This study aims to evaluate safety and effect of combining an oncolytic adenovirus (delolimogene mupadenorepvec; LOAd703) with atezolizumab in patients with melanoma. LOAd703 will be administered intratumorally for up to 12 injections while atezolizumab will be administered intravenously for the duration of the active study visits (up to 57 weeks). The patients are then monitored for survival for maximum study participation of 48 months. The treatments will be given every 3 weeks. The patients will then be monitored for toxicity, PK, ADA, immune responses, virus shedding, tumor response by RECIST 1.1 and survival.

开始日期2020-01-28

申办/合作机构

Lokon Pharma AB

[+1]

NCT03555149 / Terminated临床1/2期

A Phase Ib/II, Open-Label, Multicenter, Randomized Umbrella Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Metastatic Colorectal Cancer (Morpheus-CRC)

A phase Ib/II, open-label, multicenter, randomized study designed to assess the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of immunotherapy-based treatment combinations in patients with metastatic colorectal cancer (mCRC) that became refractory to first- and second-line standard therapies. Eligible patients will be assigned to one of several treatment arms.

开始日期2018-09-27

申办/合作机构

Hoffmann-La Roche Ltd.

NCT03225989 / Active, not recruiting临床1/2期

Phase I/II Trial Investigating an Immunostimulatory Oncolytic Adenovirus for Cancer

This Phase I/II trial evaluates LOAd703 in patients with cancer (pancreatic, biliary, colorectal or ovarian) together with their standard of care chemotherapy or using gemcitabine immune-conditioning. LOAd703 is administered by intratumoral image-guided injections. Maximum 50 patients can be enrolled.
LOAd703 is an immunostimulatory gene therapy using an selection replication competent adenovirus as a gene vehicle. The virus is derived from serotype 5 adenovirus with the fiber from serotype 35. It expresses the transgenes trimerized membrane-bound isoleucine zipper (TMZ) TMZ-CD40L and 41BBL under control of a cytomegalovirus (CMV) promoter.

开始日期2018-03-01

申办/合作机构

Lokon Pharma AB

[+1]

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100 项与 Delolimogene mupadenorepvec 相关的转化医学

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项与 Delolimogene mupadenorepvec 相关的文献（医药）

2021-10-01·Cancer immunology, immunotherapy : CII2区 · 医学

Boosting CAR T-cell responses in lymphoma by simultaneous targeting of CD40/4-1BB using oncolytic viral gene therapy

2区 · 医学

Article

作者: Eriksson, Emma ; Wikström, Kristina I ; Lövgren, Tanja ; Enblad, Gunilla ; Wenthe, Jessica ; Labani-Motlagh, Alireza ; Loskog, Angelica ; Naseri, Sedigheh

Abstract:

Pretreatment of B-cell lymphoma patients with immunostimulatory gene therapy using armed oncolytic viruses may prime tumor lesions for subsequent chimeric antigen receptor (CAR) T-cell therapy, thereby enhancing CAR T-cell functionality and possibly increasing response rates in patients. LOAd703 (delolimogene mupadenorepvec) is an oncolytic adenovirus (serotype 5/35) that encodes for the transgenes CD40L and 4-1BBL, which activate both antigen-presenting cells and T cells. Many adenoviruses failed to demonstrate efficacy in B-cell malignancies, but LOAd703 infect cells via CD46, which enables B cell infection. Herein, we investigated the therapeutic potential of LOAd703 in human B-cell lymphoma models, alone or in combination with CAR T-cell therapy. LOAd703 could infect and replicate in B-cell lymphoma cell lines (BC-3, Karpas422, Daudi, DG-75, U-698) and induced an overall enhanced immunogenic profile with upregulation of co-stimulatory molecules CD80, CD86, CD70, MHC molecules, death receptor Fas and adhesion molecule ICAM-1. Further, CAR T-cell functionality was boosted by stimulation with lymphoma cells infected with LOAd703. This was demonstrated by an augmented release of IFN-γ and granzyme B, increased expression of the degranulation marker CD107a, fewer PD-1 + TIM-3+ CAR T cells in vitro and enhanced lymphoma cell killing both in in vitro and in vivo xenograft models. In addition, LOAd703-infected lymphoma cells upregulated the secretion of several chemokines (CXCL10, CCL17, CCL22, CCL3, CCL4) essential for immune cell homing, leading to enhanced CAR T-cell migration. In conclusion, immunostimulatory LOAd703 therapy is an intriguing approach to induce anti-lymphoma immune responses and to improve CAR T-cell therapy in B-cell lymphoma.

