Gene therapy of thyroid cancer via retrovirally-driven combined expression of human interleukin-2 and herpes simplex virus thymidine kinase

Abstract

Objective and design: Based on our clinical experience with combined gene therapy of glioblastoma, we developed a retroviral vector expressing two therapeutic genes (i.e. thymidine kinase of herpes simplex virus, HSV-TK, and interleukin-2, IL-2 ) and evaluated its efficiency in vitro and in vivo. Methods: Expression of therapeutic genes in transduced thyroid carcinoma cells was analyzed by realtime RT-PCR. Ganciclovir sensitivity of infected cells was assessed in vitro in thyroid carcinoma cell lines and in vivo in nude mice bearing xenografted thyroid cancers. The combined effect of IL-2/ HSV-TK was compared with the effect of IL-2 alone. Results: Expression of therapeutic genes was higher in differentiated than in anaplastic thyroid carcinoma cells. Ganciclovir treatment led to dose-and time-dependent killing of transduced cells in vitro. A bystander effect was demonstrated by using mixtures of infected and non-infected cells. In vivo studies showed a significant reduction of growth and the presence of an inflammatory infiltrate in transduced thyroid tumors expressing IL-2 alone, as compared with non-infected tumors. By using the retroviral vector expressing IL-2/HSV-TK, treatment with ganciclovir led to complete eradication of anaplastic tumors and a . 80% reduction of the size of differentiated thyroid carcinomas. Histological analysis of tumor specimens showed extensive necrosis and inflammatory cell infiltrates. The combination of IL-2/HSV-TK plus ganciclovir was significantly more efficient than IL-2 alone in eradicating tumor masses. The bystander effect was also obtained in vivo.Conclusions: These findings demonstrate the feasibility and efficiency of a combined immunomodulating and suicide gene therapy approach for thyroid carcinomas.

Progress in oncolytic virotherapy for treatment of thyroid malignant neoplasm

“…GCV, which is selectively transformed into a toxic metabolite by HSV1-TK, totally eradicated rMTC-TK tumors in 60% of the animals [43]. In a similar study, the expression of both the HSV-TK and the hIL-2 therapeutic genes in infected cells was high and persistent with time and showed that treatment with GCV led to more than 90% tumor growth inhibition and 100% inhibition transduced cells proliferation [44]. Moreover, successful safety and efficacy preclinical studies were conducted in NV 1023 and G207 cell lines, both in vitro and in animal models.…”

“…This retroviral-based vector system exhibited enhanced tumor growth inhibition in animal models [89]. In addition, Barzon et al [44] used a similar retroviral vector system and evaluated its efficiency in vitro and in vivo, following GCV treatment [90]. This study showed an 80% reduction of the size of differentiated thyroid carcinomas [44].…”

Highly selective toxic and proapoptotic effects of two dimeric ribonucleases on thyroid cancer cells compared to the effects of doxorubicin

“…Moreover, RNase or other antineoplastic drug administration in the peritumoral area has been successfully used previously for the treatment of rat (Laccetti et al, 1994) or human thyroid tumour cells (Carlomagno et al, 2002;Barzon et al, 2002Barzon et al, , 2003. Obviously, the applicability of RNases in clinical situations and the site of administration of the antitumour molecules would depend largely on the type of the tumour, on its localisation and on the tumour growth rate.…”

Anaplastic thyroid cancer – an overview of genetic variations and treatment modalities

“…83 Oncolytic viruses (measles, vaccinia, and lentiviruses) expressing the NIS gene have been used to induce cell death as well as facilitate noninvasive imaging and radioiodine therapy. 69,86,94 Combinatorial therapeutic options using small molecule inhibitors such as paclitaxel, 84 bevacizumab, 89 gancliclovir, 95 and aurora kinase inhibitor AZD1152, 82 along with independent virus treatments, have also been evaluated preclinically.…”