Phase I/II Open Label Non-randomised Safety and Efficacy Study of the Viral Vectored ChAd-MVA 5T4 Vaccine in Combination With PD-1 Checkpoint Blockade in Low- or Intermediate-risk Localized or Locally Advanced Prostate Cancer and Advanced Metastatic Prostate Cancer

This is a clinical trial of a new treatment for prostate cancer that is a type of vaccine that could be a new way to treat cancer. A vaccine that could alert the immune system to the presence of cancer cells in the body may enable the immune system to target and kill those cells effectively. This vaccine is intended to work by making the immune system kill cells that have a special protein (called 5T4) that is present on the surface of cancer cells. The vaccine is made up of two recombinant viruses ("ChAdOx1"- chimpanzee adenovirus Ox1 and "MVA" - modified vaccinia Ankara) that have been designed to produce the 5T4 protein and have been modified so that they are weakened and cannot reproduce themselves within the body like normal viruses. Once injected into the body, these viruses make the 5T4 protein and help the body's immune system to learn to target this protein and destroy cancer cells.
This vaccine will be used in combination with the immunotherapy drug called nivolumab which is an anti-PD-1 (Programmed Death protein-1) monoclonal antibody. This is a molecule that releases the brakes on the immune system and helps the immune system to kill cancer cells more efficiently. Nivolumab as a monotherapy was approved for treatment of several tumour types but not for the prostate cancer.
This study will evaluate the safety and efficacy of ChAdOx1-MVA 5T4 vaccine in combination with nivolumab in low and intermediate risk prostate cancer patients who have elected to have their prostate removed and in patients with advanced metastatic prostate cancer.

开始日期2018-12-10

申办/合作机构

University of Oxford

[+1]

EUCTR2017-001992-22-GB / Unknown status临床2期IIT

Phase II open label randomised safety and efficacy study of the viral vectored ChAd-MVA 5T4 vaccine in combination with PD-1 checkpoint blockade in low- or intermediate-risk localized or locally advanced prostate cancer and advanced metastatic prostate cancer - VAccination in early and ADvanced prostate caNCEr (ADVANCE)

开始日期2018-06-12

申办/合作机构

University of Oxford

NCT02390063 / Completed临床1期IIT

A Randomized Phase I Study to Determine the Safety and Immunogenicity of ChAd-MVA Vaccination Compared to MVA Alone With and Without Low Dose Cyclophosphamide in Low and Intermediate Risk Localised Prostate Cancer

This is a clinical trial of a new treatment for prostate cancer that is a type of vaccine that could be a new way to treat cancer. A vaccine that could alert the immune system to the presence of cancer cells in the body may enable the immune system to target and kill those cells effectively. This vaccine is intended to work by making the immune system kill cells that have a special protein (called 5T4) that is present on the surface of cancer cells. The vaccine is made up of two recombinant viruses ("ChAdOx1" and "MVA") that have been designed to produce the 5T4 protein and have been modified so that they are weakened and cannot reproduce themselves within the body like normal viruses. Once injected into the body, these viruses make the 5T4 protein and help the body's immune system to learn to target this protein and destroy cancer cells.
This is a first-in-human study to evaluate the safety and immunogenicity of ChAdOx1.5T4-MVA.5T4 vaccination regime. It is evaluated in neo-adjuvant setting in low and intermediate risk localised prostate cancer patients who have either decided to have their prostate removed or are stable on active surveillance.

开始日期2015-06-01

申办/合作机构

University of Oxford

100 项与 ChAdOx1 MVA 5T4 vaccine (Vaccitech) 相关的临床结果

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100 项与 ChAdOx1 MVA 5T4 vaccine (Vaccitech) 相关的转化医学

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100 项与 ChAdOx1 MVA 5T4 vaccine (Vaccitech) 相关的专利（医药）

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项与 ChAdOx1 MVA 5T4 vaccine (Vaccitech) 相关的文献（医药）

2020-06-01·Journal for immunotherapy of cancer2区 · 医学

Safety and immunogenicity of novel 5T4 viral vectored vaccination regimens in early stage prostate cancer: a phase I clinical trial

2区 · 医学

ArticleOA

作者: Mitton, Celia ; Hollidge, Julianne ; Meier, Armin ; Morgan, Susan ; Carter, Lucy ; MacPherson, Ruth ; Redchenko, Irina ; Baker, Megan ; Catto, James ; Baines, Andrea ; Hill, Adrian V S ; Evans, Thomas ; Cappuccini, Federica ; Poulton, Ian ; Romero, Pedro J ; Harrop, Richard ; Vigano, Selena ; Pollock, Emily ; Kennish, Steven ; Verrill, Clare ; Hamdy, Freddie ; Protheroe, Andrew ; Schmidt, Guenter ; Bryant, Richard

Background:

Prostate cancer (PCa) has been under investigation as a target for antigen-specific immunotherapies in metastatic disease settings for the last two decades leading to a licensure of the first therapeutic cancer vaccine, Sipuleucel-T, in 2010. However, neither Sipuleucel-T nor other experimental PCa vaccines that emerged later induce strong T-cell immunity.

