STING-Activating GM-CSF Secreting Allogeneic Pancreas Tumor Cell Vaccine Therapy

描述(由申请人提供)：在美国，胰腺癌(PDA)的发病率为每年45,000例，而且还在增加。虽然新的化疗方案，如Abraxane和FOLFIRINOX延长了总体生存时间，但没有一种方案提供了长期无病生存的希望。我们认为免疫治疗是治疗PDA的一种有效且持久的治疗方法。在这里，我们扩展了我们已发表和未发表的临床结果，并建议通过提高辐射后的GM-CSF产生同种异体肿瘤细胞的免疫效力，即GVAX，来开发一种更先进的PDA免疫治疗方案。我们假设GVAX疫苗的一个关键缺失成分是一个有效的DC激活剂。 STINGVAX是基于一种新型和高活性的小分子免疫刺激物-环二核苷酸(CDNS)-通过靶向细胞质、TLR非依赖的病原体识别受体刺激物(干扰素基因的刺激物)来激活天然免疫。CDN是与GVAX共同形成的，导致多种肿瘤相关抗原、DC募集和增殖(GM-CSF)以及强大的DC激活刺激(CDN)的理想协同作用。我们认为，一种现成的产品可以将多种肿瘤相关抗原(包括特征的和未知的)直接递送到DC，加上强大的Th1扭曲成熟刺激，将启动强大的、持久的和广泛的肿瘤特异性T细胞反应。 该项目的总体目标是进行关键路径IND临床前药理学和毒理学研究，这将导致选择STINGVAX胰腺临床候选者，并为与FDA进行非正式讨论奠定基础，以获得关于我们建议的毒理学计划的指导，以支持1b期临床研究。在这项临床研究中，我们计划评估 小剂量环磷酰胺联合环磷酰胺在胰腺癌切除患者中的安全性和免疫原性在这个项目上，我们正在延长我们与伊丽莎白·贾菲博士长达10年的合作，她是胰腺癌免疫治疗治疗策略的前沿人物。 我们的总体假设是，CDN和GVAX的联合作用将通过刺激依赖天然免疫的方式为GM-CSF招募的DC提供深刻的成熟刺激，促进Th1、CD4和CD8T细胞免疫的启动，以对抗广泛的肿瘤抗原，从而为胰腺癌提供更有效的免疫治疗方案。 为此，我们提出了四个目标，以：(1)确认我们的先导STINGVAX新型CDN化合物的选择，这种化合物具有磷酸二酯酶抗性和非典型的磷酸键；(2)在非GLP中试毒性研究中评估所选CDN化合物的单剂局部耐受性和全身毒性；(3)开发STINGVAX胰腺的产品表征和释放分析；以及(4)向FDA提交预IND文件，并要求进行非正式讨论。这些目标的成功完成将为在第二阶段SBIR赠款申请中提出的促进IND的发展活动奠定基础。

DESCRIPTION (provided by applicant): The incidence of pancreatic adenocarcinoma (PDA) is > 45,000 cases per year in the US and is increasing. While new chemotherapy regimens such as Abraxane and FOLFIRINOX extend overall survival, none offer the promise of long-term disease-free survival. We submit that immunotherapy can be an effective and durable therapeutic option for PDA. Here we extend both our published and unpublished clinical results and propose to develop a more advanced immunotherapy regimen for PDA by enhancing the immunologic potency of irradiated GM-CSF producing allogeneic tumor cells, known as GVAX. We hypothesize that a critical missing component of GVAX vaccines has been a potent DC activator. "STINGVAX" is based on a novel and highly active small molecule immune stimulator - cyclic-dinucleotides (CDNs) - which activate innate immunity through targeting the cytoplasmic, TLR-independent pathogen recognition receptor STING (Stimulator of Interferon Genes). CDNs are co-formulated with GVAX, resulting in an ideal synergy of multiple tumor associated antigens, DC recruitment and proliferation (GM-CSF), coupled with a potent DC activation stimulus (CDN). We propose that an off-the-shelf product that delivers multiple tumor-associated antigens-both characterized and unknown-directly to DCs, together with a strong Th1-skewing maturation stimulus will initiate a potent, durable and broad tumor-specific T cell response. The overall goal of this project is to conduct critical path IND-enabling preclinical pharmacology and toxicology studies that will lead to selection of a STINGVAX Pancreas clinical candidate and set the stage for informal discussions with the FDA to receive guidance on our proposed toxicology plan to support a Phase 1b clinical study. In this clinical study, we plan to assess the safety and immunogenicity of low-dose cyclophosphamide (Cy) + STINGVAX in patients with resected pancreatic cancer. On this project, we are extending our 10-year collaboration with Dr. Elizabeth Jaffee, who is at the forefront of immunotherapy treatment strategies for pancreatic cancer. Our overall hypothesis is that that co-formulation of CDNs with GVAX will provide a profound maturation stimulus to GM-CSF recruited DCs through STING-dependent activation of innate immunity, promoting initiation of Th1 CD4 and CD8 T cell immunity against a broad repertoire of tumor antigens, resulting in a more effective immunotherapy regimen for pancreatic cancer. To this end we propose four Aims, to: (1) confirm selection of our lead STINGVAX novel CDN compound that is phosphodiesterase-resistant and has non-canonical phosphate linkages; (2) evaluate single-dose local tolerance and systemic toxicity of the selected CDN compound in non-GLP pilot toxicity studies; (3) develop product characterization and release assays for STINGVAX Pancreas; and, (4) submit a pre-preIND document to FDA and request for an informal discussion. Successful completion of these Aims will set the stage for IND-enabling development activities to be proposed in a Phase 2 SBIR grant application.