2020-12-01·Cancer gene therapy2区 · 医学

Immunostimulatory oncolytic virotherapy for multiple myeloma targeting 4-1BB and/or CD40

2区 · 医学

Article

作者: Wenthe, Jessica ; Hellström, Ann-Charlotte ; Wiklund, Helena Jernberg ; Loskog, Angelica ; Eriksson, Emma ; Naseri, Sedigheh

Abstract:

Multiple myeloma (MM) is a plasma cell malignancy that is characterized by immune dysregulation. MM is commonly treated with immunomodulating agents, but still remains incurable. Herein, we proposed and evaluated immunostimulatory Lokon oncolytic adenoviruses (LOAd) for MM treatment. LOAd viruses are serotype 5/35 chimera, which enables infection of hematopoietic cells. Oncolysis is restricted to cells with a dysregulated retinoblastoma protein pathway, which is frequently observed in MM. Further, LOAd viruses are armed with human immunostimulatory transgenes: trimerized membrane-bound CD40L (LOAd700, LOAd703) and 4-1BBL (LOAd703). LOAd viruses were assessed in a panel of MM cell lines (ANBL-6, L363, LP-1, OPM-2, RPMI-8226, and U266-84). All cells were sensitive to infection, leading to viral replication and cell killing as analyzed by quantitative PCR and viability assay. Transgene expression was verified post infection with flow cytometry. Cell phenotypes were further altered with a downregulation of markers connected to MM progression (ICAM-1, CD70, CXCL10, CCL2, and sIL-2Rα) and an upregulation of the death receptor Fas. In a co-culture of immune and MM cells, LOAd viruses promoted activation of cytotoxic T cells as seen by higher CD69, CD107a, and IFNγ expression. This was most prominent with LOAd703. In conclusion, LOAd viruses are of interest for MM therapy.

2017-10-01·Clinical cancer research : an official journal of the American Association for Cancer Research1区 · 医学

Shaping the Tumor Stroma and Sparking Immune Activation by CD40 and 4-1BB Signaling Induced by an Armed Oncolytic Virus

1区 · 医学

Article

作者: Leja-Jarblad, Justyna ; Alemany, Ramon ; Milenova, Ioanna ; Moreno, Raphael ; Eriksson, Emma ; Dimberg, Anna ; Loskog, Angelica ; Ullenhag, Gustav ; Wenthe, Jessica ; Ståhle, Magnus

Abstract:

Purpose: Pancreatic cancer is a severe indication with short expected survival despite surgery and/or combination chemotherapeutics. Checkpoint blockade antibodies are approved for several cancer indications, but pancreatic cancer has remained refractory. However, there are clinical data suggesting that stimulation of the CD40 pathway may be of interest for these patients. Oncolytic viruses armed with immunostimulatory genes represent an interesting approach. Herein, we present LOAd703, a designed adenovirus armed with trimerized CD40L and 4-1BBL that activates the CD40 and 4-1BB pathways, respectively. As many cells in the tumor stroma, including stellate cells and the infiltrating immune cells, express CD40 and some 4-1BB, we hypothesize that LOAd703 activates immunity and simultaneously modulates the biology of the tumor stroma.Experimental Design: Tumor, stellate, endothelial, and immune cells were infected by LOAd703 and investigated by flow cytometry, proteomics, and functional analyses.Results: LOAd703-infected pancreatic cell lines were killed by oncolysis, and the virus was more effective than standard-of-care gemcitabine. In in vivo xenograft models, LOAd703 efficiently reduced established tumors and could be combined with gemcitabine for additional effect. Infected stellate and tumor cells reduced factors that promote tumor growth (Spp-1, Gal-3, HGF, TGFβ and collagen type I), while chemokines were increased. Molecules involved in lymphocyte migration were upregulated on infected endothelial cells. Dendritic cells were robustly stimulated by LOAd703 to produce costimulators, cytokines and chemokines, and such DCs potently expanded both antigen-specific T cells and NK cells.Conclusions: LOAd703 is a potent immune activator that modulates the stroma to support antitumor responses. Clin Cancer Res; 23(19); 5846–57. ©2017 AACR.

