Genetic immunotherapy of established tumours with adenoviral vectors transducing murine interleukin-12 (mIL12) subunits in a rat medullary thyroid carcinoma model

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Abstract
Interleukin-12 (IL12) is a heterodimeric cytokine that plays an important role in the development of cellular immunity. Studies have demonstrated antitumour activity after systemic administration of recombinant IL12. As with other cytokines, with increasing dosage and longer exposure, systemic toxicity is observed. To reduce systemic toxicity and obtain local production of IL12, we developed a replication defective adenovirus transducing two subunits of the murine IL12 (AdCMVmIL12) gene. Two separate cassettes, expressing the p35 or p40 subunit of mIL12, under the control of human cytomeglavirus immediate early promoter, were inserted into the early1 (E1) region of adenovirus 5. Biological activity of virally expressed mIL12 was demonstrated in vitro through its ability to induce proliferation of mouse ConA blast cells. Rat medullary thyroid carcinoma (MTC) cells infected with AdCMVmIL12 lost their tumorigenicity in their syngenic WAG/Rij rat hosts. Efficient antitumour activity was found after direct injection of the AdCMVmIL12 vector into rMTC tumours. After intratumoural treatment with AdCMVmIL12, 86% of tumour bearing animals were apparently cured, and almost all remaining tumours were stabilized. Challenge studies showed that most animals cured after the first treatment remained tumour free after reinjection of wild type rMTC cells, indicating that long-term antitumour immunity developed. This study demonstrates the construction of an adenoviral vector expressing a functional heterodimeric mIL12 and its efficient antitumour activity after in vivo delivery in an animal model of medullary thyroid carcinoma.