Enhanced Therapeutic Effect of HSV-tk+GCV Gene Therapy and Ionizing Radiation for Prostate Cancer

Abstract

Standard therapies for prostate cancer including radiation, prostatectomy, and hormone ablation have significant toxicities and recurrence risk. HSV-tk gene therapy may be effective in combination with radiation therapy due to complementary mechanisms and distinct toxicity profiles. Mouse prostate tumors transplanted subcutaneously were treated by either gene therapy involving intratumoral injection of AdV-tk followed by systemic ganciclovir or local radiation therapy or the combination of gene and radiation therapy. Both single-therapy modalities showed a 38% decrease in tumor growth compared to controls. The combined treatment resulted in a decrease of 61%. In addition 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 systemic anti-tumor activity, lung metastases were generated by tail vein injection of RM-1 prostate cancer cells on the same day that they were injected subcutaneously. The primary tumors were treated as before with AdV-tk followed by ganciclovir, radiation, or the combination. The number of lung nodules was reduced by 37% following treatment with AdV-tk, whereas radiotherapy alone had no effect on metastatic growth. The combination led to an additional 50% reduction in lung colonization. Primary tumors that received the 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.

Systemic administration of radiation-potentiated anti-angiogenic gene therapy against primary and metastatic cancer based on transcriptionally controlled HSV-TK

“…24 The HSV-TK/GCV system combined with radio-sensitization has been previously studied in non-targeted, locally delivered gene delivery systems. 12,13 However, although a synergistic effect has been demonstrated, this approach ultimately failed to suppress glioblastoma multiforme in a Phase III clinical trial. 2 Endothelial cell apoptosis has been demonstrated to be involved in tumor response to radiotherapy.…”

“…12,13 It is hypothesized that the mechanism of this enhanced therapeutic effect is based on the complementing mechanisms of the two therapies. HSV-TK prodrug gene therapy may radiosensitize cells by generating high local concentration of nucleotide analogues, promoting death of cells that might otherwise repair radiation-induced DNA breaks.…”

“…As was shown in previous studies, low doses of radiotherapy demonstrated a synergistic increase in antitumor activity when combined with local HSV-TK/GCV administration. 12,13 This synergism between the HSV-TK gene and radiotherapy has been attributed to the combined effect of DNA damage and radiation-induced cell membrane breakage which may enhance the local bystander effect.…”

Gene therapy for carcinoma of the breast

“…It is hypothesized that the radiation-induced cellular membrane damage may facilitate the transfer of cytotoxic nucleotide analogs from HSV-tk-expressing cells to neighboring nontransduced cells. This combined approach has been effective in various tumor models 194 and has been shown to delay local tumor growth and prolong survival in a mouse prostate cancer model 195,196 and a mouse mammary tumor model. 197 These results indicate that multiple courses of HSV-TK therapy, in combination with radiation, improve the therapeutic efficacy of this approach and may provide therapeutic implications for the treatment of human breast cancer and other solid tumors.…”

“…It was also demonstrated that the combined therapy had a considerably better antimetastatic effect compared to HSV-tk gene therapy alone; this phenomenon was attributed to the induction of a potent local and systemic immune response, as evidenced by the abundance of CD4 þ cells in the primary tumor. 196,197 Another area likely to be investigated intensely in the coming years is the combination of immunotherapy with established conventional tumor therapies. In this regard, enhancement of antitumor immune response of granulocyte/macrophage-colony stimulating factor-secreting whole cell vaccines in Her-2/neu mice by administration of cyclophosphamide, doxorubicin, or paclitaxel could be demonstrated.…”