Malignant melanoma, metastatic

All patients in the trial who were alive at 3 years remain alive at 4 years (69.5%) with a minimum follow-up period of 4 years (median 53.0 months) The expected next key milestone for UV1 is the readout of the FOCUS trial during Q3 2024, in which the treatment combination is the same as in the UV1-103 trial June 11, 2024: Ultimovacs ASA (“Ultimovacs”) (OSE ULTI), a clinical-stage biotechnology company developing immunotherapeutic cancer vaccines, today announced encouraging overall survival (OS) data from both cohorts in the UV1-103 Phase I clinical trial in malignant melanoma. The UV1-103 study evaluates Ultimovacs’ universal cancer vaccine, UV1, in combination with the anti-PD-1 checkpoint inhibitor pembrolizumab, as first-line treatment in patients with advanced non-resectable or metastatic malignant melanoma. The study enrolled 30 patients in the U.S. in two cohorts that differed only in the concentration of GM-CSF used as vaccine adjuvant. With a minimum follow-up of 4 years (median 53.0 months), the updated OS results show that all patients who were alive at the 3-year mark remain alive at 4 years, with an OS rate of 69.5% Ultimovacs has previously reported data showing a complete response rate in the UV1-103 study of 33% (complete disappearance of tumors) and an objective response rate of 57% (complete or partial disappearance of tumors). Biomarker analyses reported in October 2022 showed robust clinical responses in patients treated with the combination of UV1 and pembrolizumab, regardless of patients’ PD-L1 status. The safety profile of UV1 in combination with pembrolizumab is comparable to that of pembrolizumab alone. “We are encouraged by the strong overall survival rate observed in this Phase I study,” said Jens Bjørheim, Chief Medical Officer at Ultimovacs. “The data show a high survival rate among patients enrolled in the UV1-103 trial, even after a minimum of 4 years of follow-up. We look forward to the read-out of the FOCUS trial in head and neck cancer, where the same treatment combination has been used”. This US-based Phase I clinical trial evaluates the Company’s lead candidate, UV1, combined with the anti-PD-1 checkpoint inhibitor, pembrolizumab, as a first-line treatment in patients with unresectable metastatic malignant melanoma. The trial evaluates safety, tolerability, and initial signs of clinical response. Thirty patients in the U.S. were treated in the study in two cohorts that differed only in the concentration of GM-CSF used as vaccine adjuvant. The 20 patients in the first cohort received a 37.5 mcg GM-CSF adjuvant dose per UV1 vaccination. The 10 patients in the second cohort received the standard 75 mcg GM-CSF adjuvant dose per UV1 vaccination. The study has completed the enrollment of 30 patients, as announced on August 18, 2020. All included patients received the drugs as first-line treatment for advanced and metastatic malignant melanoma. Compiled clinical results for the 30 patients enrolled are: Objective response rate (ORR): 57%. Complete response rate (CR): 33% Median Progression Free Survival (mPFS): 18.9 months (as measured by iRECIST) Overall survival (OS) after 12 months: 87% after 24 months: 73% after 36 months: 69.5% after 48 months: 69.5% Out of the 9 deaths, 4 happened during the first year, 4 during the second year, and one during the third year across both cohorts. Three patients in cohort 1 chose not to be followed beyond 24 months. The trial had previously reached its primary endpoint of safety and tolerability, and no unexpected safety issues related to UV1 have been observed in this trial. As a historical reference (not head-to-head comparison since dosing and the patient population are different), the registrational study for pembrolizumab, Keynote-006, showed an overall survival rate of 42% at 48 months (Long GV et al, ASCO 2018). The U.S. Food and Drug Administration (FDA) granted a dual Fast Track designation for UV1 in combination with checkpoint inhibitors in the treatment of unresectable or metastatic melanoma – either as add-on therapy to pembrolizumab or as add-on therapy to ipilimumab. Ultimovacs is a clinical-stage biotechnology leader in novel immunotherapeutic cancer vaccines. The lead cancer vaccine candidate UV1 is an off-the-shelf vaccine directed against human telomerase (hTERT), an antigen present in 