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Review
. 2019 Mar;110(3):849-857.
doi: 10.1111/cas.13948. Epub 2019 Feb 19.

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

Mari Kannagi  1 , Atsuhiko Hasegawa  1 , Yoshiko Nagano  1 , Tadafumi Iino  2 , Jun Okamura  3 , Youko Suehiro  4
Affiliations
Review

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

Mari Kannagi et al. Cancer Sci. 2019 Mar.

Abstract

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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Conflict of interest statement

The authors declare no conflicts of interest for this article.

Figures

Figure 1
Figure 1
Possible dynamics of human T‐cell leukemia virus type 1 (HTLV‐1)‐infected cell clones during adult T‐cell leukemia/lymphoma (ATL) development and allogeneic hematopoietic stem cell transplantation (allo‐HSCT). Asymptomatic HTLV‐1 carriers possess multiple HTLV‐1‐infected cell clones. Impairment of Tax‐specific cytotoxic T cells (CTL) allows expansion of the pool of HTLV‐1‐infected cell clones (A), while it is controlled in the presence of intact Tax‐specific CTL that survey Tax‐expressing infected cells (B). At the onset of ATL, one or several HTLV‐1‐infected clones expand (C). Upon intensive chemotherapy, proliferating malignant ATL cells die (D), but the residual original ATL clones or secondary dominant clones proliferate again at relapse (E). When allo‐HSCT is performed, graft‐versus‐host (GVH) and HTLV‐1‐specific T‐cell responses occur, and recipient hematopoietic cells are eliminated together with residual ATL cells (F). After hematopoietic chimerism is established, Tax‐specific CTL survey newly HTLV‐1‐infected donor‐derived cells, contributing to the maintenance of remission (G)
Figure 2
Figure 2
Development of Tax‐DC vaccine based on findings in adult T‐cell leukemia/lymphoma (ATL) patients after allogeneic hematopoietic stem cell transplantation (allo‐HSCT). Tax‐specific cytotoxic T cells (CTL) are often activated in ATL patients following allo‐HSCT. Some of the major epitopes recognized by Tax‐specific CTL have been identified (left panel).25, 26 The Tax‐DC vaccine was developed by pulsing synthetic Tax oligopeptides corresponding to the CTL epitopes onto autologous monocyte‐derived dendritic cells, and administrated s.c. to ATL patients three times with 2‐wk intervals (right panel)10
Figure 3
Figure 3
Reduction of proviral load by Tax‐DC vaccine in a rat model of human T‐cell leukemia virus type 1 (HTLV‐1) carriers with impaired Tax‐specific cytotoxic T‐cell (CTL) response. In a rat model of immune tolerance to HTLV‐1, oral HTLV‐1 infection induces persistent HTLV‐1 infection with impaired Tax‐specific CTL responses and elevated proviral load (PVL). Tax‐DC vaccine consisting of syngeneic bone marrow‐derived dendritic cells pulsed with synthetic Tax peptide corresponding to the rat Tax‐specific CTL epitope induced Tax‐specific CTL responses (left), and reduced PVL (right) in the 3 wk following vaccination, supporting the notion of a potential prophylactic effect of the Tax‐targeted vaccine on reducing the risk of adult T‐cell leukemia/lymphoma (ATL) (modified from the original article published in the Journal of Immunology. Copyright 2017. The American Association of Immunologists, Inc.)55
Figure 4
Figure 4
Potential position of the Tax‐DC vaccine in currently available adult T‐cell leukemia/lymphoma (ATL) therapies. Among currently available anti‐ATL therapies, allogeneic hematopoietic stem cell transplantation (allo‐HSCT) invokes host immunity against ATL, while other therapies reduce ATL cells. Mogamulizumab and lenalidomide also have immunomodulatory effects to support T‐cell immunity without specificity. Tax‐DC vaccine activates Tax‐specific cytotoxic T cells (CTL) to maintain remission when used after other initial therapies. It may also be an appropriate therapy for earlier stages of ATL and potentially contribute to prophylactic strategies against ATL in the future, because of its limited toxicity. Approved (solid line) and not‐approved (dotted line) usages in Japan are shown. HAM‐TSP, HTLV‐1‐associated myelopathy/tropical spastic paraparesis; IFN‐α/AZT, interferon‐α and azidothymidine; HTLV‐1, human T‐cell leukemia virus type 1
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