Methods:

In this first-in-man study, VANCE, we evaluated a novel vaccination platform based on two replication-deficient viruses, chimpanzee adenovirus (ChAd) and MVA (Modified Vaccinia Ankara), targeting the oncofetal self-antigen 5T4 in early stage PCa. Forty patients, either newly diagnosed with early-stage PCa and scheduled for radical prostatectomy or patients with stable disease on an active surveillance protocol, were recruited to the study to assess the vaccine safety and T-cell immunogenicity. Secondary and exploratory endpoints included immune infiltration into the prostate, prostate-specific antigen (PSA) change, and assessment of phenotype and functionality of antigen-specific T cells.

Results:

The vaccine had an excellent safety profile. Vaccination-induced 5T4-specific T-cell responses were measured in blood by ex vivo IFN-γ ELISpot and were detected in the majority of patients with a mean level in responders of 198 spot-forming cells per million peripheral blood mononuclear cells. Flow cytometry analysis demonstrated the presence of both CD8+ and CD4+ polyfunctional 5T4-specific T cells in the circulation. 5T4-reactive tumor-infiltrating lymphocytes were isolated from post-treatment prostate tissue. Some of the patients had a transient PSA rise 2–8 weeks following vaccination, possibly indicating an inflammatory response in the target organ.

Conclusions:

An excellent safety profile and T-cell responses elicited in the circulation and also detected in the prostate gland support the evaluation of the ChAdOx1-MVA 5T4 vaccine in efficacy trials. It remains to be seen if this vaccination strategy generates immune responses of sufficient magnitude to mediate clinical efficacy and whether it can be effective in late-stage PCa settings, as a monotherapy in advanced disease or as part of multi-modality PCa therapy. To address these questions, the phase I/II trial, ADVANCE, is currently recruiting patients with intermediate-risk PCa, and patients with advanced metastatic castration-resistant PCa, to receive this vaccine in combination with nivolumab.

Trial registration:

The trial was registered with the U.S. National Institutes of Health (NIH) Clinical Trials Registry (ClinicalTrials.gov identifier NCT02390063).

2017-07-18·Oncotarget

5T4 oncofoetal glycoprotein: an old target for a novel prostate cancer immunotherapy

Article

作者: Redchenko, Irina ; Cappuccini, Federica ; Stribbling, Stephen ; Pollock, Emily ; Hill, Adrian V.S.

The tumour-associated antigen 5T4 is an attractive target for cancer immunotherapy. However to date, reported 5T4-specific cellular immune responses induced by various immunisation platforms have been largely weak or non-existent. In the present study, we have evaluated a heterologous prime boost regime based on the simian adenovirus ChAdOx1 and modified vaccinia virus Ankara (MVA) expressing 5T4 for immunogenicity and tumour protective efficacy in a mouse cancer model. Vaccination-induced immune responses were strong, durable and attributable primarily to CD8+ T cells. By comparison, homologous MVA vaccination regimen did not induce detectable 5T4-specific T cell responses. ChAdOx1-MVA vaccinated mice were completely protected against subsequent B16 melanoma challenge, but in therapeutic settings this regime was only modestly effective in delaying tumour outgrowth. Concomitant delivery of the vaccine with monoclonal antibodies (mAbs) targeting immune checkpoint regulators LAG-3, PD-1 or PD-L1 demonstrated that the combination of vaccine with anti PD-1 mAb could significantly delay tumour growth and increase overall survival of tumour-bearing mice. Our findings support a translation of the combinatorial approach based on the heterologous ChAdOx1-MVA vaccination platform with immune checkpoint blockade into the clinic for the treatment of 5T4-positive tumours such as prostate, renal, colorectal, gastric, ovarian, lung cancer and mesothelioma.

Frontiers in oncology

Role of Adenoviruses in Cancer Therapy

Review

作者: Tseha, Sintayehu Tsegaye

Cancer is one of the leading causes of death in the world, which is the second after heart diseases. Adenoviruses (Ads) have become the promise of new therapeutic strategy for cancer treatment. The objective of this review is to discuss current advances in the applications of adenoviral vectors in cancer therapy. Adenoviral vectors can be engineered in different ways so as to change the tumor microenvironment from cold tumor to hot tumor, including; 1. by modifying Ads to deliver transgenes that codes for tumor suppressor gene (p53) and other proteins whose expression result in cell cycle arrest 2. Ads can also be modified to express tumor specific antigens, cytokines, and other immune-modulatory molecules. The other strategy to use Ads in cancer therapy is to use oncolytic adenoviruses, which directly kills tumor cells. Gendicine and Advexin are replication-defective recombinant human p53 adenoviral vectors that have been shown to be effective against several types of cancer. Gendicine was approved for treatment of squamous cell carcinoma of the head and neck by the Chinese Food and Drug Administration (FDA) agency in 2003 as a first-ever gene therapy product. Oncorine and ONYX-015 are oncolytic adenoviral vectors that have been shown to be effective against some types of cancer. The Chiness FDA agency has also approved Oncorin for the treatment of head and neck cancer. Ads that were engineered to express immune-stimulatory cytokines and other immune-modulatory molecules such as TNF-α, IL-2, BiTE, CD40L, 4-1BBL, GM-CSF, and IFN have shown promising outcome in treatment of cancer. Ads can also improve therapeutic efficacy of immune checkpoint inhibitors and adoptive cell therapy (Chimeric Antigen Receptor T Cells). In addition, different replication-deficient adenoviral vectors (Ad5-CEA, Ad5-PSA, Ad-E6E7, ChAdOx1–MVA and Ad-transduced Dendritic cells) that were tested as anticancer vaccines have been demonstrated to induce strong antitumor immune response. However, the use of adenoviral vectors in gene therapy is limited by several factors such as pre-existing immunity to adenoviral vectors and high immunogenicity of the viruses. Thus, innovative strategies must be continually developed so as to overcome the obstacles of using adenoviral vectors in gene therapy.

