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Integrating antigen-encoding mRNA (Messenger RNA) and immunostimulatory adjuvant into a single formulation is a promising approach to potentiating the efficacy of mRNA vaccines. Here, we developed a scheme based on RNA engineering to integrate adjuvancy directly into antigen-encoding mRNA strands without hampering the ability to express antigen proteins. Short double-stranded RNA (dsRNA) was designed to target retinoic acid-inducible gene-I (RIG-I), an innate immune receptor, for effective cancer vaccination and then tethered onto the mRNA strand via hybridization. Tuning the dsRNA structure and microenvironment by changing its length and sequence enabled the determination of the structure of dsRNA-tethered mRNA efficiently stimulating RIG-I. Eventually, the formulation loaded with dsRNA-tethered mRNA of the optimal structure effectively activated mouse and human dendritic cells and drove them to secrete a broad spectrum of proinflammatory cytokines without increasing the secretion of anti-inflammatory cytokines. Notably, the immunostimulating intensity was tunable by modulating the number of dsRNA along the mRNA strand, which prevents excessive immunostimulation. Versatility in the applicable formulation is a practical advantage of the dsRNA-tethered mRNA. Its formulation with three existing systems, i.e., anionic lipoplex, ionizable lipid–based lipid nanoparticles, and polyplex micelles, induced appreciable cellular immunity in the mice model. Of particular interest, dsRNA-tethered mRNA encoding ovalbumin (OVA) formulated in anionic lipoplex used in clinical trials exerted a significant therapeutic effect in the mouse lymphoma (E.G7-OVA) model. In conclusion, the system developed here provides a simple and robust platform to supply the desired intensity of immunostimulation in various formulations of mRNA cancer vaccines. [ABSTRACT FROM AUTHOR]

Gastrointestinal stromal tumors (GISTs) of the vermiform appendix are rare, measuring <3 cm in 82.4% of the reported cases. Neoadjuvant therapy with the receptor tyrosine kinase inhibitor imatinib mesylate has the potential to improve resectability and organ preservation rates in locally advanced or metastatic/recurrent GISTs. We herein report the case of a 67-year-old male patient with an unusually large GIST (22 cm in diameter) of uncertain origin in the right lower abdominal quadrant, with a solitary peritoneal metastasis. Due to the size of this GIST and presence of metastatic disease, neoadjuvant therapy with imatinib (400 mg/day orally) was administered. Follow-up imaging studies revealed marked shrinkage of the primary and metastatic tumors. Subsequently, laparoscopic exploration revealed that the main tumor originated from the tip of the vermiform appendix, and that the peritoneal metastasis was located in the ascending mesocolon. The patient underwent laparoscopic appendectomy and excision of the peritoneal metastasis, without tumor rupture. Therefore, in appropriately selected patients, neoadjuvant imatinib for borderline resectable or oligometastatic GISTs may be a reasonable choice. [ABSTRACT FROM AUTHOR]