项与 Delolimogene mupadenorepvec 相关的新闻（医药）

2023-01-02

·PRNewswire

Propulsion of Pancreatic Cancer Pipeline as Novel and Extensive 170+ Therapies Likely to Enter in the Treatment Domain | DelveInsight

The prevalence of pancreatic cancer has been rising since the past few years, which prompts the growing demand for treatment options. The increasing prevalence of cancer, the robust pipeline, and the growing research and development activities to develop novel therapies to treat Pancreatic Cancer drive the market. The companies developing the potential therapies in the last stage of development include FibroGen, Eli Lilly and Company, CARsgen Therapeutics, and several others. LAS VEGAS, Jan. 2, 2023 /PRNewswire/ -- DelveInsight's ' Pancreatic Cancer Pipeline Insight – 2022 ' report provides comprehensive global coverage of available, marketed, and pipeline pancreatic cancer therapies in various stages of clinical development, major pharmaceutical companies are working to advance the pipeline space and future growth potential of the pancreatic cancer pipeline domain. Key Takeaways from the Pancreatic Cancer Pipeline Report DelveInsight's pancreatic cancer pipeline report depicts a robust space with 150+ active players working to develop 170+ pipeline therapies for pancreatic cancer treatment. Key pancreatic cancer companies such as FibroGen, Innovent Biologics, CARsgen Therapeutics, Ascentage Pharma, NGM Biopharmaceuticals, TME Pharma AG, Lee's Pharmaceutical Limited, ImmunityBio, Inc., Rgene Corporation, CSPC ZhongQi Pharmaceutical Technology Co., Ltd., CanBas Co. Ltd., Jiangsu HengRui Medicine Co., Ltd., Bristol-Myers Squibb, SynerGene Therapeutics, Inc., AbbVie, Silenseed Ltd, Galera Therapeutics, Inc., Helix BioPharma, Golden Biotechnology Corporation, Eli Lilly and Company, Innovent Biologics (Suzhou) Co. Ltd., Panbela Therapeutics, Inc., GlaxoSmithKline, Chia Tai Tianqing Pharmaceutical Group, Roche, Prestige Biopharma Limited, Everfront Biotech Co., Ltd., XBiotech, Inc., Incyte Corporation, Ability Pharmaceuticals SL, Lokon Pharma, HCW Biologics, Amplia Therapeutics Limited, BioLineRx, Ltd., Taiho Pharmaceutical, Sanofi, Scandion Oncology, Nelum, Celldex Therapeutics, Merus N.V., Seagen Inc., GC Cell Corporation, MetiMedi Pharmaceuticals, Lumicell, Nuvation Bio Inc., ENB Therapeutics, BioNTech SE, Bayer, Genentech, Inc., Rise Biopharmaceuticals, Inc., Prestige Biopharma Limited, iOnctura, Shanghai Unicar-Therapy Bio-medicine Technology, Shanghai Hengrui Pharmaceutical Co., Ltd., Hangzhou Neoantigen Therapeutics Co., Ltd., EUSA Pharma, Inc.,Agenus Inc., Arcus Biosciences, Inc.Amgen, Biomea Fusion, and others are evaluating pancreatic cancer drugs to improve the treatment landscape. Promising pancreatic cancer pipeline therapies in various stages of development include Pamrevlumab, Niraparib, CT041, APG-1387, BNT141, ENB003, NUV-868, MCLA-128, LUM015, tisotumab vedotin, OMT-111, tusamitamab ravtansine, SCO-101, NGM120, CDX-301, NLM-001, TAS 102, Olaptesed pegol, BL-8040, Gimatecan, AMP945, N-803, HCW9218, BLEX 404, delolimogene mupadenorepvec, Mitoxantrone Hydrochloride Liposome injection, ABTL0812, CBP501, Pemigatinib, SHR-1701, Fluzoparib, XB2001, Cabiralizumab, EF-009, SGT-53, ABBV-927, PBP1510, Vemurafenib, siG12D-LODER, Penpulimab, GC4711, GSK2256098, L-DOS47, SBP-101, Antroquinonol, LY3214996, Sintilimab, RP72, PBP1510, IOA-289, U87, MVT-5873, SHR-A1904, iNeo-Vac-P01, iNeo-Vac-P01, TQB2858, Siltuximab, AGEN1423, AB680, AMG 199, BMF-219, and others. In December 2022, Targovax ASA announced that it has entered into a collaboration agreement with The University of Kansas Cancer Center (KU Cancer Center) and Agenus Inc. to run a clinical trial testing mutant RAS