41. Evaluation of Lung Cancer Virotherapy with Oncolytic Semliki Forest Virus Using Immunodeficient Rodent Tumor Model

Abstract

Top of pageAbstract Virotherapy has been postulated as a promising approach for killing tumor cells. Unlike conventional gene therapy, it uses replication competent viruses that are able to spread through tumor tissue and replicate in cancer cells, eventually causing destruction of the tumor. Most of the virotherapy studies are focused on oncolytic adenoviruses, but in this study we wanted to evaluate the efficacy of replication competent alphavirus, Semliki forest virus (SFV) strain A7 (74). It is not considered a human pathogen and also, it causes only transient and benign CNS infection to adult mice. To test the efficacy of SFV A7 (74) virotherapy, we first conducted in vitro studies with different (A549, NCI-H661 and SW900) human non small cell lung cancer (NSCLC) cell lines representing all the three main types of NSCLC. The aim was to determine, how extensively different amounts (MOI 0.1, 1 and 10) of virus destroy the target cells. After in vitro studies we determined the efficacy of the virotherapy in vivo (in immunodeficient NMRI nu/nu mice) using a subcutaneous A549 tumor model. In this experiment we compared the efficacy of virotherapy when SFV A7 (74) virus was injected systemically (i.v. and i.p.) or locally (i.t.). Virus distribution analysis (serum, brain and tumor tissues) was carried out 16 h, 2 days, 4 days and one week after viral injections. SFV A7 (74) virotherapy appeared to be very efficient in vitro, inducing in all NSCLC cell lines almost 100% cell death 48 h after infection. In subcutaneous (lung adenocarcinoma A549) tumor model, the therapeutic efficacy was better when virus was injected locally. With this approach, the tumor growth rate was reduced significantly when compared to control group. When virus was administered systemically, the tumor growth was delayed, but the tumors reached the same size as the control tumors by the end of the experiment. The distribution study showed the neurotrophic nature of the Semilki forest virus: 7 days post-infection the virus was found in the brain, but not in serum or in tumors. However there were no differences in the behaviour or overall condition of SFV A7 (74) - treated mice and control mice. Even though the study was done with an immunocompromized mice model (lack of T cell response), our results suggest that the animals were able to elicit at least a partial immune response against the virus. This was seen particularly with the systemic delivery route: viruses did not find the tumors efficiently and were unable to initiate powerful intratumoral replication. Thus, to obtain high therapeutic efficacy with SFV virotherapy, the route of virus administration and the immunogenicity of the virus should be carefully evaluated.