项与 ChAdOx1 MVA 5T4 vaccine (Vaccitech) 相关的新闻（医药）

2024-03-18

·医药观澜

爱科瑞思、非同生物、英百瑞生物等在开发，肿瘤免疫新靶点5T4有何潜力？

▎药明康德内容团队编辑2024年2月，非同生物宣布其研发的新型5T4 x 4-1BB双特异性抗体FTL008.16获得美国FDA批准临床试验，拟开发用于治疗恶性实体肿瘤。2024年1月，爱科瑞思宣布其研发的靶向5T4的抗体偶联药物（ADC）ADC2154获得中国NMPA批准临床试验，拟开发用于治疗晚期实体瘤。在2023年，英百瑞生物也曾宣布其开发的靶向5T4的CAR-NK细胞疗法已获中国NMPA批准临床，拟开发用于实体肿瘤患者的治疗。那么，5T4是什么？从双特异性抗体、ADC到细胞疗法，5T4因何具有这么广的开发潜力？除了上述药物，当前还有哪些靶向5T4的创新疗法已进入到临床试验阶段？它们又有望惠及哪些肿瘤患者？本文将结合公开资料带大家来了解下。图片来源：123RF——✦5T4：肿瘤免疫治疗新星✦——5T4又称滋养层糖蛋白（Trophoblast glycoprotein, TPBG）、Wnt激活抑制因子 1（WAIF1），是由TPBG基因编码的脊椎动物特异性单次跨膜蛋白。5T4蛋白首次在人胎盘组织中发现[1]，是N端高度糖基化的跨膜蛋白。人类5T4全长蛋白的分子量约为72kDa，蛋白序列保守，由420个氨基酸组成。该蛋白在胞外结构域中包含一个细胞外区、一个跨膜区（356-376aa）和一个胞内区（如下图所示）[2,3]，其中胞内区含有PDZ结合基序（Ser-Asp-Val），该结合基序可以与位于细胞附近囊泡相关的细胞质蛋白膜TIP-2/GIPC互相作用，从而可参与细胞迁移和黏附信号转导过程的调控[4]。▲5T4结构（截图来源：Front Mol Neurosci [5]）研究发现，5T4广泛表达于胚胎发育期的各种滋养层细胞，其在成人正常组织中表达受限，只在几种上皮细胞中表达，但却在很多癌症细胞中有表达，包括子宫癌、结肠癌、胃癌、卵巢癌、口腔癌、前列腺癌、肺癌或肾癌等。这一特点使其成为了一种有吸引力的肿瘤免疫治疗新靶点。对于5T4影响肿瘤的作用机制，目前尚不十分清晰。但有相关研究发现，5T4具有阻断经典Wnt/β-catenin通路和非经典Wnt信号通路的双重作用：一方面，5T4会与Wnt共受体LRP6结合并抑制其与Wnt受体的内吞，从而阻断Wnt/β-catenin经典信号通路，继而抑制细胞黏附和细胞骨架的形成，促进肿瘤迁移和扩散；另一方面，5T4还可通过活化DKK1来激活非经典Wnt通路，促进细胞迁移和浸润[6]。此外，还有研究认为，5T4也可能是通过影响上皮间质转化（EMT）和CXCR4/CXCL12相关通路来影响肿瘤细胞的发生、发展、转移等。基于5T4肿瘤表达的选择性模式、与肿瘤起始表型的相关性以及其在癌症扩散中的作用，研究人员认为可以针对该靶点开发不同的免疫疗法[7]，包括疫苗、抗体偶联药物、细胞疗法等等，为患者带来潜在的治疗新选择。——✦多款5T4靶向疗法已迈入临床阶段✦——公开资料显示，目前全球尚无靶向5T4的药物获批上市，但已有很多5T4靶向疗法进入到临床试验阶段。这些在研药物包括双特异性抗体、ADC、细胞疗法、融合蛋白等多种药物类型，针对的适应症均为肿瘤。下面我们将介绍部分已进入临床阶段的在研产品，仅供读者参阅。Aptevo、Alligator：ALG.APV-527作用机制：5T4 x 4-1BB双抗Aptevo Therapeutics和Alligator Biosciences共同开发的ALG.APV-527是一款同时靶向5T4和共刺激受体4-1BB（CD137）的双特异性抗体。在第35届肿瘤免疫治疗学会年会（SITC 2020）上，Aptevo曾展示了ALG.APV-527的研究结果。数据显示，ALG.APV-527具有选择性刺激和增强肿瘤中T细胞反应的潜力，而不会刺激身体其他部位的免疫系统，并在体内动物模型中有效抑制了肿瘤。目前，该候选药正在开展针对实体瘤的1/2期临床研究。非同生物：FTL008.16作用机制：5T4 x 4-1BB双抗FTL008.16是非同生物研发的一款新型5T4 x 4-1BB双特异性抗体，拟开发用于治疗恶性实体肿瘤。该产品可通过5T4抗体引导药物分子聚集于表达5T4抗原的肿瘤部位，由共刺激分子4-1BB抗体诱导肿瘤特异性的免疫细胞激活，产生肿瘤杀伤作用，同时将作用限制在肿瘤部位以降低系统毒性。2024年2月，FTL008.16获美国FDA批准临床试验。NeoTX公司：NAP作用机制：靶向5T4的融合蛋白NeoTX Therapeutics开发的NAP（Naptumomab Estafenatox，ABR-217620）是一款靶向5T4的融合蛋白，该药已完成两项分别针对晚期肾细胞癌患者、晚期或转移性NSCLC受试者的2期临床试验。此外，NAP还正在开展多项1期临床试验，分别为：与阿斯利康（AstraZeneca）PD-L1抑制剂durvalumab联合治疗晚期或转移性实体瘤患者的1期临床；以及联合默沙东（MSD）PD-1抑制剂pembrolizumab治疗尿路上皮癌患者的1期临床。爱科瑞思：ADC2154作用机制：靶向5T4的ADCADC2154是爱科瑞思研发的一款靶向5T4的抗体偶联药物（ADC）。ADC2154结构采用全新结构的拓扑异构酶抑制剂为载荷和全新释放机制的连接子，具有循环系统稳定、靶向肿瘤组织和胞内释放的特点。2024年1月，该药已获中国NMPA批准临床，拟开发用于晚期实体瘤，包括但不限于食管癌、结直肠癌、非小细胞肺癌、前列腺癌、卵巢癌、宫颈癌、胰腺癌、肾癌、乳腺癌。Asana公司、Mersana公司：ASN004作用机制：靶向5T4的ADCASN004是Asana Biosciences与Mersana Therapeutics合作开发的一款靶向5T4的ADC，拟用于治疗实体瘤。根据Asana公司官网资料，ASN004结合了一种新型单链scFv-Fc抗体，该抗体与经过临床验证的auristatin F-羟丙基酰胺细胞毒性药物相连。在临床前癌症模型中，ASN004单次给药实现了完全和持久的肿瘤消退。目前该药正处于1期临床试验阶段。Byondis：SYD-1875作用机制：靶向5T4的ADCSYD-1875是Byondis公司开发的一款靶向5T4的ADC。临床前研究显示，在5T4低、中、高表达的多种肿瘤细胞系和人源性组织异种移植（PDX）模型中，SYD-1875不仅能够实现靶向杀伤，也能够诱导旁观者效应介导的抗肿瘤活性。食蟹猴GLP毒性研究显示，该候选药具有可接受的毒性和PK特征，游离毒素水平极低。目前该药已完成了一项1期临床试验。英百瑞：IBR854作用机制：靶向5T4的CAR-raNK细胞产品IBR854是英百瑞生物研发的一款针对实体肿瘤的非基因修饰的CAR-raNK细胞疗法。其核心构造是将靶向5T4的特异性抗体通过连接子与同种异体的NK细胞进行共价偶联，能够与表达5T4靶抗原的肿瘤细胞特异性结合，从而达到靶向识别和杀伤肿瘤细胞的目的。