因突变。携带BRCA1/2基因突变的乳腺癌在临床上表现出更强的侵袭性，预后相对较差。 BRCA是人体内重要的抑癌基因，主要通过同源重组修复（HRR）途径参与DNA双链断裂修复，来“医治”细胞内因突变而造成的遗传物质的损伤，防治细胞癌变。BRCA突变包括胚系BRCA（gBRCA）突变和体细胞BRCA（sBRCA）突变，其中gBRCA突变来源于生殖细胞（卵子/精子），在三阴性乳腺癌（TNBC，ER-/PR-/HRE2-）和HR+/HER2-型乳腺癌患者中发生率较高。 PARP（多聚腺苷二磷酸核糖聚合酶）主要作用于DNA单链损伤修复，当双链断裂修复过程中的BRCA1、BRCA2和PALB2等蛋白所在的DNA同源重组修复（HRR）通路失效时，PARP就能接替HRR工作继续进行DNA修复。基于“合成致死”原理，理论上PARP抑制剂可用于治疗BRCA突变肿瘤。目前，全球获批治疗gBRCA突变、HER2阴性乳腺癌的疗法有限。其中阿斯利康与默沙东合作开发的PARP抑制剂奥拉帕利（Lynparza）于2018年1月被FDA批准用于治疗携带gBRCA基因突变、HER2-转移性乳腺癌。此外，该药还于2022年3月被FDA批准单药或联合内分泌治疗用于既往接受过新辅助或辅助化疗的gBRCA1/2突变的HER2-早期高危乳腺癌成人患者的辅助治疗。辉瑞PARP抑制剂他拉唑帕利（Talzenna）于2018年10月被FDA批准用于治疗gBRCA突变、HER2-局部晚期或转移性乳腺癌。遗憾的是，上述两款药物均未在国内获批治疗gBRCA突变、HER2-乳腺癌。不过奥拉帕利单药或联合内分泌疗法用于既往接受过新辅助或辅助化疗的gBRCA1/2突变、HER2-早期高危乳腺癌成人患者辅助治疗的上市申请正在国内接受优先审查。此外，国内还有多款PARP抑制剂被开发用于治疗gBRCA突变、HER2-乳腺癌，如天士力的TSL-1502、百济神州的帕米帕利、上海药物研究所的希明哌瑞。其中TSL-1502是天士力帝益药业开发的一款PARP抑制剂，对多种BRCA1/2突变的人肿瘤裸小鼠皮下移植模型有明显疗效，并且对BRCA野生型肿瘤明显增效其他细胞毒药物（卡铂、伊立替康）的抗肿瘤作用。而且，TSL-1502体内、体外活性总体上与奥拉帕利相当。目前，TSL-1502针对gBRCA突变、HER2-局部晚期或转移性乳腺癌的临床试验已进入2期。帕米帕利是一种PARP1和PARP2的强效、选择性抑制剂，已于2021年5月在国内被批准用于治疗既往经过二线及以上化疗的伴gBRCA突变的复发性晚期卵巢癌、输卵管癌或原发性腹膜癌。已公布的帕米帕利治疗携带gBRCA突变晚期或转移性TNBC和HR+/HER2-乳腺癌的开放标签、单臂2期临床研究BGB-290-201数据显示：TNBC队列中，独立评审委员会(IRC)评估的客观反应率（ORR）为38.2%，中位缓解持续时间(mDoR)为7.0个月，中位无进展生存期(mPFS)为5.5个月，中位总生存期(mOS)为17.1个月；HR+/HER2-队列中，IRC评估的ORR为61.9%，mDoR为7.5个月，mPFS为9.2个月，mOS未达到。而且，TNBC的ORR亚组分析显示，既往接受化疗线数较少的患者ORR更高：帕米帕利一线治疗患者的ORR达到66.7%；帕米帕利二线治疗患者ORR的为34.5%；帕米帕利三线治疗患者的ORR为9.1%。同时，与使用过铂类患者相比，未使用过铂类患者有更高的ORR：既往未接受铂治疗的患者ORR达到50.0%，既往接受铂治疗的患者ORR为24.0%。安全性方面，帕米帕利治疗乳腺癌最常见的≥3级治疗相关TEAE是血液学不良事件，包括贫血、白细胞计数水平下降和中性粒细胞计数水平下降等，发生率与其他PARP抑制剂相一致，整体安全可控。 BGB-290-201研究是首个公布PARP抑制剂专门针对中国乳腺癌患者疗效和安全性数据的临床研究，已公布的数据也算积极，帕米帕利未来或成为我国携带gBRCA突变晚期或转移性TNBC和HR+/HER2-乳腺癌患者的新选择。不过笔者疑惑的是，自2021年该研究数据公布后，帕米帕利在该适应症上未再公布新进展。总结随着下一代测序技术（NGS）的发展，BRCA基因检测更加便捷和准确。乳腺癌NCCN指南2022.v4版推荐对所有复发或转移性乳腺癌患者行胚系BRCA1/2突变评估，以确定适合接受PARP抑制剂治疗的患者。目前，全球获批治疗携带gBRCA基因突变、HER2-乳腺癌的PARP抑制剂仅有奥拉帕利和他拉唑帕利。目前，国内还未有PARP抑制剂获批治疗携带gBRCA突变、HER2-乳腺癌，该领域还存在很大未满足的市场需求。从目前相关药物进度来看，阿斯利康的奥拉帕利有望在国内率先获批。恒瑞医药开发氟唑帕利联合阿帕替尼治疗携带gBRCA基因突变、HER2-乳腺癌有望给药企在该领域开发性药物组合带来新思路。目前全球已有多款CDK4/6抑制剂被开发用于治疗HR+/HER-乳腺癌、Trop-2靶向ADC、PD-1/L单抗被批准用于治疗TNBC，或许PARP抑制剂可以联合更多类型药物治疗携带gBRCA突变、HER2-乳腺癌。【智药研习社近期课程预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

临床结果突破性疗法临床2期优先审批上市批准