As combining therapeutic agents with different action mechanisms may enhance efficacy, YSC-02, an oncolytic adenovirus with multi targets was loaded with five different genes, which were designed with the expectation that different action mechanisms would cooperate. In spite of concerns regarding many APIs, YSC-02 was constructed to be an adenovirus-based anti-cancer drug. By using our own established mouse model system suitable for efficient adenoviral infection and replication, immune activity as well as survival potential could be precisely estimated for anti-cancer drug efficacy. YSC-02 was designed to decrease tumor cell survival, metastasis and to increase tumor cell death, and immune activation. It is composed of five different target genes, including one fused form and two shRNAs, but each of these genes functions is closely linked to produce the maximal antitumor effect. YSC-02 is like an organic complex designed to be applied primarily to heterogeneous liver cancer and melanoma. The greatest difficulty in developing anticancer drugs is deeply related to the existence of many genetic variations even in the same tumor tissue. However, in our study, the downregulation of HSP27 greatly increased the death potential of most tumor cell types, irrespective of differential cell death induced by TGF-β1 or TGF-β2 isotypes. The simultaneous silencing of both HSP27 and TGF-β could significantly repress the tumor survival potential of various cancer cells, which leads to most cell types of death in the complex network of cells. These combined shRNAs have also contributed to the increase of TRAIL sensitivity. Genetically modified mouse cancer cells within syngenic mice could make it possible to estimate the superiority of YSC-02 over its derivatives including GMCSF-expressing oncolytic adenovirus or GMCSF-FETZ-expressing oncolytic adenovirus. At the immunological level, NK cells or T cells were shown to be most activated in the treatment of YSC-02, which may be another contributor of anti-tumor activity. Additionally, even the highest dose of YSC-02 did not produce any toxicity in the liver.

Citation Format: Zhezhu Han, Suyeon Je, Hye J. Choi, Dongxu Kang, Rong Xu, Hyun S. Kim, Jae J. Song. Oncolytic adenovirus YSC-02 enhanced tumor cell killing and immune response with broad spectrums, which resulted in both TGF-β and HSP27 cooperatively becoming silenced. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B81.