Targeted Therapy with Arsenic Trioxide and Interferon alpha Eradicates Leukemic Cells in SCID Mice Model of Adult T-Cell Leukemia/Lymphoma.

HTLV-I associated adult T-cell leukemia (ATL) is a severe, chemotherapy-resistant malignancy associated with poor prognosis. Recently, HTLV-I Tax transgenic mice, accurately reproducing human ATL disease were generated. To develop a more consistent and rapid model of disease development, direct transfer of Tax transgenic cells into SCID mice was assessed and showed that they die within 28 days, having developed both an extremely aggressive leukemia with characteristic flower cells, and extensive lymphomatous infiltration of the spleen, lymph nodes, bone marrow, liver, kidney and lung by malignant T lymphocytes highly expressing CD25. Furthermore, and as in ATL patients, we observed marked hypercalcemia and high level of LDH. We have previously identified in vitro several potential targeted therapies for ATL. To define the optimal schedule and drug combination to be evaluated in clinical trials, we tested the following drugs using the in vivo ATL SCID model: zidovudine, interferon alpha (IFN), arsenic trioxide, the proteasome inhibitor bortezomib, and the combinations of zidovudine and IFN, or of arsenic and IFN. The combination of zidovudine and IFN had no effect on the survival of ATL SCID mice confirming the hypothesis that this combination targets the viral replication since these animals have Tax-transgenic leukemic cells but no entire HTLV-I retrovirus, contrary to ATL patients. Inhibition of NF-kappaB using bortezomib or arsenic alone almost doubled the mice survival but was not sufficient to eradicate ATL malignant cells. Strikingly, the most relevant effect on the mice survival was obtained when we used the combination of arsenic trioxide and interferon alpha, which targets both the HTLV-I Tax oncoprotein and the constitutive activation of the NF-kappaB pathway. Indeed, after 6 months of follow up, this combination totally cured 40% of the treated mice, and tripled the survival of the remaining 60%. These impressive results suggest that double targeting of Tax and NF-kappaB by the combination of arsenic trioxide and interferon alpha may suffice to cure ATL. This combination is now tested in newly diagnosed ATL patients.