目前，IBR854正在中国开展一项1期临床试验，该研究旨在评价IBR854细胞注射液在不可切除的局部晚期或转移性实体肿瘤患者中的安全性、耐受性及初步疗效。Barinthus公司：VTP-800、VTP850作用机制：靶向5T4的免疫药物Barinthus Biotherapeutics公司开发了两款靶向5T4的免疫治疗候选药物VTP-800和VTP850，拟用于治疗前列腺癌。其中，VTP-800是Barinthus公司开发的一款靶向5T4的第一代免疫候选药物，其与PD-1抑制剂纳武利尤单抗的组合疗法已在针对前列腺癌的1期临床中取得积极效果。VTP-850是Barinthus公司基于VTP-800的1/2a期积极临床试验数据开发的一款下一代免疫候选药物，它可靶向多个与前列腺癌相关的抗原，包括5T4、PSA、PAP、STEAP等。根据Barinthus公司官网信息，该公司预计将于2025年获得VTP-850治疗前列腺癌的1/2期临床数据。当然，除了肿瘤，研究显示靶向5T4还有治疗更多疾病的可能。近年来，该靶点还被发现是帕金森病相关的新潜在基因、是先兆子痫预测和治疗的潜在遗传生物标志物、并在嗅觉和视觉系统的感觉处理中起着关键作用等[8-10]。期待5T4靶向疗法领域能够取得更多的突破，早日造福广大病患！参考资料：（可上下滑动查看） [1] Hole N, Stern PL. (1988) A 72 kD trophoblast glycoprotein defined by a monoclonal antibody. Br J Cancer. https://pubmed-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/3355761/[2] Myers KA, Rahi-Saund V, Davison MD, et al. (1994) Isolation of a cDNA encoding 5T4 oncofetal trophoblast glycoprotein. An antigen associated with metastasis contains leucine-rich repeats. J Biol Chem. https://pubmed-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/8132670/[3] Zhao Y, Malinauskas T, Harlos K, et al. (2014) Structural insights into the inhibition of Wnt signaling by cancer antigen 5T4/Wnt-activated inhibitory factor 1. Structure. https://pubmed-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/24582434/[4] Awan A, Lucic MR, Shaw DM, et al. (2002) 5T4 interacts with TIP-2/GIPC, a PDZ protein, with implications for metastasis. Biochem Biophys Res Commun. https://pubmed-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/11798178/[5] Tsuboi A. (2020) LRR-Containing Oncofetal Trophoblast Glycoprotein 5T4 Shapes Neural Circuits in Olfactory and Visual Systems. Front Mol Neurosci. https://pubmed-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/33192298/[6] Kagermeier-Schenk B, Wehner D, Ozhan-Kizil G, et al. (2011) Waif1/5T4 inhibits Wnt/β-catenin signaling and activates noncanonical Wnt pathways by modifying LRP6 subcellular localization. Dev Cell. https://pubmed-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/22100263/[7] Stern PL, Harrop R. (2017) 5T4 oncofoetal antigen: an attractive target for immune intervention in cancer. Cancer Immunol Immunother. https://pubmed-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/27757559/[8] Wang Y, Li B, Zhao Y. (2022) Inflammation in Preeclampsia: Genetic Biomarkers, Mechanisms, and Therapeutic Strategies. Front Immunol. https://pubmed-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/35880174/[9] Park S, Yoo JE, Yeon GB, et al. (2021) Trophoblast glycoprotein is a new candidate gene for Parkinson's disease. NPJ Parkinsons Dis. https://pubmed-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/34876581/[10] Tsuboi A. (2020) LRR-Containing Oncofetal Trophoblast Glycoprotein 5T4 Shapes Neural Circuits in Olfactory and Visual Systems. Front Mol Neurosci. https://pubmed-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/33192298/[11]各公司官网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「医药观澜」微信公众号留言联系我们。其他合作需求，请联系wuxi_media@wuxiapptec.com。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。

