Toxicity assessment of intratumoral injection of the herpes simplex type Ithymidine kinase gene delivered by retrovirus in patients with refractory cancer

Introduction of the herpes simplex type I thymidine kinase (HSV-TK) gene in to tumor tissue, followed by ganciclovir, initiates a phosphorylation casca de that induces formation of a toxic ganciclovir triphosphate. Animal trial s suggest that this ganciclovir triphosphate has antitumor activity. Here w e report application of the HSV-TK transfection approach using a retroviral construct. Sixteen patients (median age 61.5 years) with refractory carcin oma (13 melanoma, 1 breast cancer, 1 nonsmall-cell lung cancer, and 1 osteo genic sarcoma) received intratumoral injection of HSV-TK retroviral vector at escalating doses (0.2 x 10(7) cfu per injection x 5 daily doses) and we evaluated them for toxicity and activity. We observed grade III pain associ ated with cellulitis in one patient following injection. Analysis of blood samples drawn between 3 and 28 weeks from 14 patients for replication-compe tent retrovirus by PCR analysis of the amphotrophic envelope revealed no re plication-competent retrovirus. We injected 21 lesions. We identified no tu mor responses of the injected lesions. Of 13 patients with advanced melanom a, 6 survived over one year. Thus, injection of retroviral delivered HSV-TK in patients with refractory cancer was well-tolerated.