Prospects for herpes-simplex-virus thymidine-kinase and cytokine gene transduction as immunomodulatory gene therapy for prostate cancer

In completed and ongoing clinical trials, adenovirus-mediated (Ad.) express ion of herpes-simplex-virus thymidine-kinase (HSV-tk) gene transduction fol lowed by ganciclovir (GCV) therapy has produced limited toxicity and eviden ce of antitumor activity following injection of the prostate. Furthermore. this system has been shown to direct systemic antitumor activity in several experimental cancer models, including that of prostate cancer, which may s erve as the basis for in-situ immunomodulatory gene therapy. In a mouse mod el of prostate cancer, natural killer (NK) cells have been identified as th e mediator of antimetastatic activity following Ad.HSV-tk + GCV, resulting in the combination of Ad.HSV-tk and adenovirus-mediated expression of inter leukin 12 (Ad.IL-12) to exploit this cytokine's ability to enhance NK proli feration and cytotoxicity. Combination therapy demonstrated superior local and systemic growth suppression over that obtained with either therapy alon e. Importantly, when the metastatic tumor burden was increased to an extent that negated the growth-suppressive activity directed by Ad.HSV-tk + GCV o r Ad.IL-12 alone. combination therapy continued to demonstrate significant growth suppression. Examination of tumor-infiltrating lymphocytes documente d enhanced NK lytic activity following combination therapy. Therefore, it a ppears that the combination of Ad.HSV-tk and Ad.IL-12 should be validated i n a clinical trial for the treatment of prostate cancer.