Cancer/testis antigens are novel targets of immunotherapy for adult T-cell leukemia/lymphoma

Abstract

IntroductionAdult T-cell leukemia/lymphoma (ATLL) is a distinct hematologic malignancy caused by human T-lymphotropic virus type 1 (HTLV-1). 1,2 HTLV-1 is endemic in southwestern Japan, Africa, South America, and the Caribbean Islands, and approximately 20 million people worldwide are infected. 3 A total of 5% of the infected persons develop ATLL after a long latency period. 2 ATLL cells are CD4-positive; and the majority, if not all, of them express the transcription factor FoxP3 (Forkhead Box P3), CD25, CTLA-4, and CCR4 (CC chemokine receptor 4), and are functionally immunosuppressive, thus phenotypically and functionally resembling naturally occurring regulatory T cells (Tregs). [3][4][5][6][7][8][9] Because of its immunosuppressive property and resistance to conventional chemotherapy, aggressive ATLL has a poor prognosis with a mean survival time of less than 1 year. 2,8 A recent phase 3 trial of a dose-intensified multidrug chemotherapy for untreated ATLL patients (acute, lymphoma, and unfavorable chronic types) showed a median progression-free and overall survival of only 7.0 and 12.7 months, respectively. 10 This and other reports indicate that chemotherapy alone is of limited success for ATLL and mostly fails to cure the disease. 10,11 Allogeneic hematopoietic stem cell transplantation has been introduced over the past decade as a potential therapy for ATLL with a long-term remission in only a small fraction of patients who are young, well controlled in disease progression, and have an appropriate stem cell source. 12 More effective strategies to treat ATLL are therefore required.Several HTLV-1 components have been explored as targets for immunotherapy of ATLL. HTLV-1 Tax, which is crucial for ATLL oncogenesis, has generally been considered to be a main target of the host's cellular immune responses. Yet, the frequency of Tax expression in HTLV-1 infected cells reduces in the course of disease progression, and Tax transcripts are detected only in approximately 40% of the established ATLL cases, 13 thus limiting Tax-targeted immunotherapy to a subset of patients. HBZ (HTLV-1 bZIP factor), another HTLV-1 component, which contains an N-terminal transcriptional activation domain and a leucine zipper motif at its C-terminal, also plays an important role in the proliferation of ATLL cells and is detectable in almost all ATLL cases. 2 However, CD8 ϩ T cells specific for HBZ could only recognize peptide-pulsed target cells but not ATLL cells themselves. 14 Furthermore, HTLV-1 is transmitted mainly from mothers to infants through breast milk, and such vertical infection in early life may induce tolerance to the virus and result in insufficient HTLV-1-specific T-cell responses. 15,16 For these reasons, targeting the HTLV-1 components alone may be insufficient for successful immunotherapy of ATLL, necessitating identification of novel tumor-associated target antigens for the immunotherapy.The expression of cancer/testis (CT) antigens, of which more than 100 have been identified so far, is normally limited to human ...

Autologous Tax-Specific CTL Therapy in a Primary Adult T Cell Leukemia/Lymphoma Cell–Bearing NOD/Shi-scid, IL-2Rγnull Mouse Model

“…The tetramer-negative fractions of these expanded CD8-positive cells also produced IFN-g when stimulated with autologous ATL cells. This suggests that they recognize unidentified Tax-derived epitopes, Ags derived from HTLV-1 components other than Tax, or ATL-related tumor Ags not of viral origin such as cancer testis Ags (25). The tetramer-negative fractions of these expanded CD8-positive cells also produced IFN-g when stimulated with TCL-Kan. Because both patient 1 and TCL-Kan share HLA-A*02:07, -B*46:01, and -C*01:02, the tetramer-negative cells might be recognizing unidentified Tax-derived epitopes, other HTLV-1 Ags or ATL tumor Ag-derived epitopes presented on a different shared MHC allele.…”

Novel immunotherapy for adult T-cell leukemia/lymphoma: Targeting aurora kinase A

“…Those difficulties include limited acquisition of suitable and timely donors and comorbidities, resulting in an increased risk of treatment-related mortality. 1 Despite these difficulties, the durable disease-free survival mediated by allo-HSCT strongly suggests that a T-cell immunity-based treatment strategy is valid for the treatment of ATL. As a corollary, target antigens for T cells mediating the anti-ATL effect have been examined, with a particular emphasis on the HLTV-1-related viral proteins.…”

“…However, it is as yet unknown whether Tax and HBZ are sufficiently immunogenic to eradicate ATL tumor cells, particularly as primary ATL tumor cells express both Tax and HBZ proteins at low levels. 1 Instead, tumor-associated antigens that are abundantly expressed by ATL tumor cells have come under scrutiny, as they might offer alternative targets for immunotherapy against ATL. It has been reported that ATL cells express numerous tumor antigens, including NY-ESO-1, MAGE-A3, MAGE-A4, each of which are recognized by T cells.…”

“…1 Although a recently introduced therapeutic agent, mogamulizumab, a monoclonal antibody for anti-C-C chemokine receptor 4 (CCR4), is expected to improve the survival of ATL patients, 2 in daily practice, ATL still remains refractory to conventional chemo-radiotherapies, producing a poor prognosis. 3 On the other hand, allogeneic haematopoietic stem cell transplantation (allo-HSCT) has been favored as a viable option for effective treatment of ATL.…”

“…It has been reported that ATL cells express numerous tumor antigens, including NY-ESO-1, MAGE-A3, MAGE-A4, each of which are recognized by T cells. 1 We previously demonstrated that human Telomerase Reverse Transcriptase (hTERT) is also upregulated in ATL cells, 4 and that circulating hTERT-specific T cells responsive to ATL tumor cells were detectable in the peripheral blood of ATL patients. Unfortunately, we found previously that hTERT peptide vaccination resulted in limited clinical responses.…”