Abstract 287: Specific delivery of immunostimulatory RNA via nanoparticles blocks growth of primary and disseminated ovarian tumors

Abstract

Abstract One important mechanism of immune evasion is the accumulation of tumor-infiltrating regulatory T cells creating an immunosuppressive microenvironment in situ. Many new therapies target immune checkpoint receptors, CTLA-4 and PD-1, on immunosuppressive T-cells to reverse tumor immune evasion. Small interfering RNAs (siRNAs) are double stranded, sequence-specific inhibitors of gene expression. The paradigm for using siRNA to block cancer is to target mRNA sequences of oncogenes. Several limitations have suppressed the use of siRNA in human cancer therapy, such as off-target effects and lack of tumor-specific delivery. Additionally, certain siRNA sequence motifs activate toll-like receptors that induce the systemic innate immune response, including induction of interferon and interleukin-6 release that is traditionally considered as an undesirable clinical outcome. The hypothesis proposed here is to control the innate immune response by directing it only to tumors and not other organs by delivering an immunostimulatory siRNA (isRNA) directly to tumors. An isRNA designed to silence no human genes was synthesized as an unmodified triphosphate 19-mer double-stranded RNA with a GUGA motif on the 5′ antisense end. This isRNA was delivered into human ovarian tumors grown from SK-OV-3 cells surgically implanted into the ovaries of immunosuppressed mice by an L1CAM-targeted elastin-like polypeptide (ELP-L) nanoparticle. The isRNA/ELP-L nanocomplex was dosed into ten mice by i.p. injection 14 times at 10 mg/kg with respect to the isRNA over 28 days. The isRNA was delivered to the tumors, not to liver, spleen, heart, or lungs. The total tumor mass and number of disseminated nodules both decreased by 50% with respect to vehicle control. Six ovaries harboring tumors were resected from isRNA/ELP-L nanocomplex-dosed mice and each displayed elevated levels of interferon alpha and interleukin 6 mRNA as determined by RT-PCR. Mean AST, ALT and BUN serum biomarkers of liver and kidney function were elevated by 68%, 128% and 14%, respectively, compared to vehicle dosed mice; none of which were outside average normal levels. These results indicate that specifically targeting isRNA to tumors using a targeted nanoparticle may provide an effective therapy for ovarian cancer, either alone or in combination with agents that affect immune check point pathways in tumors. Citation Format: Thomas Primiano, Bey-ih Chang. Specific delivery of immunostimulatory RNA via nanoparticles blocks growth of primary and disseminated ovarian tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 287. doi:10.1158/1538-7445.AM2015-287