权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

TGX-1214 - Combination Strategy for the Treatment of Advanced Pancreatic Cancer

TGX-1214 - 治疗晚期胰腺癌的联合策略

基本信息

批准号：
10607971
负责人：
Mansoor M Amiji
金额：
$ 58.31万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10607971
关键词：
3-Dimensional Abraxane Acids Affect Animal Model Antibody Therapy Biodistribution CD8-Positive T-Lymphocytes California Canis familiaris Clinical Clinical Research Clinical Treatment Clinical Trials Collaborations Combined Modality Therapy Data Dedications Development Diagnosis Disease Docosahexaenoic Acids Dose Drug Combinations Drug Kinetics Evaluation Fibrosis Formulation Foundations Future Genetically Engineered Mouse Goals Growth Human Immune checkpoint inhibitor Immunotherapy In Vitro Industry KPC model Lead Link Malignant Neoplasms Malignant neoplasm of pancreas Mission Modality Modeling Nanotechnology Oils Organoids Paclitaxel Pancreas Transplantation Pancreatic Ductal Adenocarcinoma Patients Pharmaceutical Preparations Phase I Clinical Trials Polyunsaturated Fatty Acids Pre-Clinical Model Qualifying Rattus Refractory Research Personnel Safety Scientist Stromal Neoplasm System T cell infiltration Taxoids Testing Therapeutic Therapeutic Agents Therapeutic Effect Time Toxic effect Toxicology Treatment Efficacy Treatment outcome United States Universities Unresectable Water advanced pancreatic cancer anti-PD-L1 anti-PD-L1 antibodies anti-PD-L1 therapy anti-cancer therapeutic cancer immunotherapy checkpoint inhibition chemotherapy clinical development clinical translation clinically relevant cytotoxicity density effective therapy efficacy evaluation experience gemcitabine immune cell infiltrate immune checkpoint immune checkpoint blockade immunogenic improved improved outcome in vivo industry partner innovation interest lead candidate multidisciplinary multimodality nanoemulsion nanomedicine next generation novel novel therapeutic intervention novel therapeutics pancreatic cancer model pancreatic cancer patients pancreatic ductal adenocarcinoma model pancreatic neoplasm personalized medicine rational design translatable strategy treatment strategy tumor tumor growth

项目摘要

Project Summary In this Industry-Academic Partnership R01 application, a multidisciplinary team of investigators from the University of California at Davis, TargaGenix and Northeastern University are proposing to develop a highly innovative combination treatment strategy for refractory tumors, such as pancreatic ductal adenocarcinoma (PDA). The proposed studies will leverage multi-disciplinary expertise of scientists and clinicians to develop effective PDA treatment paradigm based on the combination of TGX-1214 (a nanoemulsion of our lead next generation taxoid DHA-SBT-1214) with immune checkpoint inhibition. In preliminary studies, our novel lead agent DHA-SBT-1214 strongly inhibited pancreatic cancer growth in two preclinical models of pancreatic cancer (complete tumor regression in both models). In addition, we have recently documented that the combination of an anti-PD-L1 therapy with our novel chemotherapy drug DHA-SBT-1214 formulated in a nanoemulsion (TGX- 1214), significantly increased CD8+ T-cell infiltration and enhanced the therapeutic effects of the anti-PD-L1 antibody in a pancreatic cancer syngeneic model. It is noteworthy that TGX-1214 alone on combined with an anti-PD-L1 antibody therapy strongly reduced tumor growth to a higher extent than paclitaxel, nab-paclitaxel (Abraxane), gemcitabine, or single anti-PD-L1 antibody therapy groups. Moreover, in the clinically relevant KPC genetically-engineered mouse model of PDA, TGX-1214 reduced tumor fibrosis and increased of CD8+ T-cell infiltration. Importantly, TGX-1214 appears safe and present a high therapeutic window as indicated by GLP- toxicity studies in rats and dogs. Thus, these results indicate that TGX-1214 is safe and effective in multiple preclinical models of PDA; it stimulates the immunogenic potential of PDA and provides synergistic therapeutic effects with immune checkpoint blockade therapy, warranting further evaluation. Our long-term goal is to develop safe and effective treatment strategies for PDA to test in clinical trials and ultimately to be used in humans. Based on these novel findings, we hypothesize that a combination of TGX-1214 and immune checkpoint antibody therapy will provide superior efficacy with less toxicity. The specific aims of the study are: (1): To evaluate tumor- specific delivery, biodistribution, tumor stromal density modulation, and immune cell infiltration of TGX-1214 in clinically relevant animal models of PDA; (2): To determine the therapeutic efficacy and safety of the TGX-1214 along with anti-PD-L1 antibody therapy in two clinically relevant PDA animal models (orthotopically grafted pancreatic tumor organoids and KPC mice), and (3): To determine the efficacy of TGX-1214 as monotherapy in patients with treatment-refractory PDA. At the completion of these studies, we expect that TGX-1214 in combination with cancer immunotherapy, will become part of the personalized medicine revolution that is only now beginning and will become a significant part of the future treatment paradigms to eliminate the burden of PDA, providing positive benefits in long-term treatment outcomes.

