Gene Therapy for Thyroid Cancer: Current Status and Future Prospects

Christine Spitzweg; John C. Morris

Disclosures

Thyroid. 2004;14(6) 

In This Article

Immunomodulatory Gene Therapy

Many cancers express tumor-associated antigens that can be recognized by the immune system. Tumor-associated antigens are released from tumor cells physiologically or after cytotoxic therapy. The antigens are then taken up through phagocytosis by antigen presenting cells, which process and present the tumor-associated antigens to CD8+ cytotoxic T cells and CD4+ helper T cells in the context of major histocompatibility complex (MHC) class I and II and B7.1/B7.2 costimulatory molecules. Tumors often demonstrate downregulated expression of MHC class I or costimulatory molecules, resulting in poor T-cell responses, and thereby evade the immune system. Mobilization of the immune system by delivery of genes that enhance immunogenicity of tumors and responsiveness of the immune system, is associated with a number of advantages, including inherent specificity of the immune system (decreasing normal tissue toxicity), a systemic immunogenic effect, signal amplification, and permanent antitumor immunity because of inherent memory of the immune system. Local expression of certain cytokines is able to elicit an immune response against the tumor by stimulating surrounding immunocompetent cells, targeting cytotoxic T cells and natural killer cells, thereby inducing rejection of tumor cells. Cytokines with antitumor activity include interferon-γ, tumor necrosis factor-α, interleukin-2 (IL-2), and interleukin-12 (IL-12).

IL-2 has been examined in various studies for genetic immunotherapy of thyroid cancer. Zhang et al.[35,36] used a replication-defective adenovirus harboring the IL-2 gene for treatment of medullary thyroid tumors in mice and rats. Intratumoral injection of the adenovirus resulted in tumor regression in smaller tumors and tumor stabilization in larger tumors with low in vivo toxicity after systemic application of the adenovirus. The antitumor effect was shown to be dependent on cytotoxic T lymphocyte activity against the tumor, which also prevented tumor growth after reinjection of tumor cells, indicating development of long-term antitumor immunity.

To enhance therapeutic efficacy in thyroid cancer further, the combination of suicide and immunomodulatory gene therapy has been evaluated by several groups.[37,38,39,40] Zhang et al.[38] developed an adenovirus expressing both HSV-tk and human IL-2 (AdCMVTKhIL2), which was shown to have an antitumor effect in rat medullary thyroid tumors after intratumoral injection superior to that of each single vector. In addition, systemic and long-term antitumor immunity was established in most rats after intratumoral injection of AdCMVTKhIL2.[38] Barzon et al.[40] used a retroviral vector for combined transfer of the human IL-2 and the HSV-tk gene in differentiated and anaplastic thyroid carcinoma cells and showed an enhanced therapeutic effect compared to IL2 alone. In vivo studies in nude mice showed complete eradication of xenografts derived from retrovirally transduced anaplastic thyroid tumors, and more than 80% reduction of tumor size of differentiated thyroid carcinoma xenografts. The therapeutic effect of the combination of IL-2 and HSV-tk gene therapy was associated with a significant bystander effect in vitro and in vivo.[40] To further optimize this therapeutic approach, a transcriptionally targeted retroviral vector was generated, replacing the viral enhancer with the enhancer sequence of the human Tg gene, which allowed selective transgene expression and cell killing in differentiated thyroid tumor cells, but not in anaplastic thyroid carcinoma cells or nonthyroid cells.[39]

Another cytokine with antitumor activity, IL-12, causes proliferation of natural killer cells and CD8+ T cells, and activation of macrophages. Zhang et al.[41] generated an adenovirus carrying two subunits of the murine IL-12 gene and showed efficient antitumor activity and development of long-term antitumor immunity after intratumoral injection of the adenovirus into rat medullary thyroid tumors.[41] Using the same adenovirus, a significant therapeutic effect with long-term antitumor immunity was also demonstrated in a rat thyroid follicular cancer cell line (RTC-R2) in vivo after intratumoral injection of the virus. In vivo toxicity was low after intratumoral or systemic application of the adenovirus, and in rats with two tumors, injection of the adenovirus in one tumor resulted in antitumor activity in the injected as well as noninjected tumor, indicating systemic antitumor immunity.[42] With the aim of tissue-specific antitumor activity in medullary thyroid cancer, another adenovirus was generated in which the two subunits of the murine IL-12 gene were linked to a modified calcitonin promoter. IL-12 was selectively expressed in rat medullary thyroid carcinoma cells, resulting in a significant therapeutic effect in medullary thyroid tumors in rats after intratumoral injection of the adenovirus. Tissue-specific IL-12 gene transfer was also associated with development of long-term antitumor immunity and low in vivo toxicity after local and systemic adenovirus application. Moreover, intratumoral injection of the adenovirus induced antitumor activity in injected as well noninjected tumors in the same rat.[43]

Taken together, immunomodulatory gene therapy, in particular in combination with suicide gene therapy, seems to be a promising therapeutic approach for treatment of follicular cell-derived and medullary thyroid cancer.

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