vaccine TG01 in combination with PD-1 CPI balstilimab in pancreatic cancer following surgery and standard-of-care (SoC) chemotherapy. In December 2022, Bluestar Genomics, Inc. announced the initiation of the New Onset Diabetes Management for Earlier Detection (NODMED) trial, one of the largest clinical studies in pancreatic cancer to date. The trial will use Bluestar Genomics' proprietary epigenomic methods for the detection of the disease. In December 2022, iOnctura BV, a clinical-stage biotech developing novel cancer therapies, had been granted €17.5 million ($18.6 million) funding from the European Investment Council's (EIC) accelerator program to develop IOA-289 for pancreatic cancer.The EIC's funding consists of a grant of €2.5 million ($2.7 million) and €15 million ($16 million) of equity investment. In December 2022, In the Phase I/II CodeBreaK 100 trial, the KRAS G12C inhibitor sotorasib achieved meaningful anticancer activity with an acceptable safety profile in heavily pretreated patients with KRAS G12C-mutated metastatic pancreatic cancer, according to researchers at The University of Texas MD Anderson Cancer Center. The results of the trial, published in the The New England Journal of Medicine, indicate an objective response rate of 21.1% and a median time-to-response of 1.5 months, with 84% of patients experiencing disease control. Median progression-free survival was 4 months, and overall survival was 6.9 months. In December 2022, Oncolytics Biotech® Inc. announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to pelareorep in combination with Roche's anti-PD-L1 checkpoint inhibitor atezolizumab, and the chemotherapeutic agents gemcitabine and nab-paclitaxel, for the treatment of advanced/metastatic pancreatic ductal adenocarcinoma (PDAC). This represents pelareorep's second FDA Fast Track designation. In December 2022, RemeGen Co., Ltd. announced that its latest antibody-drug conjugate (ADC), RC118 for injection, has been granted two orphan drug designations (ODD) by the United States Food and Drug Administration (FDA) for gastric cancer (including gastroesophageal junction cancer) and pancreatic cancer. This marks the Company's fourth, having previously been granted ODD twice for Disitamab Vedotin (RC48) and Telitacicept (RC18) earlier this year. In December 2022, Panbela Therapeutics, Inc. announced that the European Medicines Agency (EMA) Committee for Orphan Medicinal Products issued a positive opinion on Panbela's application for orphan designation of ivospemin ( SBP-101) in combination with gemcitabine and nab-Paclitaxel in patients with metastatic pancreatic ductal adenocarcinoma (PDA). In September 2022, Qualigen Therapeutics, Inc. announced the presentation of two posters on QN-302 at the AACR 8th Special Conference on Pancreatic Cancer. The data presented include information on the compound's safety, tolerability, and efficacy in a pancreatic cancer model. The poster included preclinical toxicology data that showed QN-302 does not produce adverse toxicological reactions in mouse models at therapeutic doses. In in vitro tests, QN-302 inhibits acetylcholinesterase (AChE) by 53% and muscarinic receptor (M2) by 70% at 1 µM. Request a sample and discover the recent advances in pancreatic cancer drugs @ Pancreatic Cancer Pipeline Report The pancreatic cancer pipeline report provides detailed profiles of pipeline assets, a comparative analysis of clinical and non-clinical stage pancreatic cancer drugs, inactive and dormant assets, a comprehensive assessment of driving and restraining factors, and an assessment of opportunities and risks in the pancreatic cancer clinical trial landscape. Pancreatic Cancer Overview Pancreatic cancer develops in the pancreas