Phase 1 Trial of SX-682, a CXCR 1/2 Inhibitor, in Combination With Standard of Care Treatment in Patients With Relapsed or Refractory Multiple Myeloma (RRMM)

This phase I trial tests the safety and side effects of SX-682 in combination with standard of care treatment carfilzomib, daratumumab-hyaluronidase, and dexamethasone in treating patients with multiple myeloma that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). SX-682 works by blocking certain sites on cells that suppress the ability of the immune system to destroy tumor cells. Blocking those specific sites allows other cells of the immune system to become "free" to kill tumor cells. Carfilzomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Daratumumab is in a class of medications called monoclonal antibodies. It binds to a protein called CD38, which is found on some types of immune cells and tumor cells, including myeloma cells. Daratumumab may block CD38 and help the immune system kill tumor cells, while hyaluronidase helps to deliver daratumumab to CD38-expressing tumor cells through a subcutaneous injection. Dexamethasone is in a class of medications called corticosteroids. It is known to kill myeloma cells and is also used to reduce inflammation and lower the body's immune response to monoclonal antibodies like dratumumab and help lessen its side effects. Giving SX-682 in combination with carfilzomib, daratumumab-hyaluronidase and dexamethasone may be safe and tolerable in treating patients with relapsed or refractory multiple myeloma

开始日期2025-04-01

申办/合作机构

Roswell Park Comprehensive Cancer Center

NCT06228053

/ Recruiting临床2期

A Phase 2, Single-Arm Study of the CXCR1/2 Inhibitor SX-682 Plus Enzalutamide in Men with Abiraterone-Resistant Metastatic Castration Resistant Prostate Cancer, the SYNERGY-201 Trial

The goal of this clinical trial is to study the combination of SX-682 plus enzalutamide in men with metastatic castration resistant prostate cancer (mCRPC) who have failed abiraterone.

开始日期2024-11-18

申办/合作机构

Syntrix Biosystems, Inc.

[+1]

NCT06149481

/ Recruiting临床1/2期IIT

Phase I/II Study of the Combination Immunotherapy Regimen: SX-682, TriAdeno Vaccine, Retifanlimab and IL-15 Agonist N-803 (STAR15) for Metastatic Colorectal Cancer (mCRC)

Background:
Each year, more than 32,000 people in the United States are diagnosed with colorectal cancer that has returned or progressed after treatment and spread to other organs. This is called metastatic colorectal cancer (mCRC). Most people with mCRC survive only about 2 years.
Objective:
To test the ability of a combination of up to 4 experimental anti-cancer drugs treat mCRC. The names of these drugs are retifanlimab, TriAdeno vaccine, N-803, and SX-682. They are described below.
Eligibility:
Adults aged 18 years or older with mCRC. Participants must have
Design:
Participants will be screened. This includes having a physical exam, blood tests, urine tests, and imaging tests. If signed on to the study, participants will have 2 tumor biopsies. One when starting the study and once about 8 weeks after bring on the study. Participants will receive $500 for each biopsy.
Participants will be treated with either 3 or 4 drugs and will receive a detailed calendar explaining when each drug is given.
Retifanlimab is given every 4 weeks through an IV (an IV is tube attached to a needle inserted into a vein in the arm). N-803 is injected under the skin on the abdomen every 4 weeks.
TriAdeno vaccine is injected under the skin of the upper arm or thigh once a month for 3 doses and then once every 3 months.
Some participants will also receive a 4th drug. SX-682 is a pill taken by mouth. Participants will take this drug 2 times a day at home for about 3 weeks of each month.
Study treatment will continue up to 2 years. Follow-up phone calls/emails may continue for 3 more years.

开始日期2024-03-26

申办/合作机构

National Cancer Institute

100 项与 SX-682 相关的临床结果

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100 项与 SX-682 相关的转化医学

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100 项与 SX-682 相关的专利（医药）

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项与 SX-682 相关的文献（医药）

2024-12-31·OncoImmunology

CXCR1/2 antagonism inhibits neutrophil function and not recruitment in cancer

Article

作者: Randolph, Timothy W. ; Huffman, Grace M. ; Kenney, Naia N. ; Houghton, A. McGarry ; Camai, Alex ; Kwak, Jeff W. ; Nguyen, Helena Q. ; Zhu, Xiaodong ; Mekvanich, Surapat

The level of tumor and circulating CXCR1/2-expressing neutrophils and CXCR1/2 ligands correlate with poor patient outcomes, inversely correlate with tumoral lymphocyte content, and predict immune checkpoint inhibitor (ICI) treatment failure. Accordingly, CXCR2-selective and CXCR1/2 dual inhibitors exhibit activity both as single agents and in combination with ICI treatment in mouse tumor models. Based on such reports, clinical trials combining CXCR1/2 axis antagonists with ICI treatment for cancer patients are underway. It has been assumed that CXCR1/2 blockade impacts tumors by blocking neutrophil chemotaxis and reducing neutrophil content in tumors. Here, we show that while CXCR2 antagonism does slow tumor growth, it does not preclude neutrophil recruitment into tumor. Instead, CXCR1/2 inhibition alters neutrophil function by blocking the polarization of transcriptional programs toward immune suppressive phenotypes and rendering neutrophils incapable of suppressing lymphocyte proliferation. This is associated with decreased release of reactive oxygen species and Arginase-1 into the extracellular milieu. Remarkably, these therapeutics do not impact the ability of neutrophils to phagocytose and kill ingested bacteria. Taken together, these results mechanistically explain why CXCR1/2 inhibition has been active in cancer but without infectious complications.