85-90% of cancers in all stages of tumor growth. A broad clinical program, with Phase II trials in five cancer indications enrolling more than 670 patients, aims to investigate UV1’s impact in combination with other immunotherapies in multiple cancer types. UV1 is a patented technology owned by Ultimovacs. In addition, Ultimovacs’ adjuvant platform, based on the proprietary Tetanus-Epitope-Targeting (TET) technology, combines tumor-specific antigens and adjuvant in the same molecule and is in Phase I clinical development. The Company is listed on the Euronext Oslo Stock Exchange (ULTI). UV1 is a therapeutic cancer vaccine designed to induce a specific T-cell response against telomerase. UV1 consists of long, synthetic peptides representing a sequence in the reverse transcriptase subunit of telomerase (hTERT), shown to induce CD4+ T-cells. These CD4+ T-cells have the potential to provide inflammatory signals, and T-cell support is believed to be critical for triggering a strong anti-tumor immune response. Following intradermal injection, antigen-presenting cells (APCs) in the skin are exposed to the vaccine peptides. These APCs will process the peptides and present vaccine epitopes on Human Leukocyte Antigen (HLA) molecules to naïve T-cells in the lymph nodes. Activated vaccine-specific T-cells will then enter the circulation and search for cells displaying their cognate antigen in the context of HLA molecules. The UV1 peptides contain several epitopes, shown to be non-restrictive in terms of (HLA) alleles for presentation. It is, therefore, not required to perform HLA pre-screening of patients, which potentially enables broad population utilization of the vaccine. UV1 is administered over three months with eight intradermal injections and the immune-modulator GM-CSF. The content above comes from the network. if any infringement, please contact us to modify.

May 01, 2024 -- Galecto, Inc. (NASDAQ: GLTO), a clinical-stage biotechnology company focused on the development of novel treatments for cancer and fibrosis, today announced that the first patient has been enrolled in an investigator-initiated Phase 2 trial to evaluate GB1211, Galecto’s first-in-class, oral small molecule galectin-3 inhibitor candidate, at the Earle A. Chiles Research Institute (EACRI), a division of Providence Cancer Institute in Portland, Oregon, USA. Under the direction of Providence investigators Dr. Brendan Curti and Dr. William Redmond, the study aims to evaluate the safety and efficacy of GB1211 at a dose of 100mg twice daily in combination with pembrolizumab for the treatment of metastatic malignant melanoma (MM) and head and neck squamous cell carcinoma (HNSCC). Drs. Curti and Redmond received an R01 Research Project Grant award from the National Cancer Institute, National Institutes of Health, for their investigator-initiated Phase 2 trial. Galecto has committed to supply GB1211 for the trial. Galectin-3 is overexpressed in many cancers, including melanoma and HNSCC. Increased galectin-3 expression in tumors is linked to tumor growth, invasiveness and metastatic potential. Furthermore, increased levels of galectin-3 in the tumor microenvironment can cause checkpoint inhibitor resistance by blocking the binding of the checkpoint inhibitor antibodies, pembrolizumab and atezolizumab (Tecentriq®), to their respective targets. Preclinical data has shown that GB1211 has the ability to reduce galectin-3 associated interference with immune checkpoint inhibition (ICI), thus alleviating galectin-3-specific ICI resistance. In the fourth quarter of 2023, Galecto reported topline results from its Phase 1b/2a GALLANT-1 clinical trial evaluating GB1211 twice daily in combination with atezolizumab for the first-line treatment of non-small cell lung cancer (NSCLC). Galecto reported that investigator-assessed objective tumor responses (defined as partial responses per RECIST criteria 1.1) were observed in three of five patients (60%) who received the recommended Phase 2 dose level of GB1211 100 mg for at least three weeks. Historically, response rates of only 22–38% have been observed with atezolizumab monotherapy in the first-line treatment of advanced NSCLC, suggesting a potential benefit of adding GB1211 to ICI. Dr. Brendan Curti, Medical Director, Providence Melanoma Program, and EACRI Member and Robert W. Franz Endowed Chair for Clinical