tissues, an abdomen organ located behind the stomach's bottom portion. The pancreas secretes hormones that help control blood sugar and enzymes that aid digestion. Pancreatic cancer is a condition in which malignant (cancer) cells develop in pancreatic tissues. The pancreas can develop tumors in various ways, including malignant and noncancerous tumors. However, the precise causes of pancreatic cancer are unknown. Individuals diagnosed with pancreatic cancer before the tumor develops or spreads have an average life expectancy of pancreatic cancer of 3 to 3.5 years. Pancreatic cancer symptoms may include jaundice, dark urine, weight loss, loss of appetite, fatigue, and others. A pancreatic cancer diagnosis is difficult because symptoms are frequently confused with those of other disorders, such as irritable bowel syndrome. The extent of the cancer determines the treatment of pancreatic cancer options. Pancreatic cancer treatment options may include surgery, chemotherapy, radiation therapy, targeted therapy, or a combination of these. Learn more about the diseases and pancreatic cancer diet @ Pancreatic Cancer Tests A snapshot of the Pancreatic Cancer Pipeline Drugs mentioned in the report: Learn more about the emerging pancreatic cancer treatment options @ Pancreatic Cancer Clinical Trials Pancreatic Cancer Therapeutics Assessment The pancreatic cancer pipeline report proffers an integral view of pancreatic cancer emerging novel therapies segmented by stage, product type, molecule type, mechanism of action, and route of administration. Scope of the Pancreatic Cancer Pipeline Report Coverage: Global Therapeutic Assessment By Product Type: Mono, Combination, Mono/Combination Therapeutic Assessment By Clinical Stages: Discovery, Pre-clinical, Phase I, Phase II, Phase III Therapeutics Assessment By Route of Administration: Inhalation, Intranasal, Intravenous, Oral, Parenteral, Subcutaneous Therapeutics Assessment By Molecule Type: Antibody, Antisense oligonucleotides, Immunotherapy, Monoclonal antibody, Peptides, Protein, Recombinant protein, Small molecule, Stem Cell, Vaccine Therapeutics Assessment By Mechanism of Action: Connective tissue growth factor inhibitors, Poly(ADP-ribose) polymerase 1 inhibitors, Poly(ADP-ribose) polymerase 2 inhibitors, Immunologic cytotoxicity, T lymphocyte replacements, Growth differentiation factor 15 inhibitors, Endothelin B receptor antagonists, Image enhancers Key Pancreatic Cancer Companies: FibroGen, Innovent Biologics, CARsgen Therapeutics, Ascentage Pharma, NGM Biopharmaceuticals, TME Pharma AG, Lee's Pharmaceutical Limited, ImmunityBio, Inc., Rgene Corporation, CSPC ZhongQi Pharmaceutical Technology Co., Ltd., CanBas Co. Ltd., Jiangsu HengRui Medicine Co., Ltd., Bristol-Myers Squibb, SynerGene Therapeutics, Inc., AbbVie, Silenseed Ltd, Galera Therapeutics, Inc., Helix BioPharma, Golden Biotechnology Corporation, Eli Lilly and Company, Innovent Biologics (Suzhou) Co. Ltd., Panbela Therapeutics, Inc., GlaxoSmithKline, Chia Tai Tianqing Pharmaceutical Group, Roche, Prestige Biopharma Limited, Everfront Biotech Co., Ltd., XBiotech, Inc., Incyte Corporation, Ability Pharmaceuticals SL, Lokon Pharma, HCW Biologics, Amplia Therapeutics Limited, BioLineRx, Ltd., Taiho Pharmaceutical, Sanofi, Scandion Oncology, Nelum, Celldex Therapeutics, Merus N.V., Seagen Inc., GC Cell Corporation, MetiMedi Pharmaceuticals, Lumicell, Nuvation Bio Inc., ENB Therapeutics, BioNTech SE, Bayer, Genentech, Inc., Rise Biopharmaceuticals, Inc., Prestige Biopharma Limited, iOnctura, Shanghai Unicar-Therapy Bio-medicine Technology, Shanghai Hengrui Pharmaceutical Co., Ltd., Hangzhou Neoantigen Therapeutics Co., Ltd., EUSA Pharma, Inc.,Agenus Inc., Arcus