2023-12-01·Gut

CRIP1 fosters MDSC trafficking and resets tumour microenvironment via facilitating NF-κB/p65 nuclear translocation in pancreatic ductal adenocarcinoma

Article

作者: Tan, Zhen ; Shi, Si ; Zhang, Yiyin ; Liu, Jiang ; Liu, Xiaomeng ; Meng, Qingcai ; Xu, Jin ; Wang, Wei ; Lei, Yubin ; Tang, Rong ; Yu, Xianjun ; Liang, Chen ; Zhang, Bo ; Hua, Jie

ObjectivePancreatic ductal adenocarcinoma (PDAC) is among the most immunosuppressive tumour types. The tumour immune microenvironment (TIME) is largely driven by interactions between immune cells and heterogeneous tumour cells. Here, we aimed to investigate the mechanism of tumour cells in TIME formation and provide potential combination treatment strategies for PDAC patients based on genotypic heterogeneity.DesignHighly multiplexed imaging mass cytometry, RNA sequencing, mass cytometry by time of flight and multiplex immunofluorescence staining were performed to identify the pro-oncogenic proteins associated with low immune activation in PDAC. An in vitro coculture system, an orthotopic PDAC allograft tumour model, flow cytometry and immunohistochemistry were used to explore the biological functions of cysteine-rich intestinal protein 1 (CRIP1) in tumour progression and TIME formation. RNA sequencing, mass spectrometry and chromatin immunoprecipitation were subsequently conducted to investigate the underlying mechanisms of CRIP1.ResultsOur results showed that CRIP1 was frequently upregulated in PDAC tissues with low immune activation. Elevated CRIP1 expression induced high levels of myeloid-derived suppressor cell (MDSC) infiltration and fostered an immunosuppressive tumour microenvironment. Mechanistically, we primarily showed that CRIP1 bound to nuclear factor kappa-B (NF-κB)/p65 and facilitated its nuclear translocation in an importin-dependent manner, leading to the transcriptional activation of CXCL1/5. PDAC-derived CXCL1/5 facilitated the chemotactic migration of MDSCs to drive immunosuppression. SX-682, an inhibitor of CXCR1/2, blocked tumour MDSC recruitment and enhanced T-cell activation. The combination of anti-PD-L1 therapy with SX-682 elicited increased CD8+T cell infiltration and potent antitumor activity in tumour-bearing mice with high CRIP1 expression.ConclusionsThe CRIP1/NF-κB/CXCL axis is critical for triggering immune evasion and TIME formation in PDAC. Blockade of this signalling pathway prevents MDSC trafficking and thereby sensitises PDAC to immunotherapy.

2023-04-19·Cancers

Regression and Eradication of Triple-Negative Breast Carcinoma in 4T1 Mouse Model by Combination Immunotherapies.

Article

作者: Huang, Yue ; Oppenheim, Joost J ; Nagy, Bethany A ; Nahar, Saifun ; Yang, De ; Rudloff, Udo ; Zebala, John A ; Maeda, Dean Y

Triple-negative breast carcinoma (TNBC) is one of the most aggressive types of solid-organ cancers. While immune checkpoint blockade (ICB) therapy has significantly improved outcomes in certain types of solid-organ cancers, patients with immunologically cold TNBC are afforded only a modest gain in survival by the addition of ICB to systemic chemotherapy. Thus, it is urgently needed to develop novel effective therapeutic approaches for TNBC. Utilizing the 4T1 murine model of TNBC, we developed a novel combination immunotherapeutic regimen consisting of intratumoral delivery of high-mobility group nucleosome binding protein 1 (HMGN1), TLR2/6 ligand fibroblast-stimulating lipopeptide (FSL-1), TLR7/8 agonist (R848/resiquimod), and CTLA-4 blockade. We also investigated the effect of adding SX682, a small-molecule inhibitor of CXCR1/2 known to reduce MDSC trafficking to tumor microenvironment, to our therapeutic approach. 4T1-bearing mice responded with significant tumor regression and tumor elimination to our therapeutic combination regimen. Mice with complete tumor regressions did not recur and became long-term survivors. Treatment with HMGN1, FSL-1, R848, and anti-CTLA4 antibody increased the number of infiltrating CD4+ and CD8+ effector/memory T cells in both tumors and draining lymph nodes and triggered the generation of 4T1-specific cytotoxic T lymphocytes (CTLs) in the draining lymph nodes. Thus, we developed a potentially curative immunotherapeutic regimen consisting of HMGN1, FSL-1, R848, plus a checkpoint inhibitor for TNBC, which does not rely on the administration of chemotherapy, radiation, or exogenous tumor-associated antigen(s).

项与 SX-682 相关的新闻（医药）

2024-10-10

·PRNewswire

Metastatic Castration-Resistant Prostate Cancer Clinical Trial Pipeline Appears Robust With 90+ Key Pharma Companies Actively Working in the Therapeutics Segment | DelveInsight

