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

STING 激活 GM-CSF 分泌同种异体胰腺肿瘤细胞疫苗疗法

• 批准号: 8715590
• 负责人: Thomas W. Dubensky
• 金额: $ 22.49万
• 依托单位: ADURO BIOTECH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-10 至 2015-09-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8715590
• 关键词: Abraxane; Adjuvant; Allogenic; Allogenic Cell Vaccine; Applications Grants; Attenuated; Biological; Biological Assay; CD8B1 gene; Cancer Vaccines; Cell Differentiation process; Cell Line; Cell Maturation; Cells; Chemotherapy-Oncologic Procedure; Clinical; Clinical Research; Clinical Trials; Collaborations; Coupled; Critical Pathways; Cyclophosphamide; Data; Dendritic Cells; Dendritic cell activation; Development; Diagnosis; Dinucleoside Phosphates; Disease; Disease-Free Survival; Dose; Drug Formulations; Effectiveness; Evaluation; Genes; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Human; Immune; Immune system; Immunity; Immunologics; Immunotherapeutic agent; Immunotherapy; Incidence; Individual; Injection of therapeutic agent; Intellectual Property; Interferons; Lead; Life; Listeria monocytogenes; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Mediator of activation protein; Mus; Natural Immunity; Nature; Oryctolagus cuniculus; Outcome; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Patients; Pharmacology and Toxicology; Phase; Phase II Clinical Trials; Publishing; Randomized; Recombinants; Recruitment Activity; Regimen; Resected; Resistance; Safety; Sentinel; Signaling Pathway Gene; Site; Small Business Innovation Research Grant; Staging; Stimulus; T cell response; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Toxicology; Treatment Efficacy; Treatment Factor; Tumor Antigens; Universities; Unresectable; Vaccine Therapy; Vaccines; Whole Cell Vaccine; base; cancer immunotherapy; cell bank; design; dosage; immunogenicity; improved; inorganic phosphate; mesothelin; mortality; neoplastic cell; novel; novel strategies; novel therapeutics; pancreas development; pancreatic neoplasm; pathogen; phosphoric diester hydrolase; pre-clinical; public health relevance; receptor; response; small molecule; success; therapeutic vaccine; treatment strategy; tumor

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.

描述（由申请人提供）：在美国，胰腺腺癌 (PDA) 的发病率每年 > 45,000 例，并且还在增加。虽然 Abraxane 和 FOLFIRINOX 等新的化疗方案可以延长总体生存期，但没有一种方案能够保证长期无病生存。我们认为免疫疗法可能是 PDA 的有效且持久的治疗选择。在这里，我们扩展了已发表和未发表的临床结果，并建议通过增强经照射的 GM-CSF 产生的同种异体肿瘤细胞（称为 GVAX）的免疫效力，开发一种更先进的 PDA 免疫治疗方案。我们假设 GVAX 疫苗缺失的一个关键成分是一种有效的 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）——它通过靶向细胞质、不依赖于 TLR 的病原体识别受体 STING（干扰素基因刺激剂）来激活先天免疫。 CDN 与 GVAX 共同配制，从而产生多种肿瘤相关抗原、DC 募集和增殖 (GM-CSF) 以及有效的 DC 激活刺激 (CDN) 的理想协同作用。我们建议，一种现成的产品可以将多种肿瘤相关抗原（包括特征抗原和未知抗原）直接传递给 DC，并结合强烈的 Th1 倾斜成熟刺激，从而引发有效、持久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 支持的临床前药理学和毒理学研究，这将导致选择 STINGVAX Pancreas 临床候选药物，并为与 FDA 的非正式讨论奠定基础，以获得有关我们提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 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 Elizabeth Jaffee 博士长达 10 年的合作，她处于胰腺癌免疫治疗策略的前沿。 我们的总体假设是，CDN 与 GVAX 的联合配制将通过 STING 依赖性激活先天免疫，为 GM-CSF 招募的 DC 提供深刻的成熟刺激，促进针对广泛肿瘤抗原的 Th1 CD4 和 CD8 T 细胞免疫的启动，从而产生更有效的胰腺癌免疫治疗方案。 为此，我们提出了四个目标：（1）确认我们的主要 STINGVAX 新型 CDN 化合物的选择，该化合物具有磷酸二酯酶抗性并具有非规范的磷酸酯键； (2) 在非GLP先导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 Pancreas 的产品表征和释放检测方法； (4) 向 FDA 提交 pre-preIND 文件并请求进行非正式讨论。成功完成这些目标将为第 2 阶段 SBIR 拨款申请中提出的支持 IND 的开发活动奠定基础。