Adenovirus vectors are the most commonly used gene therapy vectors in clinical trials. Administrated systemically or intratumorally the virus is capable of inducing immune responses against the tumor per se, but this effect can also be amplified by arming the viruses with immune system stimulating factors. Moreover, we have discovered that adenoviruses enhance adoptive T-cell therapy in a potent manner. Our previous data also shows that the most promising factors to stimulate immune system are interleukin (IL) -2 and Tumor Necrosis Factor alpha (TNFα). IL-2 is a commonly used cytokine in treating malignant melanoma and renal cell carcinoma. However, systemic IL-2 can in some cases lead to severe side effects. Like IL-2, TNFα activates immune cells, but it is also known for its anti-tumor properties and it is for example capable of promoting tumor cell death by apoptosis and necrosis. Arming oncolytic viruses with cytokines results in long lasting, high level expression locally but low level systemically. Currently, we are developing oncolytic adenoviruses with expression of one or both of the above mentioned human cytokines. The viruses have an Ad5/3 chimera that is generated through replacement of the Ad5 fiber knob with the Ad3 knob while the Ad5 shaft and tail are retained. The chimera has proven to have an improved cancer cell transduction as well as antitumor efficacy. In addition, the viral genome has an E2F promoter and a 24-basepair deletion at the E1A domain, which makes it selective to retinoblastoma protein defective cells (most tumor cells). The viral particles are produced in A549 lung adenocarcinoma cell line. The genomes are sequenced and the functionality of the viruses and the cytokines proven with various methods. The secretion of cytokines is tested with ELISA and by using indicator cell lines. The functionality of the viruses is studied by infecting different cells lines with variable amount of viral particles and measuring the proportion of surviving cells with MTS-assay. Our data proves oncolytic and cytokine production capability of Ad5/3-E2F-D24-hTNFα/hIL2 adenoviruses. The results indicate that these viruses can be used in further investigations in vivo.
Citation Format: Riikka Havunen, Suvi Parviainen, Mikko Siurala, Akseli Hemminki. Characterization of T-cell therapy enhancing oncolytic adenoviruses with human cytokine expression. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B07.
- ©2015 American Association for Cancer Research.