Natural history of adult T-cell leukemia/lymphoma and approaches to therapy

Abstract

After cell-to-cell transmission, HTLV-I increases its viral genome by de novo infection and proliferation of infected cells. Proliferation of infected cells is clonal and persistent in vivo. During the carrier state, infected cells are selected in vivo by the host's immune system, the genetic and epigenetic environment of proviral integration sites, and other factors. In leukemic cells, tax gene expression is frequently impaired by genetic and epigenetic mechanisms. Such loss of Tax expression enables ATL cells to escape the host immune system. On the other hand, ATL cells acquire the ability to proliferate without Tax by intracellular genetic and epigenetic changes. Despite advances in support and the development of novel treatment agents, the prognosis for ATLL remains poor. A number of therapies, however, do appear to improve prognosis compared to CHOP (VEPA). These include interferon-a plus zidovudine (probably after 1-2 cycles of CHOP), intensive chemotherapy as in LSG-15 with G-CSF support and Allo-SCT (which includes the potential for cure). Emerging novel approaches include HDAC inhibitors, monoclonal antibodies, and proteasome inhibitors. Comparison between different therapeutic approaches is complicated by the range of natural history of ATLL, different recruitments of naı¨ve-to-therapy, refractory or relapsed patients, and variations in the reporting of outcome that frequently excludes difficultto-evaluate patients. Moreover, results from relatively small proof-of-principle studies have not been extended with randomized, controlled trials. As a result, currently, there is no clear evidence to support the value of any particular treatment approach over others. To avoid further unnecessary patient suffering and to identify optimal therapy as rapidly as possible, large randomized, controlled trials encompassing multicenter, international collaborations will be necessary.

Reduced Frequency, Diversity, and Function of Human T Cell Leukemia Virus Type 1-Specific CD8+ T Cell in Adult T Cell Leukemia Patients

“…These observations suggest that the lower frequency and diversity of anti-Tax CD8 ϩ T cells is risk for ATL development. A recent report demonstrated insufficient expression of HTLV-1 Tax in vivo in ATL patients and suspected a role of Tax-specific CTL for therapy or prevention of ATL (48). However, other researchers, as well as our group, demonstrated clear expression of HTLV-1 Tax in short-term cultures of fresh ATL cells (24 -26).…”

HBZ is an immunogenic protein, but not a target antigen for human T-cell leukemia virus type 1-specific cytotoxic T lymphocytes

“…HBZ was found to inhibit Taxmediated transactivation of viral transcription from the 59LTR by interaction with cellular factors of the JUN and ATF/CREB families (Basbous et al, 2003;Lemasson et al, 2007). The HBZ transcript is reportedly detectable in all ATL cases without exception (Taylor& Matsuoka, 2005). Importantly, it has been reported that downregulation of HBZ results in inhibition of ATL cell growth, and that conversely, the expression of HBZ in human T-cell lines promotes their proliferation (Satou et al, 2006).…”

“…Because Tax-specific cytotoxic T lymphocytes (CTLs) are frequently detected in peripheral blood of patients with ATL who have undergone allogeneic HSCT (Harashima et al, 2004), immunotherapy targeting Tax might be a promising strategy for treatment of ATL. However, universal clinical application of Tax-targeted immunotherapy seems unlikely because tax mRNA is detected in only about 40 % of ATL cases (Taylor& Matsuoka, 2005). Therefore, identification of a novel target antigen recognized by CTLs and directed against ATL cells is desirable.…”

Retracted: A modified version of galectin‐9 suppresses cell growth and induces apoptosis of human T‐cell leukemia virus type I‐infected T‐cell lines

“…However, at present, there is no accepted curative therapy for ATL and the condition often progresses to death with a median survival time of 13 months in aggressive ATL. 4 Chemotherapies that are specifically known to be active against other lymphoid malignancies are ineffective for treating aggressive forms of ATL. Death is usually due to severe infection or hypercalcemia.…”