Effective gene therapy for medullary thyroid carcinoma using recombinant adenovirus inducing tumor-specific expression of interleukin-12

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Abstract
No satisfactory treatment of metastatic medullary thyroid carcinoma (MTC) is available. Cell-specific gene therapy offers a new approach. We have constructed a recombinant replication-defective adenoviral vector expressing murine interleukin-12 (mIL-12), driven by a modified CALC-I promoter (TCP). This vector (AdTCPmIL-12) includes two separate cassettes encoding mIL-12 p35 or p40 subunit controlled by TCP inserted in the E1 region of adenovirus type 5. In vitro and in vivo reporter gene expression using TCP revealed its cell-specific activity. AdTCPmIL-12-infected rat MTC (rMTC) cells produced high amounts of functional mIL-12 cells in vitro, while other cell lines infected with AdTCPmIL-12 did not. AdTCPmIL-12-transduced rMTC cells completely lost their tumorigenicity in syngenic WAG/Rij rats. Direct injection of 1 × 109 plaque forming units of AdTCPmIL-12 into subcutaneous rMTC tumors in WAG/Rij rats caused tumor regression in over 60% of animals within 20 days. Rats cured of tumors did not develop tumors after re-injection of naive rMTC cells, demonstrating lasting immunity. Treatment with AdTCPmIL-12 of one tumor resulted in regression of an established tumor at a distant site. Moreover, intratumoral or intravenous injection of AdTCPmIL-12 did not induce evident toxicity. These results indicate AdTCPmIL-12 can contribute to effective and less toxic gene therapy of MTC.