Research, said, “Our ability to perform bench-bedside research is a great strength of the Providence Cancer Institute. The insights from Dr. Redmond’s lab about how to use galectin inhibitors to alter the tumor microenvironment and promote anti-tumor activity, as well as our initial observations in patients, provide a robust rationale for our phase II clinical trial in patients with melanoma and HNSCC.” Dr. William Redmond, Member and Director, EACRI Immune Monitoring Lab, and co-principal investigator for the trial, stated, “We have published a significant amount of data on the important role of galectin-3 in creating immune suppression within the tumor microenvironment. We are excited to start this study in melanoma and HNSCC patients to potentially counteract ICI resistance and increase the efficacy of ICI by combining GB1211 and pembrolizumab.” “We are excited that the Providence Cancer Institute and Drs. William Redmond and Brendan Curti have initiated this trial. Dr. Redmond is a world-leading expert on the role of galectin-3 in cancer and ICI resistance and has demonstrated how galectin inhibition can be used to enhance tumor treatment,” stated Dr. Hans Schambye, CEO of Galecto. “Following the encouraging topline results from the GALLANT-1 trial that we reported in the fourth quarter of 2023, we look forward to exploring potential synergies with another leading ICI, pembrolizumab. This new trial marks a significant stride towards exploring GB1211's potential to enhance the effectiveness of ICI in various cancer indications.” The randomized, double-blind placebo-controlled, investigator-initiated Phase 2 trial will evaluate whether the addition of GB1211 increases the response rate of pembrolizumab in metastatic melanoma and HNSCC patients. The study will employ a fixed dose of GB1211 in conjunction with the standard therapeutic dose of pembrolizumab in patients with unresectable or metastatic MM or recurrent or metastatic HNSCC progressing during or after platinum-containing chemotherapy. In addition to monitoring for toxicity and clinical response, biospecimens will be obtained to assess immunologic measures relevant to galectin biology and T-cell checkpoint inhibition. Tumor volume will be assessed by immune response RECIST criteria (iRECIST criteria 1.1). It is anticipated that early data from this trial could be available as early as 2025. Increased galectin-3 expression in tumors is linked to tumor growth, invasiveness, and metastatic potential. In the tumor tissue, galectin-3 supports the creation of fibrosis, tumor proliferation, metastasis, and immune avoidance. Preclinical data announced at the 2022 ASCO Annual Meeting furthermore suggest that galectin-3 can enhance PD-1 and PD-L1 binding and avert the interference of anti-PD-1/anti-PD-L1 therapies by blocking the binding of the antibodies to their respective targets. GB1211 is specifically designed to counter these anti-checkpoint inhibitor effects of galectin-3. GB1211 demonstrated an anti-cancer effect and antifibrotic activity in multiple preclinical models and has successfully completed a Phase 1 trial in 78 healthy volunteers. In the Phase 1 trial, GB1211 was well-tolerated and exhibited dose-dependent pharmacokinetics. Galecto is a clinical stage company incorporated in the U.S. that is developing small molecule-based inhibitors of galectin-3 and LOXL2. Galecto has multiple Phase 2 clinical opportunities in fibrosis and cancer, including (i) an orally active LOXL2 inhibitor (GB2064) for the treatment of myelofibrosis; (ii) an orally active galectin-3 inhibitor (GB1211) for the treatment of liver cirrhosis; and (iii) an orally active galectin-3 inhibitor (GB1211) in combination with a checkpoint inhibitor for various oncology indications. Providence Cancer Institute of Oregon, a part of Providence St. Joseph Health, offers the latest in cancer services, including diagnostic, treatment, prevention, education, support and internationally renowned research. Providence Cancer Institute is home to the Earle A. Chiles Research Institute, a world-class research facility located within the Robert W. Franz Cancer Center in Portland, Oregon, and is a recognized leader in the field of cancer immunotherapy since 1993. Learn more at www.providence.org/ORcancer. The content above comes from the network. if any infringement, please contact us to modify.