细胞疗法免疫疗法抗体药物偶联物

2023-09-03

·动脉网

医疗投资出海八年，腾讯卷不动了

憋了8个月，终于开了一单。2023年8月，尼日利亚医药供应链服务商Remedial Health宣布完成1200万美元的A轮融资，我们终于在一众投资方中看到了腾讯。这是今年腾讯在海外医疗领域的第一笔投资。不过这并不是腾讯今年新物色的标的。2022年9月，Remedial Health的种子轮中腾讯便是投资方之一。此后，腾讯暂停了海外医疗布局，直到最近。今年“医疗出海”是行业里的热点话题。在这一轮“出海”中，我们一方面谈论国产崛起，国内企业纷纷出海淘金；另一方面，我们也看到，2023年过去8个月，国内资本“到海外去投项目”的步伐在减缓。腾讯医疗投资出海已八年，疫情后的三四年间，在海外悄悄囤了13个项目，几乎追平前五年，是“卷王之王”。尤其在同行们“断崖式”捂住钱袋子的2022年，腾讯反而加快海外投资：全年出手6次，是腾讯医疗投资出海8年的又一高峰之年。图：数据统计自动脉橙、IT桔子可2022对腾讯而言，却不是个好年——中期业绩腰斩，全年投资数量紧缩至2021年的1/3（2021年共280笔投资，2022年91笔投资）。一进一退间，一个进击的腾讯医疗似乎正在出炉。去年腾讯在医疗板块共出手12次，在投资数量的大盘中占比超过13%，远高于往年医疗板块的占比。但当我们想进一步关注时，腾讯“刹车”了。腾讯投资的“Gap year”不同往年，2023年上半年腾讯VC业务几乎停滞。根据此前发布的半年报，2023年腾讯Q2投资组合账面价值为7137亿元，与Q1的7132亿元基本持平，公允价值环比减少258亿元，对腾讯利润的影响非常小。再看23年Q1的财报，“其他收益净额”仅为9.44亿，同比下滑了92.81%；其中“处置及视同处置投资公司的收益净额”为10.44亿，同比下滑了94.47%；2023年Q1于联营、合营企业的投资收益为0.80亿，同比增101.27%，去年同期为-62.8亿。总的来说，今年腾讯投资业务相关的数值几乎缩减到“忽略不计”。根据IT桔子数据，2023年腾讯1-8月仅布局22个项目，投资金额39.28亿。可以说，今年腾讯VC的活跃度“一夜回到10年前”。2019年，腾讯总裁刘炽平曾对外表示，投资已经是腾讯的核心战略。时隔4年核心战略不只是“紧缩”，而是“停下来”。腾讯在等什么？战车何时重启？我们不得而知。但时代确实变了，大厂在换方式讲故事了。此时，腾讯投资的“Gap year”或许才刚刚开始。尽管自2019年起大家就在讨论“互联网流量见顶”。但腾讯投资的巅峰是在2021年。全年入手280个项目，平均1.3天就有一次出手。2021年半年财报显示，投资业务已经撑起了腾讯利润的“半边天”。然而紧缩也来得快。2021年年底腾讯以中期派息的方式将手中持有近九成、价值超千亿港元的京东股票全部派发，吹响了全线收缩投资阵线的号角。进入2022年，腾讯业绩承压，回归主业、降本增效成“主基调”。VC业务在紧缩中“调仓换道”。一是“变硬”，如大规模减持美团，在二级市场抛售华谊兄弟、新东方在线等，转而增加对硬科技、实体领域的投资；二是“出海”，2022全年91笔投资中，41%是海外项目，海外占比历年最高。翻看近2年的财报，投资业务确实给了腾讯“稳稳的幸福”。但细观业务内部却发现它正在快速震荡——从历史高点到全线收缩，再到“调仓换道”，再到今年的几乎停滞。这既表明内外部环境在剧烈变化，也反应出腾讯非常“焦虑”。互联网大厂的投资业务本质上是深挖“护城河”。投资业务快速变动，显然是为了寻找更多增长曲线，因而，即使艰难如2022，腾讯VC也仍然在奔波。去年，腾讯向未来写了很多新故事，不仅投了多家人工智能、无人驾驶、生物医疗公司，还加码了农业领域。也因此，医疗板块海外布局在2022年迎来高峰。这一年，腾讯出手速度加快是一方面；另一方面，投资时，更喜欢去高校“淘”项目，以及积极寻找新兴市场。比如，Microbiotica的研究基于与剑桥大学合作，Manifold Bio是哈佛大学孵化的项目。以及第一次投向了尼日利亚的医疗服务。