Metastatic Castration-Resistant Prostate Cancer (mCRPC) refers to prostate cancer that has spread (metastasized) to other parts of the body and continues to progress despite treatments that lower testosterone levels (androgen deprivation therapy or ADT) major pharmaceutical companies are heavily investing in research and development of new treatments, including immunotherapy (e.g., sipuleucel-T) and targeted therapies, which are seen as the next frontier in treating mCRPC. The use of precision medicine to identify genetic profiles in patients has further expanded the potential for targeted treatment. LAS VEGAS , Oct. 10, 2024 /PRNewswire/ -- DelveInsight's ' Metastatic Castration-Resistant Prostate Cancer Pipeline Insight 2024 ' report provides comprehensive global coverage of pipeline mCRPC therapies in various stages of clinical development, major pharmaceutical companies are working to advance the pipeline space and future growth potential of the mCRPC pipeline domain. Key Takeaways from the Metastatic Castration-Resistant Prostate Cancer Pipeline Report DelveInsight's mCRPC pipeline report depicts a robust space with 90+ active players working to develop 100+ pipeline therapies for mCRPC treatment. Key mCRPC companies such as Regeneron Pharmaceuticals, AstraZeneca, Hinova Pharmaceuticals, Zenith Epigenetic, Eli Lilly and Company, Astellas Pharma, Seagen, Pfizer, Progenics Pharmaceutical, Molecular Insight Pharmaceuticals, Bayer, Accutar Biotechnology Inc, Hinova Pharmaceuticals, Forma Therapeutics, Inc., HALDA THERAPEUTICS INC., Tavanta Therapeutics, Lantheus, Pfizer, AB Science, Syntrix Pharmaceuticals, Exelixis, Laekna Therapeutics Shanghai Co. Ltd., Cardiff Oncology, Ipsen, Norroy Bioscience, Astellas Pharma, Novartis, Johnson & Johnson, Tempest Therapeutics, and others are evaluating new mCRPC drugs to improve the treatment landscape. Promising mCRPC pipeline therapies such as REGN 4336, Capivasertib, Deutenzalutamide, ZEN003694, Abemaciclib, Enfortumab vedotin, Talazoparib, I-131-1095, Pelgifatamab corixetan, AC176, HP518, FT-7051, HLD-0915, TAVT-45, PNT2002, Mevrometostat, Masitinib, SX-682, XL092, LAE001, Onvansertib, Tazemetostat, 177Lu-NYM032, PRL-02, 225 Actinium PSMA 617, ARX51, TPST-1120, and others are under different phases of mCRPC clinical trials. In October 2024, Curium announced that it had entered into a strategic partnership with PDRadiopharma Inc, a wholly-owned subsidiary of PeptiDream, for the clinical development, regulatory filing, and commercialization in Japan of 177Lu-PSMA-I&T and 64Cu-PSMA-I&T. The two agents 177Lu-PSMA-I&T and 64Cu-PSMA-I&T target prostate-specific membrane antigen (PSMA) expressed on prostate cancer cells and are being investigated for prostate cancer treatment and diagnostics. In July 2024, the US FDA granted fast-track designation to the prostate-specific membrane antigen (PSMA)–targeted radiopharmaceutical 225Ac-FL-020 for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). In July 2024, Merck and Orion Corporation announced the mutual exercise of option providing Merck global exclusive rights to Opevesostat, an investigational CYP11A1 inhibitor, for the treatment of Metastatic Castration-Resistant Prostate Cancer. In July 2024, the US FDA granted fast-track designation to the antibody-drug conjugate (ADC) BNT324/DB-1311 to potentially treat patients with unresectable advanced or metastatic castration-resistant prostate cancer (mCRPC) whose disease had progressed on or after standard systemic regimens. In July 2024, FutureChem announced that the FC-705 has received orphan drug designation from the Ministry of Food and Drug Safety (MFDS) for the treatment of prostate cancer. In June 2024, CAR T-Cell Therapy demonstrated promising results for mCRPC according to Phase I trial results. In January 2024, Lava Therapeutics announced that it has signed a clinical trial collaboration and supply agreement with Merck to evaluate its prostate cancer therapy LAVA-1207 as a combination treatment with MSD's Keytruda (pembrolizumab). In July 2024, Blue Earth Therapeutics announced the signing of a clinical research collaboration with University College London (UCL). The collaboration is centered on a Phase I/II trial designed to evaluate the safety, tolerability, radiation dosimetry, and antitumor activity of the 225Ac-rhPSMA-10.1 in men with metastatic castrate-resistant prostate cancer who have previously responded to lutetium 177 (177Lu)-PSMA therapy. Request a sample and discover the recent advances in mCRPC treatment drugs @ Metastatic Castration-Resistant Prostate Cancer Pipeline Report The mCRPC pipeline report provides detailed profiles of pipeline assets, a comparative analysis of clinical and non-clinical stage mCRPC drugs, inactive and dormant assets, a comprehensive assessment of driving and restraining factors, and an assessment of opportunities and risks in the mCRPC clinical trial landscape. Metastatic Castration-Resistant Prostate Cancer Overview Metastatic castration-resistant prostate cancer (mCRPC) is an advanced stage of prostate cancer that continues to grow and spread despite hormone therapy aimed at lowering testosterone levels. The term "metastatic" refers to cancer spreading to other parts of the body, such as the bones, lymph nodes, or distant organs, while "castration-resistant" indicates that the cancer no longer responds to treatments that reduce testosterone, a key driver of prostate cancer growth. mCRPC is typically more aggressive and challenging to treat than earlier stages of prostate cancer. The causes of mCRPC stem from genetic and environmental factors. Genetic mutations in the androgen receptor pathway can make cancer cells less dependent on testosterone, allowing them to thrive even under hormone-suppressing treatments. Environmental factors like diet, lifestyle, and exposure to certain chemicals may also contribute to the development and progression of prostate cancer. Symptoms of mCRPC often include pain in bones, fatigue, difficulty urinating, weight loss, and general weakness. As the cancer spreads, it can impair the function of other organs, depending on the site of metastasis. Diagnosis of mCRPC usually involves a combination of tests, including prostate-specific antigen (PSA) blood tests, imaging studies like CT scans, MRIs, or bone scans, and sometimes biopsies to confirm the spread and resistance to treatment. Treatment options for mCRPC are more complex and may include newer hormonal therapies (e.g., abiraterone, enzalutamide), chemotherapy (docetaxel or cabazitaxel), immunotherapy (e.g., sipuleucel-T), or targeted therapies such as PARP inhibitors. Bone-targeting therapies, radiation, and palliative care can also be used to manage symptoms and improve the quality of life. Treatment is typically tailored to the individual based on the extent of the disease and the patient health. Find out more about mCRPC treatment drugs @ Drugs for Metastatic Castration-Resistant Prostate Cancer Treatment A snapshot of the mCRPC Pipeline Drugs mentioned in the report: Learn more about the emerging mCRPC pipeline therapies @ Metastatic Castration-Resistant Prostate Cancer Clinical Trials Metastatic Castration-Resistant Prostate Cancer Therapeutics Assessment The mCRPC pipeline report proffers an integral view of the mCRPC emerging novel therapies segmented by stage, product type, molecule type, mechanism of action, and route of administration. Scope of the Metastatic Castration-Resistant Prostate 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: Oral, Intravenous, Subcutaneous Therapeutics Assessment By Molecule Type: Small molecule, Cell therapy, Peptides, Polymer, Small molecule, Gene therapy Therapeutics Assessment By Mechanism of Action: Androgen receptor degradation enhancers, Antibody-dependent cell cytotoxicity, Proto-oncogene protein c-akt inhibitors, Androgen receptor antagonists, Bromodomain and extraterminal domain protein inhibitors, Cyclin-dependent kinase 4 inhibitors, Cyclin-dependent kinase 6 inhibitors, Ionizing radiation emitters, PPAR alpha antagonists. Key Metastatic Castration-Resistant Prostate Cancer Companies: Regeneron Pharmaceuticals, AstraZeneca, Hinova Pharmaceuticals, Zenith Epigenetic, Eli Lilly and Company, Astellas Pharma, Seagen, Pfizer, Progenics Pharmaceutical, Molecular Insight Pharmaceuticals, Bayer, Accutar Biotechnology Inc, Hinova Pharmaceuticals, Forma Therapeutics, Inc., HALDA THERAPEUTICS INC., Tavanta Therapeutics, Lantheus, Pfizer, AB Science, Syntrix Pharmaceuticals, Exelixis, Laekna Therapeutics Shanghai Co. Ltd., Cardiff Oncology, Ipsen, Norroy Bioscience, Astellas Pharma, Novartis, Johnson & Johnson, Tempest Therapeutics, and others. Key Metastatic Castration-Resistant Prostate Cancer Pipeline Therapies: REGN 4336, Capivasertib, Deutenzalutamide, ZEN003694, Abemaciclib, Enfortumab vedotin, Talazoparib, I-131-1095, Pelgifatamab corixetan, AC176, HP518, FT-7051, HLD-0915, TAVT-45, PNT2002, Mevrometostat, Masitinib, SX-682, XL092, LAE001, Onvansertib, Tazemetostat, 177Lu-NYM032, PRL-02, 225 Actinium PSMA 617, ARX51, TPST-1120, and others. Dive deep into rich insights for new drugs for mCRPC treatment, visit @ Metastatic Castration-Resistant Prostate Cancer Drugs Table of Contents For further information on the mCRPC Cancer pipeline therapeutics, reach out @ Metastatic Castration-Resistant Prostate Cancer Treatment Drugs Related Reports Metastatic Castration-Resistant Prostate Cancer Market Metastatic Castration-Resistant Prostate Cancer Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, market share of the individual therapies, and key mCRPC companies including AstraZeneca, Merck Sharp & Dohme, Hinova Pharmaceuticals, Pfizer, Astellas Pharma, Modra Pharmaceuticals, AB Science, Eli Lilly and Company, Zr Pharma & GmbH, Bristol-Myers Squibb, Ipsen, Exelixis, Takeda, Janssen Research & Development, Tesaro, Lantheus Holdings, Kintor Pharmaceutical, MacroGenics, Daiichi Sankyo, Madison Vaccines, Novartis, Point Biopharma, Xencor, Essa Pharma, Telix International, Bayer, Arvinas, among others. Metastatic Prostate Cancer Market Metastatic Prostate Cancer Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, market share of the individual therapies, and key metastatic prostate cancer companies including AstraZeneca, Arvinas, Madison Vaccines, Phosplatin Therapeutics, Hinova Pharmaceuticals, Bristol Myers Squibb, Merck, MacroGenics, Daiichi Sankyo, Seagen, Taiho Pharmaceutical, Modra Pharmaceuticals, Xencor, Point Biopharma, Lantheus Holdings, Zenith Epigenetics, Essa Pharma, Telix Pharmaceuticals, Kintor Pharmaceutical, AB Science, Eli Lilly and Company, Exelixis among others. Metastatic Castration-Sensitive Prostate Cancer Market Metastatic Castration-Sensitive Prostate Cancer Market Insights, Epidemiology, and Market Forecast – 2034 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology, market share of the individual therapies, and key mCSPC companies including Myovant Sciences, Pfizer, Bayer, Orion, Novartis, AstraZeneca, Pfizer, Janssen, Merck, Eli Lilly, among others. Metastatic Castration-Sensitive Prostate Cancer Pipeline Metastatic Castration-Sensitive Prostate Cancer Pipeline Insight – 2024 report provides comprehensive insights about the pipeline landscape, including clinical and non-clinical stage products, and the key mCSPC companies, including Myovant Sciences, Pfizer, Bayer, Orion, Novartis, AstraZeneca, Pfizer, Janssen, Merck, Eli Lilly, among others. About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Contact Us Shruti Thakur [email protected] +14699457679 Logo: SOURCE DelveInsight Business Research, LLP WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

快速通道免疫疗法临床1期临床结果

2024-09-19

·Pharmaceutical Technology

Lupin and Takeda to commercialise Vonoprazan in India

The agreement will allow Lupin to expand its gastroenterology portfolio in the Indian market. Credit: Orawan Pattarawimonchai/Shutterstock. Pharmaceutical company Lupin has announced a non-exclusive patent licence agreement with Takeda Pharmaceutical for the commercialisation of Vonoprazan tablets in India. The medication will be sold under the brand name Lupin’s Lupivon in the Indian market. Vonoprazan will be made available in 10mg and 20mg strengths. A potassium-competitive acid blocker (P-CAB), the drug differs from traditional acid suppressants such as proton pump inhibitors by offering rapid and complete proton pump inhibition from the first dose. Its longer duration of action also ensures effective control of nocturnal acid breakthrough, and it can be dosed independently of meals. See Also: Trilaciclib by G1 Therapeutics for Triple-Negative Breast Cancer (TNBC): Likelihood of Approval SX-682 by Syntrix Pharmaceuticals for Human Epidermal Growth Factor Receptor 2 Negative Breast Cancer (HER2- Breast Cancer): Likelihood of Approval The Drug Controller General of India (DCGI) has approved Vonoprazan for the treatment of gastric ulcers, reflux esophagitis and duodenal ulcers, and as part of the Helicobacter pylori eradication regimen. The agreement will allow Lupin to expand its gastroenterology portfolio in the Indian market, where acid peptic disorders (APD) are claimed to be highly prevalent. APDs encompassing gastroesophageal reflux disease (GERD) and peptic ulcer disease (PUD), impact a significant portion of the Indian population. GERD prevalence varies from 5% to 28.5%, while PUD affects approximately 8%. Older age, higher body mass index, non-vegetarian diets, consumption of tea or coffee and lifestyle choices such as smoking and alcohol intake are the risk factors for GERD. Lupin India Region Formulations president Rajeev Sibal stated: “We are very pleased to commercialise Vonoprazan, a novel treatment option for acid peptic disorders. “This is a further step in strengthening our gastroenterology portfolio and is in line with our commitment to introduce innovative medicines to address the unmet needs of our patients.” In November 2023, Lupin introduced the fixed-dose triple combination (FDC) drug , Vilfuro-G, to manage chronic obstructive pulmonary disease in India.

引进/卖出上市批准

2024-01-13

·佰傲谷BioValley

构建肿瘤免疫微环境的15个细胞因子

细胞因子调节肿瘤微环境中各类免疫细胞，影响抗肿瘤免疫反应。1. IL-1βIL-1β是一种有效的促炎细胞因子，参与调节自身免疫性炎症、促炎反应、细胞增殖和细胞分化。这种细胞因子主要由活化的巨噬细胞产生一种pro-IL-1β 的前蛋白，通过炎性Caspase-1（CASP1/ICE）蛋白水解加工成活性形式IL-1β，随后与IL-1受体CD121a/IL1R1和CD121b/IL1R2亚基结合。其他细胞类型产生和分泌IL-1β，促进肿瘤进展。包括脂肪细胞、单核细胞、DC、成纤维细胞、B细胞、TAMs和一些癌细胞等。Immunity. 2019在TME中，IL-1β在乳腺癌等多种实体瘤中巨噬细胞和肿瘤细胞上调表达，可控制肿瘤侵袭，上调原发肿瘤的发生和发展，增加管腔乳腺癌细胞的侵袭性，并通过NF-κB通路增加IL-6的产生，促进肿瘤生长和侵袭性。IL-1β与乳腺癌等肿瘤的不良预后有关。IL-1β是上游细胞因子，抑制恶性肿瘤中IL-1β信号传导，被认为是癌症治疗的有效策略，IL-1β抑制剂Canakinumab尝试进行了非小细胞肺癌的3期临床（CANOPY-A study），但是没有达到主要终点（DFS）（诺华官网https://www.novartis.com/news/media-releases/novartis-provides-update-phase-iii-canopy-study-evaluating-canakinumab-adjuvant-treatment-non-small-cell-lung-cancer）。但是目前仍有两项肿瘤相关临床研究在进行，一项是哥伦比亚大学的透明细胞性肾细胞癌（NCT04028245）;另一项是M.D. Anderson Cancer Center的肺癌预防性研究（NCT04789681）。2. IL-2IL-2作为T细胞生长因子被发现（IL-2/IL-2R研究简史及药物开发），在肿瘤微环境肿可以促进T细胞（含Treg）活化、扩增。对IL-2的开发，一直是抗肿瘤免疫的热点，走过了很多的弯路，也获得很多经验。最近罗氏的PD1-IL2v成为新的方向（罗氏领衔PD1-IL2，赛诺菲带队PD(L)1-IL15）。3.IL-6IL-6是一种多功能细胞因子和脂肪因子，显然具有促肿瘤和促炎作用。它最初被确定为B细胞刺激因子-2（B cell stimulating factor-2， BSF-2）和免疫球蛋白产生的诱导剂。IL-6促进Th2分化，同时抑制Th1极化，维持Th1和Th2免疫细胞之间的动态平衡，并调节产生IL-17的Th17细胞与Treg之间的平衡。IL-6由非恶性细胞产生，如单核细胞、巨噬细胞、T细胞、B细胞、成纤维细胞、内皮细胞和脂肪细胞。在肿瘤微环境中，其主要来源是一些癌细胞、TAMs、髓源性抑制细胞（MDSC）、Th2细胞和CAFs。IL-6是慢性炎症性疾病、自身免疫性疾病、癌症和肿瘤免疫的主要参与者。IL-6结合其受体，下游通过JAK-STAT、MAPK-ERK和PI3K-Akt通路传递信号，激活转录。其中STAT3信号通路被认为是癌症炎症的主要途径，在恶性细胞中经常被激活，并在调节肿瘤微环境炎症相关关键基因转录中发挥关键作用。癌症炎症对于抗肿瘤起着双重作用，即具有一定抗肿瘤的作用，但是也促进细胞外基质降解，癌症血管新生，内皮细胞激活，癌症细胞迁移能力增强，这些都给癌症进展和转移的提供了良好的生态位。肿瘤微环境中的IL-6的作用（（Nat. Rev. Immunol. 2018）因此，阻断IL-6，以及靶向IL-6-STAT3轴是一种潜在抗肿瘤治疗策略，可能有益于乳腺癌的治疗。目前有多项托珠单抗治疗肿瘤（尤其是乳腺癌）的临床研究在进行。4. IL-7 IL-7 是IL-2之外另外一种T细胞生长因子，可以促进T细胞等多种免疫细胞活化增殖，有助于根除肿瘤。然而，上皮癌可以异常表达 IL-7Rα 和 IL-7，促进炎症，肿瘤细胞增殖，对化疗产生耐受，导致促肿瘤环境形成。5. IL-8IL-8，也称为CXCL8，是一种促炎趋化因子，由单核细胞、巨噬细胞、中性粒细胞、T细胞、成纤维细胞、上皮细胞和血管内皮细胞表达。IL-8被称为中性粒细胞趋化因子，可诱导中性粒细胞和粒细胞募集、脱颗粒和吞噬作用，与肥胖、癌症有关，并可诱导炎症细胞和氧化应激介质募集到局部炎症中以发挥细胞毒性活性。肿瘤微环境中，TAMs、CAFs和一些癌细胞分泌IL-8，可促进多种抑制性免疫细胞（如MDSCs等）募集、增殖和存活，抑制CD8+ T细胞活性，并刺激细胞分泌有助于乳腺癌等进展的其他生长因子。（IL-8促进肿瘤发展，免疫治疗新靶点）IL-8介导肿瘤进展（Pharmacol Ther. 2020 ）使用小分子或抗体阻断CXCL8-CXCR1/2轴，可能会产生抗肿瘤活性。目前还在研的药物是Syntrix Biosystems的SX-682(CXCR1/2抑制剂)，抑制MDSCs招募，联合O药治疗转移性胰腺导管腺癌（NCT04477343）,联合K药治疗治疗转移性黑色素瘤（NCT03161431），单要或联合地西他滨治疗骨髓增生异常综合征（NCT04245397）。6. IL-10IL-10被称为人细胞因子合成抑制因子（ cytokine synthesis inhibitory factor），在免疫调节、感染、炎症、自身免疫、移植和肿瘤发生方面具有多种多效性作用。它通过抑制炎性细胞因子（如 TNF-α、IL-6 和 IL-1）的表达，而具有强效抗炎作用，被认为是肿瘤进展中最重要的免疫抑制细胞因子之一。J Exp Med (2020)一般来说，IL-10主要由Th2、Th1、Treg和Th17产生，也可由CD8+ T细胞、单核细胞、巨噬细胞、DCs、B细胞、肥大细胞、嗜酸性粒细胞、角质形成细胞、上皮细胞甚至一些肿瘤细胞产生。