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

项目摘要 在这个产学合作伙伴R01的申请中，一个由来自 加州大学戴维斯分校、TargaGenix和东北大学正在提议开发一种高度 难治性肿瘤的创新联合治疗策略，如胰腺导管腺癌 (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来开发 基于TGX-1214(我们的Lead Next的纳米乳剂)组合的有效PDA治疗范例 产生具有免疫检查点抑制的紫杉类化合物DHA-SBT-1214)。在初步研究中，我们的新技术领先于 DHA-SBT-1214在两种胰腺癌临床前模型中对胰腺癌生长的强烈抑制作用 (在两种模型中，肿瘤完全消退)。此外，我们最近还记录到， 我们的新化疗药物DHA-SBT-1214在纳米乳剂(TGX-TGX-1)中配制，用于抗PD-L1治疗。 1214)，显著增加CD8+T细胞的浸润，增强抗PD-L1的治疗作用 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抗体治疗对肿瘤生长的抑制作用强于紫杉醇、NaB-紫杉醇 (Abraxane)、吉西他滨或单抗PD-L1抗体治疗组。此外，在临床相关的KPC中 TGX-1214基因工程小鼠PDA模型降低肿瘤纤维化和增加CD8+T细胞 渗透。重要的是，TGX-1214似乎是安全的，并呈现出GLP所表明的高治疗窗口。 对大鼠和狗的毒性研究。这些结果表明，TGX-1214在多种情况下是安全有效的 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 免疫检查点阻断治疗的效果，需要进一步评估。我们的长远目标是发展 安全有效的PDA治疗策略将在临床试验中进行测试，并最终用于人体。基座 根据这些新发现，我们假设TGX-1214和免疫检查点抗体的组合 治疗将提供更好的疗效和更少的毒性。研究的具体目的是：(1)：评估肿瘤- TGX-1214在裸鼠体内的特异性传递、生物分布、肿瘤间质密度调节和免疫细胞侵袭 临床相关的动脉导管未闭动物模型；(2)：测定TGX-1214的疗效和安全性 在两个临床相关的PDA动物模型(原位移植)中进行抗PD-L1抗体治疗 胰腺肿瘤器官和KPC小鼠)，以及(3)：确定TGX-1214作为单一治疗药物的疗效。 治疗难治性PDA患者。在这些研究完成后，我们预计TGX-1214将在 与癌症免疫治疗相结合，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范例的重要组成部分，以消除 PDA，在长期治疗结果中提供积极的好处。

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.