Abstract
BackgroundAdult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by long-term human T-cell leukemia virus type I (HTLV-1) infection. Survivin-responsive, conditionally replicating adenoviruses regulated by multiple tumor-specific factors (Surv.m-CRAs), in which the expression of the adenoviral early region 1A gene is regulated by the survivin (BIRC5) promoter, can be used to treat several cancers. As survivin is overexpressed in ATL, we examined the effects of Surv.m-CRAs on ATL-selective replication and survival.MethodsWe tested two ATL cell lines and four HTLV-1-infected T-cell lines. The cells were subjected to infection with either E1-deleted, replication-defective adenoviruses or Surv.m-CRAs at various multiplicities of infection.ResultsStrong activation of survivin promoter was observed in all six cell lines. Moreover, the expression of the coxsackie and adenovirus receptor (CAR), which is important for adenoviral infection, was high in the cell lines. In contrast, we observed the absence of survivin promoter activity and a low expression of CAR in activated peripheral blood lymphocytes (PBLs) from healthy subjects. Surv.m-CRAs actively replicated and induced cytocidal effects in five out of six cell lines; conversely, we observed minimal viral replication and no marked cytotoxicity in normal activated PBLs.ConclusionsThis is the first report demonstrating that Surv.m-CRAs constitute attractive potential anti-ATL agents.
Highlights
Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by long-term human T-cell leukemia virus type I (HTLV-1) infection
We developed a unique vector, which is regulated by multiple tumor-specific factors (m-Conditionally replicating adenoviruses (CRAs)) [11, 12], by additional modification of a CRA derived from a human adenovirus
As survivin is overexpressed in ATL, especially in acute-type ATL [20], we examined the effects of Surv.mCRAs on ATL-selective replication and the induction of cytocidal activity, with the ultimate goal of applying Surv.Multiple tumor-specific factors (m-CRA) clinically for the treatment of ATL in the future
Summary
Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by long-term human T-cell leukemia virus type I (HTLV-1) infection. Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy of mature peripheral T lymphocytes that results from long-term infection with human T-cell leukemia virus type I (HTLV-1). Distinct from standard cytotoxic chemotherapy treatments, are expected to lead to the eradication of ATL [1, 2]. A meta-analysis revealed that compared to chemotherapy alone, first-line management with interferon-alpha and zidovudine was markedly more effective for patients with acute-type ATL. As an immunotherapeutic approach that can induce long-term survival, allogeneic hematopoietic stem cell transplantation (HSCT) is recurrently conducted for the treatment of aggressive ATL in Japan. Some promising therapeutic advances in the management of patients with ATL in Japan include the introduction of the anti-CCR4 monoclonal antibody, mogamulizumab, and the immunomodulatory drug, lenalidomide [9, 10]
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