A “Distant” Bystander Effect of Suicide Gene Therapy: Regression of Nontransduced Tumors Together with a Distant Transduced Tumor

Abstract

Antitumor gene therapy using herpes simplex type 1 thymidine kinase (TKh) and ganciclovir (GCV) treatment has revealed an important intratumoral bystander effect. A whole tumor can be eliminated when only a fraction of its tumor cells express TKh. We now report that the bystander effect not only acts within a tumor, but also between distant tumors. One TKh⁺ tumor was generated simultaneously with one or multiple TKh¯ tumors in different rat liver lobes such that there was no contact between the resulting tumors. Both the TKh⁺ and the TKh¯ tumors regressed after GCV treatment and showed infiltration with macrophages and T lymphocytes. This distant bystander effect, which is likely immune mediated, should be of major importance for gene therapy of disseminated tumors.

Overview summary

Gene therapy efficacy depends in large part on gene transfer efficacy. This later is limited not only by difficulties for targeting enough tumor cells within a tumor, but also for targeting disseminated tumors that might not be easily accessible. The previous recognition of a strong intratumoral bystander effect using the TKh/GCV system has brought down the first limitation to obtaining gene transfer to only a small portion of the tumor cells. We show here that, at least in the liver, there also exists a distant bystander effect that might overcome the necessity of targeting all of the tumors.