Seminar

Use of alphavirus vectors for cancer treatment

Christian Smerdou, PhD

Alphaviruses are self-replicating RNA vectors which express high levels of heterologous proteins in many cell types, including tumor cells. These vectors induce apoptosis in infected cells, which contributes to their antitumoral efficacy. We have developed vectors based on Semliki Forest virus (SFV) expressing cytokines like interleukin-12 (IL-12) that showed a high antitumoral efficacy in subcutaneous transplantable tumor models. Interestingly, when the same tumors were implanted in the liver the efficacy of the vector was considerably reduced. By characterizing differences in immune responses generated in responder and non-responder animals we observed that maintenance of a population of memory T cells is an important requirement to achieve complete tumor regressions. To test our vectors in a more relevant preclinical setting we have used two models of liver spontaneous tumors. The first one was based on transgenic mice that overexpress the oncogene c-myc in the liver. In this model SFV-IL-12 induced growth arrest in most tumors, improving the survival rate. The second model was based on woodchucks chronically infected with woodchuck hepatitis virus (WHV). These animals develop hepatocellular carcinomas (HCC) which are heterogeneous and reach a size similar to that observed in humans during HBV-induced hepatocarcinogenesis. In >80% woodchucks a partial tumor remission was observed after SFV-IL-12 treatment with reductions of up to 80% in tumor volume. Intratumoral treatment also produced transient changes in WHV viremia and antigenemia, with significant reductions in serum WHV DNA. These experimental observations suggested that intratumoral administration of SFV-IL-12 may represent a strategy for treatment of chronic HBV infection and associated HCC in humans, although further improvements are probably needed. An optimal viral vector for cancer gene therapy should be able of infecting tumors with high efficiency, inducing specific and high level expression of transgenes and destroying selectively tumor cells. For that purpose we constructed a hybrid vector composed of a high capacity adenovirus containing a SFV-IL-12 replicon under the transcriptional control of the alphafetoprotein (AFP) promoter. This hybrid vector induced specific and high level expression of IL-12 in AFP-expressing HCC cells, leading to a strong antitumoral activity without accompanying toxicity in a rat ortothopic liver tumor model. This new type of adenovirus-alphavirus hybrid vectors may provide a potent and safe tool for cancer gene therapy.