Enhanced therapeutic effect of HSV-tk plus GCV gene therapy and ionizing radiation for prostate cancer

Standard therapies for prostate cancer including radiation, prostatectomy, and hormone ablation have significant toxicities and recurrence risk. HSV-t k gene therapy may be effective in combination with radiation therapy due t o complementary mechanisms and distinct toxicity profiles. Mouse prostate t umors transplanted subcutaneously were treated by either gene therapy invol ving intratumoral injection of AdV-tk followed by systemic ganciclovir or l ocal radiation therapy or the combination of gene and radiation therapy. Bo th single-therapy modalities showed a 38% decrease in tumor growth compared to controls. The combined treatment resulted in a decrease of 61%. In addi tion the combined-therapy group had a mean survival of 22 days versus 16.6 days for single therapy and 13.8 days for nontreated controls. To analyze s ystemic anti-tumor activity, lung metastases were generated by tail vein in jection of RM-1 prostate cancer cells on the same day that they were inject ed subcutaneously. The primary tumors were treated as before with AdV-tk fo llowed by ganciclovir, radiation, or the combination. The number of lung no dules was reduced by 37% following treatment with AdV-tk, whereas radiother apy alone had no effect on metastatic growth. The combination led to an add itional 50% reduction in lung colonization. Primary tumors that received th e combination therapy had a marked increase in CD4 T cell infiltrate. This is the first report showing a dramatic systemic effect following the local combination treatment of radiation and AdV-tk. A clinical study using this strategy has been initiated and patient accrual is ongoing.