Adult T-cell Leukemia (ATL)
Alfa Cytology offers comprehensive drug development services specifically tailored to address the challenges of Adult T-cell Leukemia (ATL). With our expertise in biomedical research and commitment to advancing therapeutic options, we provide cutting-edge solutions to accelerate the development of effective treatments for ATL.
Introduction to ATL
The precise mechanism underlying HTLV-1-induced malignancy remains incompletely understood. Chronic HTLV-1 infection is considered the initial crucial event in a multistep oncogenic process. Activation of the viral promoter leads to alterations in cellular pathways, including an autocrine loop involving IL-2, IL-15, and their receptors. This ultimately initiates ATL and leukemia development. The viral genes Tax and HBZ play pivotal roles in viral transcription and promoting T-cell proliferation. The diagram below depicts cellular proliferation after HTLV-1 infection in vivo.
Fig. 1. Propagation of HTLV-1-infected cells. (Yasunaga, J., 2020)
Current Status of ATL
ATL occurs in HTLV-1 endemic regions: southwestern Japan, Caribbean Islands, Central/South America, tropical Africa, and the Middle East. Japan has 1.1 million carriers, globally 5-10 million. About 1,000 deaths from ATL occur annually in Japan. Current treatment is unsatisfactory, but lenalidomide or mogamulizumab shows promise for refractory/relapsed cases. Targeted therapies, including arsenic/interferon, monoclonal antibodies, and epigenetic therapy, require further clinical research.
Drug Development of ATL
Classical Therapeutic Options of ATL
Fig. 2. Therapeutic strategy for ATL. (Cook, L.B.; Phillips A A., 2021)
The standard treatment strategies for ATL are watchful waiting for indolent ATL, conventional chemotherapy, a combination of two antiviral drugs, and allogeneic hematopoietic stem cell transplantation (HSCT). Chemotherapy or antiviral treatment regimens are typically employed as first-line therapy for aggressive subtypes of ATL.
| Therapeutic strategies | Description |
|---|---|
| Antiviral therapy | AZT/IFN has been demonstrated to be highly effective in the chronic and smoldering subtypes of ATL, as well as in the acute subtype subgroup with wild-type P53, leading to a significant improvement in survival rates. |
| Chemotherapy | In Japan, the VCAP-AMP-VECP combination is presently an established chemotherapy regimen for treating aggressive ATL. In the United States, other suggested alternative regimens comprise dose-adjusted EPOCH, CHOP, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone. |
| Watch and Wait Policy | Favorable ATL subtypes (chronic or smoldering) are closely monitored without chemotherapy, except for topical therapy for cutaneous lesions. This helps detect progression towards unfavorable subtypes. |
| HSCT | In contrast to autologous HSCT, allogeneic HSCT represents a crucial curative treatment option for patients with aggressive ATL. |
Innovative Therapies of ATL
The present management approaches for aggressive ATL subtypes yield unsatisfactory results. The absence of a curative therapy and the low survival rates necessitate the exploration of novel targeted treatments to enhance survival and achieve a cure for ATL patients. The following table showcases some drugs currently under development for ATL.
| Drugs | Phase | Title |
|---|---|---|
| valemetostat | II | Valemetostat Tosylate (DS-3201b), an Enhancer of Zeste Homolog (EZH) 1/2 Dual Inhibitor, for Relapsed/Refractory Peripheral T-Cell Lymphoma (VALENTINE-PTCL01) |
| Anti-CCR4 Monoclonal Antibody KW 0761 | II | KW 0761 or Investigator's Choice in Subjects With Previously Treated Adult T-cell Leukemia-Lymphoma (ATL) |
| Romidepsin CHOP | III | Efficacy and Safety of Romidepsin CHOP vs CHOP in Patients With Untreated Peripheral T-Cell Lymphoma |
| Carfilzomib, Romidepsin | I/II | Combination Therapy With Carfilzomib, Romidepsin, Lenalidomide in Patients With Relapsed or Refractory B- and T-cell Lymphomas |
Recent studies have indicated that anti-ATL vaccines hold potential as therapeutic options for ATL. The Tax-DC vaccine aims to enhance Tax-specific cytotoxic T lymphocyte (CTL) responses. Clinical trials are currently underway. Another candidate therapeutic vaccine for ATL is known as THV02, which consists of two lentiviral vectors for prime-boost strategies. THV02 has been shown to induce cellular responses in animal models and requires clinical trials to test its efficacy.
Alfa Cytology possesses vast expertise in HTLV-1 virus detection method development and the advancement of antiviral therapeutics. Leveraging our in-depth knowledge of the pathophysiology of ATL, we provide a wide range of services focused on developing therapeutic approaches specifically tailored for ATL. If you have a project in this field or are interested in ATL, we encourage you to contact us for further information.
References
- Yasunaga, J. Strategies of human T-cell leukemia virus type 1 for persistent infection: Implications for leukemogenesis of adult T-cell leukemia-lymphoma. Frontiers in Microbiology. 2020, 11: 979.
- Adkins, B.D.; et al. Updates in lymph node and skin pathology of adult T-cell leukemia/lymphoma, biomarkers, and beyond. Seminars in Diagnostic Pathology. 2020, 37(1): 1-10.
- Cook, L.B.; Phillips A.A. How I treat adult T-cell leukemia/lymphoma. Blood. 2021, 137(4): 459-470.