而不久前完成的投资，也正是对北非市场的进一步加码。而如果我们把2021年的投资连在一起看，这种趋势就更明显。图：数据统计自动脉橙、IT桔子11个项目中，与剑桥、牛津、哈佛相关的项目占比45%，它们主要是创新药物研发商。除了上面提到的首次关注非洲市场，对成熟市场的关注，也不再倚重北美，政策风险更小的的欧洲市场大受青睐。通看过去两年的海外医疗投资，在投资风格上与2015年相似，彼时腾讯主要看医疗服务，现在更偏向于生物科技、医药科技。但都投小、投早、出手频繁。图：数据统计自动脉橙、IT桔子不过，2022年的腾讯更看中“效用”。这一轮的押注，60%以上的项目选择B轮进入而非种子轮。这些企业的技术硬核、商业模式基本成熟，已经有一些市场化探索。接下来，就是等待这些新故事成熟。硬科技和实体产业的增长主要靠新技术、新产品驱动，而非此前互联网公司习惯的品类扩张、规模扩张。这些时间既要留给被投企业成长，也要留给腾讯做“思维转型”。今年是腾讯投资业务大调后的第一年。因此，即便2023年中期业绩好转，VC业务却真正进入了“Gap year”。进入2023年，腾讯的确“不卷了”，因为已经囤出“一篮子”。接下来，这些新市场、更前沿项目的市场成绩究竟如何，或许才是腾讯之后征战海外的关键参考。海外投资难见成效今年医疗海外布局“暂停”，或许也跟过往海外的战绩相关。互联网大厂出海本质是在去找海外复刻更多“中国式互联网”。但事实上，缺了流量驱动和业务协同的腾讯，海外医疗故事并不一帆风顺。2015年，腾讯早早地看上了印度市场。彼时的Practo是印度最大的互联网医疗平台，市占率达90%，已进入菲律宾、新加坡。国内的投资经验让腾讯希望在印度也找到互联网医疗的明星。于是在公司9000美元的C轮融资中，腾讯决定领投。这是2015年腾讯医疗板块在海外最大的一笔投资。1年半之后，Practo的D轮融资中，腾讯也继续加码，成为公司第二大股东。海外布局8年，腾讯只复投过3个项目，足见腾讯对Practo寄予厚望。但Practo至今仍在亏损。根据2022年财报，Practo收入为20.2亿卢比，但亏损从21财年的9.95亿卢比飙升至22财年的20.33亿卢比。而它的竞争对手则快速增长。如1Mg，22财年收入规模翻倍达到了62.7亿卢比；MFine，2022年收入5亿卢布，实现盈利。这些“后来者”背靠印度本土资本信实集团（Reliance group）和塔塔集团（tata），正上演着逆袭。同样不尽如人意的还有Atomwise。这家公司是AI制药界的“第一梯队”，也是腾讯、百度出海都在投的公司。2012年，卷积神经网络（CNN）首次在 ImageNet 图像识别竞赛中表现人类水平的能力，也就是这一年，海外冒出了首批AI制药公司，Atomwise也是其中之一，腾讯参与其A、B轮投资。但起了大早，却没赶上早集。相比同时起步的Exscientia和Benevolent AI两家英国公司，Atomwise的管线进展却明显落后了。目前，两家英国公司均已上市，多个自研管线进入临床。外部合作项目上，Exscientia和赛诺菲达成1亿美元首付款，潜在价值50亿美元的大额合作；BenevolentAI也多次向阿斯利康交付里程碑成果。反观Atomwise，如今仍停在B轮。2020年B融资时Atomwise就宣布推进自有管线的研发，但目前仍未传出进入临床阶段的消息。互联网巨头切入医疗健康赛道，本质上是其对于主营业务的延伸和补充，其切入的形式脱胎于自己的“基因”。腾讯擅长“连接一切”，本土作战腾讯在资本优势之外，还有“社交+内容+支付”巨无霸生态做支撑。因而，即使跨界做医疗，腾讯仍然在医疗资源、用户资源、流量资源、内容资源、财务数据上有巨大优势。但在海外，腾讯的“魔法”显然无法发挥，投资效率和国内相去甚远。在国内，腾讯在行业里是“稳准狠”的代表。比如，腾讯在天使轮投资了水滴互助，在B轮投资了思派健康，腾讯最早在2014年就投给了丁香园7000万美元，在2020年丁香园5亿美元融资中，腾讯也是主要投资者……而自2019年起，腾讯就通过IPO退出的方式获取收益。