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）的发病率每年> 45，000例，并且正在增加。虽然新的化疗方案，如Abraxane和FOLFIRINOX延长了总生存期，但没有一种方案能保证长期无病生存。我们认为免疫疗法是治疗PDA的一种有效和持久的治疗选择。在这里，我们扩展了我们已发表和未发表的临床结果，并建议开发一种更先进的免疫治疗方案，PDA通过增强辐射GM-CSF生产同种异体肿瘤细胞，称为GVAX的免疫效力。我们假设GVAX疫苗的一个关键缺失成分是一种有效的DC激活剂。 “STINGVAX”基于一种新型的高活性小分子免疫刺激剂-环状二核苷酸（CDN）-通过靶向细胞质、TLR非依赖性病原体识别受体STING（干扰素基因刺激因子）激活先天免疫。CDN与GVAX共配制，导致多种肿瘤相关抗原、DC募集和增殖（GM-CSF）与有效的DC活化刺激（CDN）的理想协同作用。我们建议，一个现成的产品，提供多种肿瘤相关的抗原，无论是特征和未知的直接到DC，连同一个强大的Th 1-倾斜成熟刺激将启动一个强大的，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使临床前药理学和毒理学研究，这将导致选择STINGVAX胰腺临床候选药物，并为与FDA进行非正式讨论奠定基础，以获得我们提出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 低剂量环磷酰胺（Cy）+ STINGVAX在胰腺癌切除患者中的安全性和免疫原性。在这个项目中，我们将延长与伊丽莎白·贾菲博士的10年合作，她是胰腺癌免疫治疗策略的最前沿。 我们的总体假设是，CDN与GVAX的共制剂将通过先天免疫的STING依赖性激活向GM-CSF募集的DC提供深刻的成熟刺激，促进针对广泛的肿瘤抗原库的Th 1 CD 4和CD 8 T细胞免疫的启动，从而产生用于胰腺癌的更有效的免疫治疗方案。 为此，我们提出了四个目标：（1）确认我们的领导STINGVAX新型CDN化合物的选择，该化合物是磷酸二酯酶抗性的并且具有非典型的磷酸酯键;（2）在非GLP初步毒性研究中评估所选CDN化合物的单剂量局部耐受性和全身毒性;（3）开发STINGVAX胰腺的产品表征和释放测定;以及（4）向FDA提交pre-preIND文件，并请求进行非正式讨论。这些目标的成功完成将为在第2阶段SBIR赠款申请中提出的IND使能开发活动奠定基础。

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 Here we extend both our published and unpublished clinical results and propose to develop a more advanced immunotherapy regimen for PDA by enhancing the immunologic potency of irradiated GM-CSF producing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.