Stimulator of interferon genes (STING) is a cytosolic receptor that senses both exogenous and endogenous cytosolic cyclic dinucleotides (CDNs), activating TBK1/IRF3 (interferon regulatory factor 3), NF-κB (nuclear factor κB), and STAT6 (signal transducer and activator of transcription 6) signaling pathways to induce robust type I interferon and proinflammatory cytokine responses. CDN ligands were formulated with granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing cellular cancer vaccines--termed STINGVAX--that demonstrated potent in vivo antitumor efficacy in multiple therapeutic models of established cancer. We found that rationally designed synthetic CDN derivative molecules, including one with an Rp,Rp dithio diastereomer and noncanonical c[A(2',5')pA(3',5')p] phosphate bridge structure, enhanced antitumor efficacy of STINGVAX in multiple aggressive therapeutic models of established cancer in mice. Antitumor activity was STING-dependent and correlated with increased activation of dendritic cells and tumor antigen-specific CD8(+) T cells. Tumors from STINGVAX-treated mice demonstrated marked PD-L1 (programmed death ligand 1) up-regulation, which was associated with tumor-infiltrating CD8(+)IFNγ(+) T cells. When combined with PD-1 (programmed death 1) blockade, STINGVAX induced regression of palpable, poorly immunogenic tumors that did not respond to PD-1 blockade alone.

The use of neoadjuvant chemotherapy or radiation for borderline resectable pancreatic adenocarcinoma (BL-PDAC) is increasing. However, the impact of neoadjuvant chemotherapy and radiation therapy on the outcome of BL-PDAC remains to be elucidated. We performed a retrospective analysis of 93 consecutive patients who were diagnosed with BL-PDAC and primarily followed at Johns Hopkins Hospital between February 2007 and December 2012. Among 93 patients, 62% received upfront neoadjuvant chemotherapy followed by chemoradiation, whereas 20% received neoadjuvant chemoradiation alone and 15% neoadjuvant chemotherapy alone. Resectability following all neoadjuvant therapy was 44%. Patients who underwent resection with a curative intent had a median overall survival (mOS) of 25.8 months, whereas those who did not undergo surgery had a mOS of 11.9 months. However, resectability and overall survival were not significantly different between the three types of neoadjuvant therapy. Nevertheless, 22% (95% CI, 0.13-0.36) of the 58 patients who received upfront chemotherapy followed by chemoradiation remained alive for a minimum of 48 months compared to none of the 19 patients who received upfront chemoradiation. Among patients who underwent curative surgical resection, 32% (95% CI, 0.19-0.55) of those who received upfront chemotherapy remained disease free at least 48 months following surgical resection, whereas none of the eight patients who received upfront chemoradiation remained disease free beyond 24 months following surgical resection. Neoadjuvant therapy with upfront chemotherapy may result in long-term survival in a subpopulation of patients with BL-PDAC.