Biosciences, Inc., Amgen, Biomea Fusion, and others. Key Pancreatic Cancer Pipeline Therapies: Pamrevlumab, Niraparib, CT041, APG-1387, BNT141, ENB003, NUV-868, MCLA-128, LUM015, tisotumab vedotin, OMT-111, tusamitamab ravtansine, SCO-101, NGM120, CDX-301, NLM-001, TAS 102, Olaptesed pegol, BL-8040, Gimatecan, AMP945, N-803, HCW9218, BLEX 404, delolimogene mupadenorepvec, Mitoxantrone Hydrochloride Liposome injection, ABTL0812, CBP501, Pemigatinib, SHR-1701, Fluzoparib, XB2001, Cabiralizumab, EF-009, SGT-53, ABBV-927, PBP1510, Vemurafenib, siG12D-LODER, Penpulimab, GC4711, GSK2256098, L-DOS47, SBP-101, Antroquinonol, LY3214996, Sintilimab, RP72,PBP1510, IOA-289, U87, MVT-5873, SHR-A1904, iNeo-Vac-P01, iNeo-Vac-P01, TQB2858, Siltuximab, AGEN1423, AB680, AMG 199, BMF-219, and others. Dive deep into rich insights for pancreatic cancer research; visit @ New Treatment for Pancreatic Cancer Table of Contents For further information on pancreatic cancer prevention, reach out @ Pancreatic Cancer Drug Treatment Related Reports Pancreatic Cancer Epidemiology Pancreatic Cancer Epidemiology Forecast – 2032 report delivers an in-depth understanding of the disease, historical, and forecasted pancreatic cancer epidemiology in the 7MM. Pancreatic Cancer Market Pancreatic Cancer Market Insight, Epidemiology, and Market Forecast – 2032 report delivers an in-depth understanding of the market trends, market drivers, market barriers, and key pancreatic cancer companies, including FibroGen, NeoImmuneTech, NOXXON Pharma, Silenseed Ltd., Amgen, NGM Biopharmaceuticals, among others. Advanced Pancreatic Cancer Market Advanced Pancreatic Cancer Market Insight, Epidemiology, and Market Forecast – 2032 report delivers an in-depth understanding of the market trends, market drivers, market barriers, and key advanced pancreatic cancer companies, including AstraZeneca, Merck Sharp & Dohme LLC, Bayer, Roche, among others. Advanced Pancreatic Cancer Pipeline Advanced Pancreatic Cancer Pipeline Insight – 2022 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key advanced pancreatic cancer companies, including FibroGen, NeoImmuneTech, NOXXON Pharma, Silenseed Ltd., Amgen, NGM Biopharmaceuticals, among others. Metastatic Pancreatic Cancer Market Metastatic Pancreatic Cancer Market Insight, Epidemiology, and Market Forecast – 2032 report delivers an in-depth understanding of the market trends, market drivers, market barriers, and key metastatic pancreatic cancer companies, including Takeda Oncology, Salspera, Eli Lilly and Company, among others. Metastatic Pancreatic Cancer Pipeline Metastatic Pancreatic Cancer Pipeline Insight – 2022 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key metastatic pancreatic cancer companies, including Takeda Oncology, Salspera, Eli Lilly and Company, among others. Other Trending Oncology Reports Follicular lymphoma | Indolent lymphoma | Severe Toxicities In Lymphoma | Marginal Zone Lymphoma | Vulvar Squamous Cell Carcinoma | Cholangiocarcinoma | Metastatic Cutaneous Squamous cell Carcinoma | Nasopharyngeal Carcinoma | Ductal Carcinoma in Situ | Oncolytic Virus Cancer Therapy | Cancer Cachexia | Intratumoral Cancer Therapies | Brain Cancer Related Healthcare Blogs Upcoming Oncology Drugs Oncology Market Outlook Future of Oncology Market Related Cases Studies Competitive Intelligence Market Assessment Product Assessment Epidemiology Assessment Related Healthcare Services Healthcare Business Consulting Healthcare Competitive Intelligence Services Healthcare Asset Prioritization Services About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. Connect with us at LinkedIn Contact Us Shruti Thakur [email protected] +1(919)321-6187 Logo: SOURCE DelveInsight Business Research, LLP