IT桔子数据显示，2014年起，腾讯医疗板块国内共出手70次，退出项目7个，退出占比10%，其中不少企业在发展的早期就受到腾讯的关注。图：数据统计自动脉橙、IT桔子而在海外投资中，退出获取收益的仅GRAIL。2020年，Illumina拟斥资80亿美元收购GRAIL，腾讯在收购案中退出。在IPO的斩获上，仅有通用疫苗研发公司Vaccitech。这家公司是阿斯利康新冠肺炎疫苗的设计方，2021年腾讯B轮进入。2个月后，Vaccitech登陆纳斯达克，但目前市值已缩水至上市时的1/6。事实上，在海外腾讯医疗的投资思路与国内一致，在成熟度高的市场（如欧洲、北美），偏向生物医药、前沿科技类项目；在新兴市场（如印度、尼日利亚），以互联网医疗、医疗服务切入，本质上都是国内投资经验在国外的延伸。但在海外，当腾讯的社交优势、业务协同不再，医疗服务、互联网医疗的故事讲起来难度剧增，使得腾讯即使在擅长的领域，也不能完全施展。而从投资效率来看，现阶段腾讯医疗板块的出海仍是战略目标大于财务目标，以寻找新技术风口，帮助腾讯快速在新市场、新技术中占有一席之地而服务。BAT中最早出海，版图如何？全球版图雏形初现。出海8年，腾讯全球布局了24个项目。在赛道覆盖上，互联网医疗、精准诊断、药物研发、医疗数字化、高值医疗器械、合成生物学等多个核心赛道均纳入其中，其中还包括宠物医疗。腾讯对全球医疗创新持续看好。在市场覆盖上，腾讯在北美、澳洲、欧洲、印度、北非均有布局。近几年腾讯布局的思路也更加清晰。初次进入新兴市场，如瑞典、印度、尼日利亚，从医疗服务入局，回归基础需求，寻求之后的规模化。此前，投资的瑞典数字医疗保健服务商Doktor.se就表示正在准备上市。而在进入成熟市场，如美国、英国，则宁缺毋滥，寻找“硬核创新”+“已有一定市场规模”项目买入，投资轮次相比前几年略有靠后。如Microbiotica 、Novome都是可能引发行业技术变革。我们可以把这些年腾讯在海外的“招兵买马”看作是国内在医疗领域“攻城略地”的精简版和先锋版，如今全球布局雏形初具。图：数据统计自动脉橙、IT桔子，国家未标明的为美国项目当然，上面的这些梳理，可能也只是腾讯资本出海在医疗领域的一部分，腾讯本身也作为LP参与到很多其他投资中去。回到文章开头提到的今年医疗出海的趋势，我们更应注意到，当前资本出海正在迭代。这一轮的资本出海，伴随着中国企业的”全球化”：大批企业基于国内的供应链、技术、人才积累，去做全球生意，资本给出海助推。医疗行业如是。实际上这对应着出海红利期的转变——从之前以品牌、模式为主的互联网出海红利期逐渐变成科技、产业出海的红利期。这种趋势越来越明显。因而，随着腾讯医疗梦想的向前，未来腾讯系医疗创新企业和自研产品的出海，也必然是其海外布局的另一面。腾讯也开始了尝试。比如，在高端国际医疗服务领域。2022年4月，北京盛诺一家发生工商变更，腾讯在其中持股20%，这是一家与国外知名医院建立官方合作、为中国患者提供海外医疗全程咨询与服务的专业机构。盛诺一家目前是国内最大的出国看病服务机构。再比如，腾讯在医疗器械上布局。2021年9月，腾讯自主研发的“肺炎CT影像辅助分诊及评估软件”已经正式获批第三类医械注册证。腾讯成为国内互联网科技行业首个获得医疗AI三类证获得者。2022年3月，腾讯入股深圳赛禾医疗技术有限公司，成为其第二大股东，正式开始销售医疗器械。腾讯也自研了首款将人工智能技术运用到医学领域的产品，腾讯觅影。从这个角度上讲，腾讯的医疗板块出海远远没有停下来。接下来，腾讯可能需要从去国外找“中国故事”，转向去国外讲“中国故事”。过去10年，腾讯已成为国内VC界的“榜一大哥”，手上的项目超过1500个。医疗板块是腾讯投资的“第二梯队”，也囤了近百个项目，如何把更多中国医疗的创新、创业者推上全球舞台？这是腾讯VC新一轮大机会。或许，这也是腾讯更为长远而宏伟的叙事。*封面图片来源：unsplash近期推荐声明：动脉网所刊载内容之知识产权为动脉网及相关权利人专属所有或持有。未经许可，禁止进行转载、摘编、复制及建立镜像等任何使用。动脉网，未来医疗服务平台

