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 Here we extend both our published and unpublished clinical results and propose to develop a more advanced immunotherapy regimen for PDA by enhancing the immunologic potency of irradiated GM-CSF producing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.
The incidence of pancreatic adenocarcinoma is more than 45,000 cases per year in the US, and is increasing. The majority of patients present with advanced, unresectable cancer. Despite recent advances in chemotherapeutic regimens for metastatic disease, these treatment strategies are not curative. Strategies to harness patients'own immune systems to specifically recognize and destroy their tumors have shown increasing clinical success. We propose to conduct critical path development studies that will ultimately enable evaluation of our novel therapeutic cancer vaccine in humans with pancreatic cancer. This therapeutic vaccine, known as STINGVAX, utilizes an inactivated whole cell vaccine-already shown to be safe in clinical trials- that secretes GM-CSF, a factor known to recruit immune sentinels known as dendritic cells (DCs). STINGVAX contains cyclic dinucleotides, proprietary small molecules that provide a profound activating stimulus to DCs and potentiate the effectiveness of the therapeutic vaccine.