快速通道孤儿药临床结果免疫疗法

2022-06-08

·生物制药小编

罗氏/BNT强强联合|个体化癌症疫苗临床初战告捷

随着mRNA技术的发展，这一技术在癌症疫苗方面似乎正准备证明其卓越的功效。近日（6月5日），此前以新冠mRNA疫苗技术名声大噪的BioNTech公司在美国临床肿瘤学会（ASCO）年会上报告了其个体化mRNA癌症疫苗Autogene Cevumeran与罗氏PD-L1检查点抑制剂atezolizumab和化疗在接受手术切除导管的腺癌患者中联合应用的第一阶段初步数据。结果显示，早期数据显示了良好的安全性和令人鼓舞的临床活动指征。Autogene Cevumeran及其iNeST技术平台Autogene Cevumeran（前名RO7198457）是基于BNT的iNeST技术平台开发的个体化mRNA疫苗。（iNeST=Individualized Neoantigen Specific Immunotherapy个体化新抗原特异性免疫治疗）人体的T细胞能够针对肿瘤突变导致的抗原新表位，驱动癌症免疫。然而这一突发的自发免疫识别是低效的，常常在肿瘤及其附近受到抑制，因此BNT引入了个体化癌症疫苗的概念。他们通过建立了从对个体突变的全面识别，新表位的计算预测，到为每个患者设计和制造独特的疫苗这一完整体系构筑了iNeST的技术平台。其中的平台的全流程包括：1.首先需要从患者体内提取血液和癌症组织；2.通过血液分析获取患者的基因组材料，且研究肿瘤分子组分；并通过将两者对比分析发现肿瘤的基因突变；经过比对后，由于这些突变需要被用来帮助免疫系统识别肿瘤细胞，因此只有同时发生在癌细胞的DNA和RNA中的突变才有资格接受BNT的mRNA癌症疫苗治疗；3.BNT将从这些突变中，通过软件挑选其中至多20个能让免疫系统最可能识别的突变抗原，并通过这种方式设计个性化疫苗；4.疫苗经过按需定制的生产线，需要花费4-6个星期并最终交付给患者。5.在给药后，患者的免疫系统将通过产生T细胞反应，诱发针对肿瘤细胞特定的个体靶结构的免疫反应。而T细胞会攻击肿瘤并摧毁肿瘤细胞。图：Autogene Cevumeran生产的全流程从黑色素瘤临床到现在的胰腺癌临床此前这一疗法曾经在黑色素瘤中进行首次应用，研究于2017年发表在了Nature，临床结果显示所有患者都完成了最多20剂新表位疫苗的治疗，他们耐受良好，没有相关的严重不良事件。单独的新表位疫苗可以预防高危患者的疾病复发。此外，它们提供了将疫苗与PD-1/PD-L1阻断组合的基本原理。研究人员发现，在新表位疫苗接种后，由于其中一位P07号患者疾病进展迅速，进行同情性抗PD-1（帕博利珠单抗）治疗时，这位患者中被报告发现了迅速产生完全应答。该患者在两个月内经历了多发性黑色素瘤病变大小减少80%,并且最终完全缓解。疫苗诱导的T细胞在疫苗接种结束后持续长达9个月研究人员认为这一情况是由于新表位特异性T细胞亚群为PD-1阳性和记忆表型，疫苗后肿瘤遭到损伤会上调PD-L1并抑制这些T细胞亚群。因此患者在接种疫苗后使用PD-1抗体治疗时，迅速产生了免疫应答反应。2017年这项研究为现在疫苗与PD-1/PD-L1免疫检查点抑制剂联用的临床提供了依据。此次发布的临床数据又为这一联合用药的可行性增加了几分：来自16名手术后接受疫苗接种的患者数据表明，这一疗法耐受性良好，只有一名患者出现了疫苗相关的3级发热和高血压。该疗法在一半的患者中诱导了新抗原特异性T细胞反应。而与以前检测不到的水平相比，针对新抗原的T细胞水平上升到了总水平的2.9%。此外，在18个月的早期中位随访中，与没有疫苗诱导的免疫反应的患者相比，有重新免疫反应的患者显示出显著更长的无复发生存期(RFS)。罗氏的Tecentriq（atezolizumab）在胰腺癌上的联用胰腺癌被称为癌症之王，而PD-1/PD-L1抑制剂单药在胰腺癌中的表现不尽如人意。近年来随着对PD-1/PD-L1免疫检查点分子机制研究的逐渐深入，各种联合治疗方法如PD-1/PD-L1抑制剂和其他检查点抑制剂联合或在阻断PD-1/PD-L1信号通路的同时使用激动剂，抗体，疫苗等方式治疗胰腺癌的临床试验也在不断进行。除了此次的癌症疫苗，在胰腺癌这一癌种上，在化疗药物之外，Tecentriq的联合治疗还选择了赛诺菲ICOS单抗KY1044，舒泰神的 C5a单抗BDB-001，Lokon公司的溶瘤病毒LOAd703，iPSC衍生的CAR-NK细胞疗法FT500和FT536，缺氧激活前药CP-506共同进行。 Tecentriq可以说是在K药和O药之外销售额最高的PD-1/PD-L1抑制剂，如果能够在胰腺癌的联合治疗中证明联合疗法的疗效有助于开拓这一难治癌种的巨大市场。小编总结肿瘤疫苗的好处在于能够将体内T细胞激发后，产生新生抗原，能够在肿瘤组织内富集，并有效杀伤肿瘤细胞。虽然癌症疫苗的尝试一直以失败告终，但最近OSE-2101（Tedopi）的积极阳性结果以及此次的捷报可能使得癌种疫苗的可行性得到进一步的认可。参考来源：Sahin, U., Derhovanessian, E., Miller, M. et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 547, 222–226 (2017). https://doi-org.libproxy1.nus.edu.sg/10.1038/nature23003https://investors.biontech.de/news-releases/news-release-details/positive-phase-1-data-mrna-based-individualized-neoantigen——END——由中国医药质量管理协会和佰傲谷发起主办的2022QbD生物药质量科学大会，特设全球药品政策法规论坛将于8月12日下午至8月13日全天在北京召开！本次大会以“坚守质量高地，剑指国际化”为主题，特设四大专场论坛，并邀请到了罗氏/基因泰克公司全球质量控制部产品质控负责人焦吉祥莅临大会现场做演讲报告！点击“阅读原文”，进入官网立即报名~