本次培训针对CGT企业或研发机构有一定CMC基础的工艺和质量主管进阶提升，讲述工艺与治疗关键点，给与尽可能多的避坑指南，帮助其成为独当一面的CMC专家。IL-15，曾被视为癌症免疫治疗领域中最有前景的靶点之一。作为一种刺激性细胞因子，其在临床前研究中对抑制肿瘤生长和抗转移特性表现出显著效果。也正因此，IL-15在癌症免疫治疗研究中备受瞩目。早在2008年，美国国家癌症研究所就将其列为最具潜力的候选药物。然而，新药研发的道路并非坦途。由于IL-15半衰期较短，导致其在疗效与安全性之间难以取得平衡。直至2024年，才真正迎来了破冰者。4月22日，ImmunityBio宣布FDA批准了Anktiva（N-803），联合卡介苗用于治疗对卡介苗无反应的非肌层浸润性膀胱癌伴原位癌患者。N-803的获批上市，标志着它成为IL-15激动剂领域的先驱，也将激励更多药企在这一赛道上加速前行。总体来看，有效性、安全性和半衰期是IL-15激动剂研发和优化的三大关键因素。在这三者间找到平衡点，是实现药物成功的关键。也就是说，IL-15激动剂的研发之路远未结束。随着更多药企的发力，属于IL-15激动剂开发的黄金时代，正缓缓拉开帷幕。1免疫系统“激动剂”作为一种多效性细胞因子，IL-15在免疫系统的发育和维持中扮演着关键角色，能够通过多种机制促进NK细胞和CD8+ T细胞的存活与增殖。首先，IL-15能够刺激抗凋亡蛋白Bcl-2的表达，帮助防止细胞死亡，从而提高NK细胞和CD8+ T细胞的存活率。其次，IL-15能够促进与细胞增殖密切相关的蛋白Ki67的表达，推动NK细胞和CD8+T细胞的快速分裂和数量增加。NK细胞和CD8+T细胞是免疫系统中重要的细胞毒性细胞，能够识别并杀死肿瘤细胞。因此，它们的数量增加和活性提升，直接增强了对肿瘤的免疫打击能力。IL-15的作用不仅限于此，研究发现，IL-15激活的肿瘤浸润NK细胞和CD8+ T细胞会上调名为XCL1的趋化因子的分泌。XCL1能够招募常规I型树突状细胞（cDC1）至肿瘤组织，cDC1具有强大的交叉呈递抗原的能力，有效激活肿瘤引流淋巴结中的初始CD8+ T细胞，促使其进入肿瘤病灶协同杀伤肿瘤细胞，进一步增强抗肿瘤效果。此外，活化的NK细胞和CD8+T细胞分泌的IFN-γ能刺激cDC1分泌CXCL9和CXCL10，这些因子能将外周的CXCR3+NK细胞和CD8+T细胞吸引至肿瘤组织，形成免疫正反馈回路，维持对肿瘤的免疫监视。同时，IL-15在肿瘤微环境中对维持记忆T细胞的稳态存活、增殖激活以及维持效应细胞毒性T淋巴细胞（CTL）具有重要作用。记忆T细胞的形成，能够增强免疫系统对肿瘤复发的快速响应能力。此外，目前的研究已表明，IL-15能够增强抗体依赖性细胞介导的对NK细胞的细胞毒性作用，以及增强免疫疗法的功效。综上所述，IL-15作为一种有前景的免疫治疗剂，不仅直接增强免疫细胞的战斗力，提高其渗透肿瘤微环境的能力，还能与药物分子结合或构建多功能分子，产生协同作用，提高治疗效果。因此，IL-15激动剂作为潜在的癌症免疫治疗剂，受到医学界的广泛关注。数据现实，全球已启动近200项使用不同IL-15药物治疗癌症的临床试验。2从理想到现实将理论转化为实践的过程中，往往充满了挑战和不确定性。最初，医学界主要通过重组技术开发了第一代IL-15激动剂——重组人白细胞介素-15（rhIL-15）。rhIL-15是一种在大肠杆菌中产生的约13kDa的非糖基化IL-15单体。2015年发表的rhIL-15首次人体I期临床试验结果显示，在转移性恶性黑色素瘤或转移性肾细胞癌患者中，rhIL-15的抗肿瘤效果并不理想。首先，从疗效角度来看，rhIL-15的表现并不理想。