项目摘要在这个行业-学术合作伙伴关系R 01应用程序中，一个多学科的研究人员团队，加州大学戴维斯分校、TargaGenix和东北大学正提议开发一种高度胰腺导管腺癌等难治性肿瘤的创新联合治疗策略（PDA）。拟议的研究将利用科学家和临床医生的多学科专业知识，基于TGX-1214（我们的下一个领导者的纳米乳液）组合的有效PDA治疗范例代紫杉烷DHA-SBT-1214）。在初步研究中，我们的新线索在胰腺癌的两个临床前模型中，DHA-SBT-1214试剂强烈抑制胰腺癌生长（两种模型中肿瘤完全消退）。此外，我们最近的文件表明，使用我们的新型化疗药物DHA-SBT-1214的抗PD-L1治疗，该药物配制在纳米乳剂（TGX-1214）中， 1214），显著增加了CD 8 + T细胞浸润并增强了抗PD-L1抗体的治疗效果。抗体在胰腺癌同基因模型中的作用。值得注意的是，单独的TGX-1214与一种抗肿瘤药物组合，抗PD-L1抗体治疗在更高程度上强烈降低了肿瘤生长，（Abraxane）、吉西他滨或单一抗PD-L1抗体治疗组。此外，在临床相关的KPC中，在PDA基因工程小鼠模型中，TGX-1214减少了肿瘤纤维化，并增加了CD 8 + T细胞浸润重要的是，TGX-1214似乎是安全的，并提供了一个高的治疗窗口，如GLP-1所示。大鼠和犬的毒性研究。因此，这些结果表明，TGX-1214在多种疾病中安全有效。 PDA的临床前模型;它刺激PDA的免疫原性潜力，并提供协同治疗免疫检查点阻断治疗的效果，有待进一步评估。我们的长期目标是发展在临床试验中测试PDA的安全和有效的治疗策略，并最终用于人类。基于基于这些新发现，我们假设TGX-1214和免疫检查点抗体的组合治疗将提供上级功效和较小毒性。本研究的具体目的是：（1）评价肿瘤- TGX-1214的特异性递送、生物分布、肿瘤间质密度调节和免疫细胞浸润，临床相关的PDA动物模型;（2）：确定TGX-1214的疗效和安全性沿着抗PD-L1抗体治疗，在两种临床相关PDA动物模型（原位移植胰腺肿瘤类器官和KPC小鼠），以及（3）：确定TGX-1214作为单药治疗在难治性PDA患者。在这些研究完成后，我们预计TGX-1214在与癌症免疫疗法相结合，将成为个性化医学革命的一部分，现在开始并将成为未来治疗模式的重要组成部分，以消除 PDA，在长期治疗结果中提供积极的益处。