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.

项目概要在这个行业学术合作 R01 申请中，来自加州大学戴维斯分校、TargaGenix 和东北大学提议开发一个高度针对难治性肿瘤（如胰腺导管腺癌）的创新联合治疗策略（掌上电脑）。拟议的研究将利用科学家和临床医生的多学科专业知识来开发有效的 PDA 治疗范例基于 TGX-1214（我们领先的纳米乳剂）的组合一代紫杉烷 DHA-SBT-1214) 具有免疫检查点抑制作用。在初步研究中，我们的小说主角 DHA-SBT-1214 在两种胰腺癌临床前模型中强烈抑制胰腺癌生长（两种模型中肿瘤均完全消退）。此外，我们最近记录了以下组合：使用我们的新型化疗药物 DHA-SBT-1214 进行抗 PD-L1 治疗，该药物配制在纳米乳剂 (TGX- 1214），显着增加 CD8+ T 细胞浸润并增强抗 PD-L1 的治疗效果胰腺癌同基因模型中的抗体。值得注意的是，TGX-1214 单独与抗 PD-L1 抗体疗法比紫杉醇、白蛋白结合型紫杉醇更强地抑制肿瘤生长 (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 PDA 基因工程小鼠模型，TGX-1214 减少肿瘤纤维化并增加 CD8+ T 细胞浸润。重要的是，TGX-1214 看起来很安全，并且具有高治疗窗口（GLP-表明）大鼠和狗的毒性研究。因此，这些结果表明 TGX-1214 在多种疾病中是安全有效的。 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疗法的效果，值得进一步评估。我们的长期目标是发展安全有效的 PDA 治疗策略将在临床试验中进行测试并最终用于人类。基于根据这些新发现，我们假设 TGX-1214 和免疫检查点抗体的组合治疗将提供优异的疗效和较低的毒性。该研究的具体目的是：（1）：评估肿瘤- TGX-1214 的特异性递送、生物分布、肿瘤基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的治疗效果和安全性在两种临床相关的 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 作为单一疗法的疗效难治性 PDA 患者。这些研究完成后，我们预计 TGX-1214 与癌症免疫疗法相结合，将成为个性化医疗革命的一部分现在开始并将成为未来治疗范式的重要组成部分，以消除患者的负担 PDA，为长期治疗结果带来积极的好处。