疫苗免疫疗法抗体信使RNA细胞疗法

100 项与 Delolimogene mupadenorepvec 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
黑色素瘤	临床2期	美国	Lokon Pharma AB	2020-01-28
黑色素瘤	临床2期	瑞典	Lokon Pharma AB	2020-01-28
结直肠癌	临床2期	瑞典	Lokon Pharma AB	2018-03-01
卵巢癌	临床2期	瑞典	Lokon Pharma AB	2018-03-01
胆道肿瘤	临床2期	瑞典	Lokon Pharma AB	2018-03-01
胰腺癌	临床2期	美国	Lokon Pharma AB	2016-11-01
多发性骨髓瘤	临床前	瑞典	Lokon Pharma AB	2019-08-15

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临床结果

适应症

分期

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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


NCT02705196 (LOKON001, Pubmed)	临床1/2期	不能切除性胰腺癌	22	LOAd703	糧遞鹽淵夢選壓觸顧艱(窪窪艱襯範遞鹹壓網選) = 觸餘遞醖積遞餘願齋窪觸觸選齋齋鏇鏇憲夢糧 (衊窪餘製襯齋遞窪壓簾 ) 更多	积极	2024-04-01
NCT03555149 (MORPHEUS, CTgov)	临床1/2期	转移性结直肠癌	96	Regorafenib (Regorafenib (Control))	淵鬱選鹽淵製憲憲蓋壓(衊鹽獵衊獵膚蓋餘憲膚) = 襯鬱憲網襯簾鹽製鏇範製繭鑰衊衊網淵餘製鏇 (衊憲鑰繭餘鬱餘範積構, 鑰糧鏇壓選鹹簾艱製觸 ~ 鹹積範願齋夢廠餘繭選) 更多	-	2023-11-07
NCT03555149 (MORPHEUS, CTgov)	临床1/2期	转移性结直肠癌	96	Imprime PGG+Atezolizumab+Bevacizumab (Atezolizumab + Imprime PGG + Bevacizumab)	淵鬱選鹽淵製憲憲蓋壓(衊鹽獵衊獵膚蓋餘憲膚) = 範範憲網繭糧選艱鬱築製繭鑰衊衊網淵餘製鏇 (衊憲鑰繭餘鬱餘範積構, 顧憲獵獵餘窪壓蓋蓋鹹 ~ 餘遞壓憲衊網製獵憲網) 更多	-	2023-11-07
NCT03225989 (LOKON002, AACR2023) 人工标引	临床1/2期	晚期恶性实体瘤	28	LOAd703	簾膚醖構膚鹽簾鹹艱壓(艱齋選遞鬱顧鬱繭膚衊) = 襯膚鑰齋築選壓膚醖觸簾獵範簾衊網膚獵觸淵 (齋襯醖糧築齋蓋簾糧網 ) 更多	积极	2023-04-14
NCT02705196 (ASCO2022) 人工标引	临床1/2期	晚期胰腺腺癌	22	LOAd703+nab-paclitaxel+gemcitabine	鬱糧範製觸壓壓製餘積(糧積積壓繭範鬱糧鹹遞) = 糧夢獵醖憲壓窪憲繭築憲夢襯願構鏇糧鏇齋製 (顧鑰遞獵齋襯鏇選夢鬱 ) 更多	积极	2022-06-02