通过静脉推注（IVB）连续12天给药，虽然在一定程度上增加了外周血中的NK细胞和CD8+T细胞数量，但在18例患者中未观察到任何客观缓解，最佳结果仅为疾病稳定。其次，rhIL-15的毒副作用较强。在该临床试验中，观察到剂量依赖性毒性反应，包括发热和寒战、血小板减少症和低血压。尽管后来通过皮下注射的方式改善了rhIL-15的毒副作用，但疗效问题仍然难以解决。核心问题在于rhIL-15的半衰期较短，导致其在体内迅速被清除。如果频繁且大剂量给药，可能导致毒性问题；如果剂量降低控制安全性，效果方面又难以突破。为了克服rhIL-15的缺点，研究人员采取了两种主要的优化策略：一是对IL-15本身进行突变或修饰，这是蛋白质药物常见的修饰策略；二是开发IL-15/IL-15Rα复合物。这两种策略都旨在提高药物分子的活性和稳定性。N-803正是在这一阶段率先取得突破的候选药物。作为一种IL-15超激动剂复合物，N-803由IL-15突变体（IL-15N72D）、IL-15Rα sushi结构域和IgG1 Fc融合蛋白组成。IL-15Rα sushi结构域的设计使得N-803能够绕过天然IL-15所必需的反式呈递方式来激活下游信号通路，而IgG1 Fc片段显著延长了药物的半衰期。药代动力学分析显示，N-803的半衰期约为7.2-8小时。在与卡介苗（BCG）联合治疗的临床研究中，N-803展现了良好的潜力。在针对160例BCG无反应性非肌层浸润性膀胱癌（NMIBC）患者的联合治疗中，无论是伴有或不伴有乳头状肿瘤（CIS队列）的患者，均显示出71%的完全缓解率，中位持续时间为24个月。在非CIS队列中，1年时的无病率为57%，2年时为48%。总体而言，大部分患者（CIS队列中91%，非CIS队列中95%）能够暂时避免进行膀胱切除术，并且联合治疗的安全性良好，没有报告与治疗相关的严重副作用。正因为这些积极的临床结果，FDA批准了N-803联合卡介苗治疗BCG无反应性NMIBC的适应症上市。N-803由此成为IL-15激动剂领域的先驱。3步入黄金时代历时十几年，IL-15激动剂终于迎来了破冰者，但N-803的上市并不是IL-15激动剂领域探索的终点，而是标志着该领域进入了发展的黄金时代。可以看到，基于上述理念对IL-15激动剂进行改造的药企不在少数，且它们的方法存在一定的差异性。例如，Nektar公司设计的NKTR-255是一种新型的重组人IL-15（rhIL-15）聚乙二醇（PEG）偶联物，它保留了与所有受体结合的能力，并维持了IL-15的全部生物学特性。与rhIL-15相比，NKTR-255展现出了更优的药物动力学特性，其半衰期达到了15.2小时。这一领域，也出现了一些创新的设计，几种新的靶向/多功能IL-15激动剂正在研发之中。例如，pro-IL-15是首个采用前药设计策略的IL-15激动剂分子。该药物基于IL-15-IL-15RαSu-Fc结构，通过N端的MMP-14可切割肽连接子将IL-15Rβ的胞外结构域连接起来形成pro-IL-15。Pro-IL-15阻断了IL-15的结合位点，使其在外围循环中失活。该理念的目的是，在富含基质金属蛋白酶（MMP）的肿瘤微环境中，肽连接子被酶切除，导致IL-15Rβ脱落，从而恢复分子的活性。HCW Biologics公司则开发了双功能分子HCW9218。这是一种含有可溶性TGF-βRII和IL-15/IL-15RαSu的异二聚体融合蛋白，能够中和TGF-β（抑制肿瘤进展和缓解免疫抑制），同时直接激活免疫细胞。在这场IL-15研发竞赛中，国内药企也没有缺席，包括恒瑞医药、博际生物、奥赛康在内的公司都参与其中，布局相关管线。那么，最终哪家公司能够脱颖而出呢？近期直播推荐: