HTLV-1 Tax-Specific CTL Epitope–Pulsed Dendritic Cell Therapy Reduces Proviral Load in Infected Rats with Immune Tolerance against Tax

Andò, Sebastiano; Hasegawa, Atsuhiko; Murakami, Yuji; Zeng, Na; Takatsuka, Natsuko; Maeda, Yasuhiro; Masuda, Tohru; Suehiro, Yutaka; Kannagi, Mari

doi:10.4049/jimmunol.1601557

Cited by 10 publications

(9 citation statements)

References 48 publications

(47 reference statements)

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“…In a rat model of oral HTLV‐1 infection, HTLV‐1‐specific T‐cell tolerance was established with higher PVL than in rats infected through other routes, resembling the situation in HTLV‐1 carriers with impaired CTL responses. This was resolved by Tax‐DC vaccination, resulting in activation of Tax‐specific CTL responses and reduced HTLV‐1 PVL (Figure ) . This observation supports the idea of prophylactic use of Tax‐targeted vaccines in HTLV‐1 carriers with impaired Tax‐specific CTL responses.…”

Section: Tax‐targeted Vaccine As a Potential Early And/or Prophylactisupporting

confidence: 71%

Maintenance of long remission in adult T‐cell leukemia by Tax‐targeted vaccine: A hope for disease‐preventive therapy

et al. 2019

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Adult T‐cell leukemia/lymphoma (ATL) is an aggressive lymphoproliferative disease caused by human T‐cell leukemia virus type 1 (HTLV‐1). Multi‐agent chemotherapy can reduce ATL cells but frequently allows relapses within a short period of time. Allogeneic hematopoietic stem cell transplantation (allo‐HSCT) following chemotherapy is now a standard therapy for ATL in Japan as it can achieve long‐term remission in approximately one‐third of recipient ATL patients; however, it also has a risk of treatment‐related mortality. Allo‐HSCT often induces HTLV‐1 Tax‐specific cytotoxic T cells (CTL) as well as graft‐versus‐host (GVH) response in ATL patients. This observation led to development of a new therapeutic vaccine to activate Tax‐specific CTL, anticipating anti‐ATL effects without GVH response. The newly developed Tax‐DC vaccine consists of autologous dendritic cells pulsed with Tax peptides corresponding to CTL epitopes that have been identified in post‐allo‐HSCT ATL patients. In a pilot study of Tax‐DC therapy in three ATL patients after various initial therapies, two patients survived for more than 4 years after vaccination without severe adverse effects (UMIN000011423). The Tax‐DC vaccine is currently under phase I trial, showing a promising clinical outcome so far. These findings indicate the importance of patients’ own HTLV‐1‐specific T‐cell responses in maintaining remission and provide a new approach to anti‐ATL immunotherapy targeting Tax. Although Tax‐targeted vaccination is ineffective against Tax‐negative ATL cells, it can be a safe alternative maintenance therapy for Tax‐positive ATL and may be further applicable for treatment of indolent ATL or even prophylaxis of ATL development among HTLV‐1‐carriers.

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Section: Tax‐targeted Vaccine As a Potential Early And/or Prophylactisupporting

confidence: 71%

Maintenance of long remission in adult T‐cell leukemia by Tax‐targeted vaccine: A hope for disease‐preventive therapy

et al. 2019

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“…Promising new therapies include vorinostat and romidepsin (histone deacetylase inhibitors), alemtazumab (anti-CD52 antibody), and brentuximab vedotin (anti-CD30 antibody) [ 468 ]. A recent animal model indicated that pulsed dendritic cell therapy may decrease PVL by stimulating HTLV-1 responsive cytotoxic lymphocytes [ 469 ]. A pilot clinical trial using belinostat in combination with AZT-based maintenance therapy for aggressive leukemic ATL types is currently underway (NCT02737046).…”

Section: Human T-cell Lymphotropic Virus-1mentioning

confidence: 99%

Viral Oncology: Molecular Biology and Pathogenesis

Mui

Haley

Tyring

2017

JCM

137

147

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Oncoviruses are implicated in approximately 12% of all human cancers. A large number of the world’s population harbors at least one of these oncoviruses, but only a small proportion of these individuals go on to develop cancer. The interplay between host and viral factors is a complex process that works together to create a microenvironment conducive to oncogenesis. In this review, the molecular biology and oncogenic pathways of established human oncoviruses will be discussed. Currently, there are seven recognized human oncoviruses, which include Epstein-Barr Virus (EBV), Human Papillomavirus (HPV), Hepatitis B and C viruses (HBV and HCV), Human T-cell lymphotropic virus-1 (HTLV-1), Human Herpesvirus-8 (HHV-8), and Merkel Cell Polyomavirus (MCPyV). Available and emerging therapies for these oncoviruses will be mentioned.

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“…These ACs may be the possible target population for prophylactic therapy. In a rat model of oral HTLV-1 infection with immune tolerance, Tax-DC vaccine successfully induced Tax-specific CTLs and reduced the HTLV-1 proviral load, suggesting the promising prophylactic potential of Tax-targeting vaccines against ATL [127].…”

Section: Significance Of Tax-targeted Therapeutic Vaccine In the Antimentioning

confidence: 99%

Impact of host immunity on HTLV-1 pathogenesis: potential of Tax-targeted immunotherapy against ATL

et al. 2019

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Human T-cell leukemia virus type-1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATL), HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and other inflammatory diseases. There is no disease-specific difference in viral strains, and it is unclear how HTLV-1 causes such different diseases manifesting as lymphoproliferation or inflammation. Although some progress has been made in therapies for these diseases, the prognosis for ATL is still dismal and HAM/TSP remains an intractable disease. So far, two regulatory proteins of HTLV-1, Tax and HBZ, have been well studied and shown to have pleiotropic functions implicated in viral pathogenesis. Tax in particular can strongly activate NFκB, which is constitutively activated in HTLV-1-infected cells and considered to contribute to both oncogenesis and inflammation. However, the expression level of Tax is very low in vivo, leading to confusion in understanding its role in viral pathogenesis. A series of studies using IL-2-dependent HTLV-1-infected cells indicated that IL-10, an anti-inflammatory/immune suppressive cytokine, could induce a proliferative phenotype in HTLV-1-infected cells. In addition, type I interferon (IFN) suppresses HTLV-1 expression in a reversible manner. These findings suggest involvement of host innate immunity in the switch between lymphoproliferative and inflammatory diseases as well as the regulation of HTLV-1 expression. Innate immune responses also affect another important host determinant, Tax-specific cytotoxic T lymphocytes (CTLs), which are impaired in ATL patients, while activated in HAM/TSP patients. Activation of Tax-specific CTLs in ATL patients after hematopoietic stem cell transplantation indicates Tax expression and its fluctuation in vivo. A recently developed anti-ATL therapeutic vaccine, consisting of Tax peptide-pulsed dendritic cells, induced Tax-specific CTL responses in ATL patients and exhibited favorable clinical outcomes, unless Tax-defective ATL clones emerged. These findings support the significance of Tax in HTLV-1 pathogenesis, at least in part, and encourage Tax-targeted immunotherapy in ATL. Host innate and acquired immune responses induce host microenvironments that modify HTLV-1-encoded pathogenesis and establish a complicated network for development of diseases in HTLV-1 infection. Both host and viral factors should be taken into consideration in development of therapeutic and prophylactic strategies in HTLV-1 infection.

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HTLV-1 Tax-Specific CTL Epitope–Pulsed Dendritic Cell Therapy Reduces Proviral Load in Infected Rats with Immune Tolerance against Tax

Cited by 10 publications

References 48 publications

Maintenance of long remission in adult T‐cell leukemia by Tax‐targeted vaccine: A hope for disease‐preventive therapy

Maintenance of long remission in adult T‐cell leukemia by Tax‐targeted vaccine: A hope for disease‐preventive therapy

Viral Oncology: Molecular Biology and Pathogenesis

Impact of host immunity on HTLV-1 pathogenesis: potential of Tax-targeted immunotherapy against ATL

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