财报

2023-06-13

·PipelineReview

Vaccitech Doses First Patient in PCA001, a Prostate Cancer Phase 1/2 Clinical Trial of VTP-850 Immunotherapeutic Candidate in Men with Rising PSA after Definitive Local Therapy

OXFORD, UK I June 12, 2023 I Vaccitech plc (NASDAQ: VACC) (the Company, we or us), a clinical-stage biopharmaceutical company engaged in the discovery and development of novel immunotherapeutics for the treatment of autoimmunity, chronic infectious diseases and cancer, today announced the dosing of the first patient in the PCA001 clinical trial (NCT05617040). PCA001 is a multi-centre, Phase 1/2 clinical trial designed to determine the recommended Phase 2 regimen and evaluate the safety, efficacy, as measured by prostate-specific antigen (PSA) response, and T cell response of VTP-850 monotherapy in men with rising PSA after definitive local therapy for their disease ( i.e. , biochemical recurrence). VTP-850 is a next-generation prostate cancer immunotherapeutic candidate which utilizes Vaccitech’s sequential dosing approach of two proprietary nonreplicating viral vectors, ChAdOx and MVA. PCA001 builds on the previous promising data from the University of Oxford VANCE01 (NCT02390063) and ADVANCE (NCT03815942) trials, Phase 1 and Phase 1/2 clinical trials respectively, of VTP-800, the first-generation product candidate which encoded 5T4, an antigen expressed by most prostate cancers. 1,2 VTP-850 is a multi-antigen immunotherapeutic candidate containing four prostate-associated antigens: PSA, PAP, STEAP1 and 5T4. The first phase of the trial is enrolling participants in the US, with plans to open further sites in Italy and Spain. “20-40% of patients will unfortunately experience biochemical recurrence following initial local therapy for prostate cancer with the potential to experience metastases. 3 VTP-850 is our next-generation, multi-antigen product candidate designed to induce a targeted polyclonal T cell response to kill remaining tumor cells and prevent advancement to metastatic disease,” said Bill Enright, Chief Executive Officer of Vaccitech. “We saw very encouraging data from the VANCE01 and ADVANCE trials, and we are excited to begin PCA001 where VTP-850 will be evaluated as a monotherapy in a patient population with important unmet medical needs.” “VTP-850 encodes four prostate cancer antigens and is designed to induce a broader T cell response to tumor cells,” said Dr. Meg Marshall, Chief Medical Officer of Vaccitech. “When the immune system targets multiple molecules on tumor cells, it is generally harder for tumor cells to escape destruction by the immune system.” About Prostate Cancer In 2020, prostate cancer was the fourth most common cancer worldwide, with 1.4 million new cases diagnosed. 4 In the US, out of every 100 American men, about 13 will get prostate cancer during their lifetime. 5 In the UK, prostate cancer is the most common cancer in men, with more than 52,000 people diagnosed with the disease on average each year. 6 20-30% of patients experience rising levels of PSA after local therapy (e.g. prostatectomy), indicating that disease was not cured by local therapy. 7 Of men who do experience biochemical recurrence, there is a 1 in 9 chance of developing metastases. 8 About Vaccitech Vaccitech is a clinical-stage biopharmaceutical company focused on the development of novel T cell immunotherapeutics designed to harness the power of the immune system to treat and cure chronic infectious diseases, autoimmune diseases, and cancer. The Company stands apart through a proprietary, multi-platform approach that has shown the ability to induce higher magnitudes of T cells compared with other technologies. Vaccitech is uniquely positioned to address the needs of large, underserved patient populations through a diverse clinical-stage pipeline of investigational therapies targeting diseases that pose significant public health risk and have limited treatment options. The Company’s lead product candidates include VTP-300, an immunotherapy product candidate designed as a component of a potential functional cure for chronic hepatitis B viral (HBV) infection; VTP-200, a non-invasive, early-stage investigational treatment for persistent, high-risk human papillomavirus (HPV) infection; VTP-850, a novel T cell investigational therapy for prostate cancer; and VTP-1000, a preclinical T cell therapeutic candidate designed to restore immune tolerance in celiac disease. Vaccitech has proven drug development and scientific expertise in the field of immunization, co-inventing a COVID-19 vaccine with the University of Oxford, which is now approved and exclusively licensed worldwide to AstraZeneca. For more information, visit www.vaccitech.co.uk . SOURCE: Vaccitech

免疫疗法疫苗临床研究临床2期临床结果

100 项与 ChAdOx1 MVA 5T4 vaccine (Vaccitech) 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
前列腺癌	临床2期	英国	Vaccitech (UK) Ltd.	2019-05-04

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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


NCT02390063 (VANCE, Pubmed \| J Immunother Cancer)	临床1期	前列腺癌	40	ChAdOx1-MVA 5T4 vaccine	構襯憲構築壓夢艱鏇鏇(簾觸鬱獵淵襯鹽餘製壓) = Some of the patients had a transient PSA rise 2-8 weeks following vaccination, possibly indicating an inflammatory response in the target organ 選廠鏇齋築膚積糧醖範 (憲淵襯顧遞鹹獵壓餘艱 )	-	2020-06-01
ASCO2008	N/A	转移性肾细胞癌	25	MVA-5T4 vaccine	窪製願蓋窪艱壓衊窪淵(遞齋鏇鬱選築夢廠窪蓋) = 願顧遞顧蓋鬱夢顧壓構鹽壓艱淵遞鹹製憲窪餘 (選顧淵願窪蓋鏇簾襯淵 )	-	2008-05-20
ASCO2008	N/A	转移性肾细胞癌	25	High-dose interleukin-2	窪製願蓋窪艱壓衊窪淵(遞齋鏇鬱選築夢廠窪蓋) = 遞糧選糧選壓襯鹽憲製鹽壓艱淵遞鹹製憲窪餘 (選顧淵願窪蓋鏇簾襯淵 )	-	2008-05-20