受体IL-10受体是一种双受体复合物，由IL-10受体1（IL-10R1）和IL-10R2的两个拷贝组成。这两个亚基都属于II类细胞因子受体家族。IL-10R1与IL-10形成特异性高亲和力相互作用，而IL-10R2是一种共享的低亲和力受体。DCs、T细胞、B细胞、NK、Treg细胞和肥大细胞表达IL-10R1，而IL-10R2亚基普遍表达。信号通路在人类中，IL-10首先与IL10R1结合，然后该复合物与IL10R2结合，形成异四聚体（两个IL10R1/两个IL10R2），从而组装IL-10R复合物，这是启动IL-10信号通路的第一步。一旦复合物组装，分别与 IL-10R1 和 IL-10R2 相关的 Jak1 和 Tyk2 被激活并磷酸化IL10R1 亚基的细胞内细胞质尾部，导致STAT3和STAT1或STAT5的募集和磷酸化/激活，STAT3与IL-10信号转导最显著相关，驱动阻断各种炎症通路的抗炎介质的表达。肿瘤微环境IL-10 在调节肿瘤免疫反应，取决于 TME 免疫细胞上表达的 IL-10 受体的数量。IL10主要由肿瘤微环境中M2/TAM、淋巴细胞和癌细胞产生和表达，促进肿瘤生长、血管生成、肿瘤逃逸和转移。此外，IL-10水平增加Treg细胞和巨噬细胞分泌另外一种抑制性细胞因子TGF-β。7. IL-12IL-12是异二聚体促炎细胞因子小家族的成员，主要由APC（DC和活化的巨噬细胞）产生和表达。IL-12刺激先天性和适应性免疫的效应细胞，激活巨噬细胞极化为M1型，并增强TME中的抗肿瘤细胞毒性免疫应答。 Immunity 2019IL-12受体由IL-12Rβ1和IL-12Rβ2亚基组成，通常在T细胞、NK细胞、NKT细胞、单核细胞、巨噬细胞和DC群体中表达。IL-12与其在靶细胞上表达的受体结合后，JAK2和TYK2促进STAT4的磷酸化和同源二聚化，活化的STAT4诱导转录因子T-box（T-bet）的转录，控制Th1细胞产生IFN-γ，以募集和募集细胞毒性 NK 和 CD8+ T 细胞。T-bet和STAT4下调RORγt，从而限制了Th17和Treg在肿瘤内的产生和增殖。IL-12促进初始CD8+T细胞分化为效应表型，并作为CD8+ T抗凋亡因子，通过释放穿孔素和蛋白水解酶直接破坏微生物和癌细胞。目前有众多的重组IL-12或者IL-12 mRNA在临床阶段。例如ADV/IL-12 治疗转移性非小细胞肺癌（NCT04911166）；NHS-IL12 治疗卡波西肉瘤（NCT04303117）等。8.IL-15IL-15是另外一个非常有前景的抗肿瘤免疫细胞因子，可以刺激T细胞增殖、产生细胞毒性T淋巴细胞、刺激B细胞合成免疫球蛋白以及NK细胞的产生和持续存活。IL-15 受体包括与IL-2、IL-4、IL-7、IL-15 和 IL-21 共享的 γc亚基，以及与 IL-2 共享的 IL-2Rβ 以及 IL-15 特异性亚基 IL15Rα，该受体通过 JAK1/3 和 STAT5/STAT3 系统发出信号。与 IL-2 相比，IL-15对Tregs没有明显的作用。2022年5月23日，ImmunityBio向FDA递交IL-15超级激动剂N-803的上市申请，与卡介苗联合治疗卡介苗不响应的非肌肉浸润性膀胱癌（NMIBC），前期数据显示CR可达70%以上，后因CMO存在问题而上市受阻，目前重新递交上市申请。9. IL-17AIL-17A是参与过敏反应相关的促炎细胞因子。在人类中，IL-17A水平升高与感染、抗菌免疫、慢性炎症性疾病、肥胖和自身免疫性疾病有关。（IL-17与肿瘤免疫，敌人or朋友？）IL-17产生细胞除了经典的Th17细胞之外，现在IL-17产生细胞已经拓展至更大的群体，包括：Th17细胞IL-17+CD8+T细胞γδT17细胞Th1细胞NK细胞中性粒细胞巨噬细胞部分内皮细胞IL-17与肿瘤免疫IL-17来源广泛，因而在抗肿瘤免疫中，作用多样，概括起来，还是同时具有抗肿瘤活性和促肿瘤进展的作用。IL-17产生细胞与肿瘤免疫（Immune Netw. 2020）乳腺微环境中高水平的IL-17A与乳腺癌的高度侵袭性和侵袭性表型有关。IL-17A诱导ERK1/2磷酸化、p38 MAPK和STAT3（IL-6-STAT3）信号通路的激活，并促进肿瘤生长、组织侵袭、组织重塑和基质降解物质（如MMP，包括MMP2和MMP9、迁移、抑制细胞凋亡和血管生成（通过激活VEGF和CXCL8表达）。10.IL-21IL21使用共同的 γc 及其细胞因子特异性 IL-21Rα 链, 调节先天性和适应性免疫反应。IL-21 在 B 细胞分化为浆细胞和T 滤泡辅助细胞（Tfh）的发育中起主要作用; 诱导CD8+ T、NK 细胞激活、抗病毒活性和抗肿瘤活性增强; 可以促进Th17细胞的发育。IL-21R 已被证明在多种造血恶性肿瘤中表达。在慢性淋巴细胞白血病（CLL）、滤泡性淋巴瘤、弥漫性大 B 细胞淋巴瘤（DLBCL）和套细胞淋巴瘤。鉴于其增强 CD8+ T 细胞和 NK 细胞细胞毒性活性的能力，IL-21 已被评估用于治疗癌症。11.IL-23IL-23 是一种异二聚体促炎细胞因子，属于 IL-12 细胞因子家族。这两者有一个共同的p40亚基，该亚基与p35亚基共价连接形成IL-12，或与p19亚基共价连接形成IL-23。它是Th17细胞分化、维持和扩增的关键细胞因子。IL-23主要由DC和巨噬细胞产生，但也由单核细胞、中性粒细胞、先天淋巴细胞、γδ T细胞、B细胞和M2/TAM细胞产生。异二聚体IL-23细胞因子受体由IL12Rβ1（IL-12受体）和IL-23R组成，前者通过酪氨酸激酶-2（tyrosine kinase-2， TYK2）发出信号，后者通过JAK2发出信号以激活STAT3。IL-23受体可在T细胞、NK细胞、NKT细胞、肿瘤细胞中表达，在单核细胞、巨噬细胞和DC细胞群中表达较弱。IL-23 被确定参与肿瘤相关炎症与肿瘤免疫逃逸，可直接影响多种癌前病变和恶性肿瘤。IL-23参与乳腺癌细胞转移，并与较高的乳腺癌肿瘤大小和分期有关。12. IFN-γIFN-γ因其干扰病毒生长的能力而得名，是一种多能细胞因子，在免疫调节、抗微生物/抗病毒宿主防御、过敏、自身免疫性疾病、肥胖和抗肿瘤免疫中发挥有争议的作用。它增强了对炎症分子（TLR配体和TNF）的反应、NK细胞的细胞毒性功能以及M1巨噬细胞的数量，以提供吞噬活性。它是先天免疫应答中的重要自分泌信号，也是适应性应答中的旁分泌信号。在炎症期间，CD4+ Th1细胞是IFN-γ的主要来源，可促进Th1和NK细胞产生IFN-γ。IFN-γ通过促进初始CD4+ T细胞分化为Th1和Th2细胞，增加CD8+ T细胞的杀伤能力并减少Tregs的增殖，触发促炎反应的激活。在DC中，IFN-γ信号通路有助于其成熟、IL-12、IL-1β的产生以及CD4+和CD8+ T细胞的活化。在 TME 中，IFN-γ 的浓度决定了其功能是抗肿瘤还是促肿瘤。高剂量IFN-γ刺激JAK-STAT1信号转导，并可诱导癌细胞死亡和凋亡。然而，宿主浸润细胞或免疫治疗期间在肿瘤部位产生的低剂量IFN-γ可提高肿瘤细胞存活率，通过激活癌细胞中的ICAM1-PI3K-Akt-Notch1信号转导诱导转移风险和EMT转录因子表达。13. TNF-αTNFα 是一种主要的炎性细胞因子和脂肪因子，在高浓度存在时被描述为出血性肿瘤坏死的循环和内毒素诱导因子。它主要由巨噬细胞产生，少部分由 B 和 T（细胞毒性 CD8+ 和 CD4+ Th1）细胞、NK 细胞、肥大细胞、成纤维细胞、破骨细胞、内皮细胞和肌肉细胞产生。它既可以作用于自分泌信号转导，也可以作用于旁分泌信号转导。一般来说，作为一种脂肪因子，它与肥胖有关，促进胰岛素抵抗和2型糖尿病。它参与促炎反应的产生，因为它可以激活和上调400多个炎症基因，并刺激许多不同的细胞反应。TNFα参与乳腺癌细胞存活和/或增殖、促肿瘤、侵袭性、促肿瘤巨噬细胞浸润、CAF表型、炎性趋化因子表达（如C-X-C基序配体8（CXCL8/IL-8））和血管生成，其过度表达通常与侵袭性癌症行为和不良预后有关。TNFα 和 IL-1β 是 TME 中常见的促炎细胞因子。因此，阻断TNFα或其受体可能具有显著的抗肿瘤作用。14. GM-CSFGM-CSF 是一种 23 kDa 的糖蛋白，与由 1 型细胞因子受体家族亚基组成的异二聚体受体结合。GM-CSF 是活化的 T 淋巴细胞、成纤维细胞、内皮细胞、巨噬细胞和基质细胞的产物。GM-CSF 刺激中性粒细胞、嗜酸性粒细胞、巨噬细胞、巨核细胞和红系细胞系的造血集落形成细胞的存活。GM-CSF刺激抗原呈递给免疫系统，诱导巨噬细胞和 DC 上 II 类 MHC 和 Fc 受体的表达。GM-CSF 刺激中性粒细胞、单核细胞和巨噬细胞介导 ADCC 的能力。GM-CSF在抗肿瘤临床研究阶段，用于治疗黑色素瘤、神经母细胞瘤等。15. TGF-βTGF-β配体几乎由所有细胞类型分泌，包括上皮细胞、成纤维细胞和免疫细胞，它们无活性并储存在肿瘤微环境。 TGF-β信号转导可以抑制良性细胞的细胞生长，但促进癌细胞生长。在良性细胞中，TGF-β可诱导细胞周期停滞、分化、细胞凋亡和自噬，上皮细胞分泌的TGF-β可以抑制基质成纤维细胞和炎症细胞中旁分泌因子的产生。然而，一旦良性细胞转化为癌细胞，TGF-β信号转导通过调节免疫逃逸、纤维化和上皮-间充质转化（EMT）来促进癌症进展。（TGF-β抑制8类免疫细胞--作用重要，成药困难。）参考文献Alberto Mantovani et al, Interleukin-1 and Related Cytokines in the Regulation of Inflammation and Immunity,Immunity. 2019 Apr 16;50(4):778-795. doi: 10.1016/j.immuni.2019.03.012.Jones, S.A.; Jenkins, B.J. Recent Insights into Targeting the IL-6 Cytokine Family in Inflammatory Diseases and Cancer. Nat. Rev. Immunol. 2018, 18, 773–789Kristen Fousek et al，Interleukin-8: A chemokine at the intersection of cancer plasticity, angiogenesis, and immune suppression，Pharmacol Ther. 2020 Sep 24;107692.Margarida Saraiva, Paulo Vieira，Anne O’Garra，Biology and therapeutic potential of interleukin-10，J Exp Med (2020) 217 (1): e20190418.https://doi.org/10.1084/jem.20190418Tait Wojno, E.D.; Hunter, C.A.; Stumhofer, J.S. The Immunobiology of the Interleukin-12 Family: Room for Discovery. Immunity 2019, 50, 851–870Da-Sol Kuen et al，IL-17-Producing Cells in Tumor Immunity: Friends or Foes? Immune Netw. 2020 Feb;20(1):e6本周好文推荐如需转载请联系佰傲谷并在醒目位置注明出处﹀ ········

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适应症	最高研发状态	国家/地区	公司	日期
胰腺腺癌	临床2期	美国	BeiGene Ltd.	2023-11-08
胰腺腺癌	临床2期	美国	Syntrix Biosystems, Inc.	2023-11-08
转移性非小细胞肺癌	临床2期	美国	Syntrix Biosystems, Inc.	2023-04-06
复发性非小细胞肺癌	临床2期	美国	Syntrix Biosystems, Inc.	2023-04-06
结肠转移性腺癌	临床2期	美国	Syntrix Biosystems, Inc.	2020-10-14
转移性结直肠癌	临床2期	美国	Syntrix Biosystems, Inc.	2020-10-14
转移性微卫星稳定结直肠癌	临床2期	美国	Syntrix Biosystems, Inc.	2020-10-14
RAS 突变结直肠癌	临床2期	美国	Syntrix Biosystems, Inc.	2020-10-14
直肠腺癌	临床2期	美国	Syntrix Biosystems, Inc.	2020-10-14
不能切除的大肠癌	临床2期	美国	Syntrix Biosystems, Inc.	2020-10-14

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适应症

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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


NCT03161431 (ASCO2024) 人工标引	临床1期	转移性黑色素瘤	51	PEM682SX-682g BID	(積繭製醖顧膚顧廠醖糧) = NO identified 廠鑰獵壓鬱積積獵鬱獵 (窪衊鬱膚鬱壓繭艱築糧 ) 更多	积极	2024-05-24
				PEM + SX-682SX-682(200 mg) expanded BID 150 mg
NCT04245397 (HL142389, ASH 12022 \| ASH 22022) 人工标引	临床1期	骨髓增生异常综合征	17	SX-682	(蓋顧鑰夢廠醖鹹鑰壓鹽) = 鏇鏇膚糧衊鹽淵繭繭憲鬱製選憲鹽夢顧餘繭醖 (夢淵顧鏇範繭鹹顧構淵 )	积极	2022-11-15
				SX-682 (25 mg)	(製淵構襯繭夢顧夢鏇廠) = 餘構製襯構鹹憲憲鹽糧艱繭齋繭簾積顧廠選鹹 (衊構餘獵構顧獵壓膚遞 )