Recent Advance in Antigen-Specific Immunotherapy for Acute Myeloid Leukemia

Relapse after chemotherapy is inevitable in the majority of patients with acute myeloid leukemia (AML). Thus, it is necessary to develop novel therapies that have different antileukemic mechanisms. Recent advances in immunology and identification of promising leukemia-associated antigens open the possibilities for eradicating minimal residual diseases by antigen-specific immunotherapy after chemotherapy. Several methods have been pursued as immunotherapies for AML: peptide vaccines, granulocyte-macrophage colony-stimulating factor-secreting tumor vaccines, dendritic cell vaccines, and adoptive T cell therapy. Whereas immunogenicity and clinical outcomes are improving in these trials, severe adverse events were observed in highly avid engineered T cell therapies, indicating the importance of the balance between effectiveness and side effects in advanced immunotherapy. Such progress in inducing antitumor immune responses, together with strategies to attenuate immunosuppressive factors, will establish immunotherapy as an important armament to combat AML

Programmed cell death 1‐expressing CD56‐negative natural killer (NK) cell expansion is a hallmark of chronic NK cell activation during dasatinib treatment

Dasatinib treatment markedly increases the number of large granular lymphocytes including natural killer (NK) cells in a proportion of Ph+ leukemia patients, which associates with a better prognosis. In-depth immune profiling of NK cells can predict therapeutic response in these patients. In the present study, we showed that CD56-negative (CD56neg) NK cells increased exclusively in cytomegalovirus-seropositive (CMV+) patients treated with dasatinib. The increase longitudinally paralleled with progressive differentiation of CD56dim NK cells during dasatinib therapy driven by CMV reactivation as shown by principal component analysis on 19 NK cell markers. The CD56neg NK cells showed downregulation of NK-activating receptors, upregulation of PD-1, and lower cytotoxicity and cytokine production, indicating that these cells are anergic and dysfunctional as seen in chronic infections with HIV-1 or hepatitis C virus. Moreover, cytolytic activity of CD56dim and CD56neg NK cells against leukemia cells was partially restored by nivolumab in proportion to the frequency of PD-1+ NK cells. The proportion of patients who achieved deep molecular responses at 2 years was significantly higher in dasatinib-treated patients with ≥3% CD56neg NK cells than in those with fewer CD56neg NK cells (54.5% vs 15.8%, P = .0419). These findings suggest that CD56neg NK cells may be an exhausted population induced by chronic activation through CMV reactivation during dasatinib therapy. Expansion of CD56neg NK cells is a hallmark of chronic NK cell activation in patients treated with dasatinib and may predict a better clinical outcome. Furthermore, PD-1 blockade may enhance anti-leukemia responses of such NK cells

The CD70-CD27 interaction during the stimulation with dendritic cells promotes naive CD4+ T cells to develop into T cells producing a broad array of immunostimulatory cytokines in humans

CD70 expressed on dendritic cells (DCs) has been shown to play a critical role in inducing effective CD8+ T cell responses and a Th1 response in mice. However, it has not been extensively examined whether human primary DCs express CD70 and whether the CD70–CD27 interaction promotes naive CD4+ T cells to acquire the ability to produce effector cytokines during the DC–T cell interaction in humans. Here, we show that human myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells stimulated with CD40 ligand together with pro-inflammatory cytokines or Toll-like receptor ligands express CD70. Thymic stromal lymphopoietin plus prostaglandin E2 also induced CD70 on mDCs. Naive CD4+ T cells stimulated with DCs but not with anti-CD3/CD28 microbeads expressed CD70. Stimulation with CD70 together with anti-CD3/CD28 microbeads imparted the ability to produce Th1 (IFN-), Th2 (IL-4, IL-5, IL-13) cytokines, IL-2 and tumor necrosis factor- to naive CD4+ T cells. The production of IFN- was associated with the induction of T-bet. Naive CD4+ T cells stimulated with mDCs acquired an enhanced ability to produce a broad array of immunostimulatory cytokines in a CD70-dependent manner. These data suggest that human CD70 expressed on mDCs and activated T cells transmits a ‘basal level’ signal, rather than a ‘polarizing’ signal, to naive CD4+ T cells, in that CD70 promotes the development of CD4+ T cells that produce a variety of effector cytokines including both Th1 and Th2 types, thus contributing to the enhancement of a broad spectrum of immune responses

Central Nervous System Peripheral T Cell Lymphoma Manifesting as Lymphomatosis Cerebri That Was Misdiagnosed as Neuro-Behçet’s Disease: A Case Report

Background: Lymphomatosis cerebri (LC) is a unique form of primary central nerves lymphoma (PCNSL), which presents as diffuse infiltration of lymphoma cells characteristically in the white matter rather than tumor formation. However, the involvement of central nervous system (CNS) is unclear because of the lack of contrast enhancement. Case Presentation: We treated a 53-year-old woman with LC and brain lesions resembling neuro-Behcet’s disease. She had a past history of acute uveitis and current symptoms of somnolence and gait disturbances progressing for one month. Cranial magnetic resonance imaging (MRI) revealed high signal lesions in the brain stem. Based on her past history and present clinical findings, she was clinically diagnosed with neuro-Behcet’s disease, which was treated with 1 g of methylprednisolone (mPSL) pulse therapy. Repeated mPSL pulse therapy resulted in a minor response, but the cerebral lesions persisted. After a short remission of several months, signal changes of the brain stem lesion recurred and her consciousness level worsened at 4 months after diagnosis. Upon admission to our hospital, positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro-D-glucose integrated with computed tomography revealed abnormal uptake in the systemic lymph nodes (LNs), including the bilateral inguinal LNs. A diagnosis based on a biopsy of the left inguinal LNs was primary central nervous system lymphoma with inguinal LN lesions, manifesting as LC from malignant peripheral T cell lymphoma, not otherwise specified. Four courses of high-dose methotrexate (3.5 g/m2) therapy lead to temporary recovery of consciousness, but there was no improvement in other neurological findings. All nodal lesions tentatively regressed. Serum soluble interleukin-2 receptor (sIL-2R) (normal range: 121–613 U/mL) was constitutively decreased from 8,520 U/mL before chemotherapy to 740 U/mL after chemotherapy. We observed cerebral micro-bleeds in the center of LC lesions during chemotherapy, but no surgical intervention was required. Two months later, LC recurred in the brain, which was fatal. Conclusions: Neuro-Behçet’s disease is difficult to distinguish from LC when other clinical findings, including human leukocyte antigen disparity, serum sIL-2R, or cerebrospinal IL-6, are lacking. LC should be differentiated from CNS lymphoma before corticosteroid therapy

Distinct Cytokine Profiles of Neonatal Natural Killer T Cells after Expansion with Subsets of Dendritic Cells

Natural killer T (NKT) cells are a highly conserved subset of T cells that have been shown to play a critical role in suppressing T helper cell type 1–mediated autoimmune diseases and graft versus host disease in an interleukin (IL)-4–dependent manner. Thus, it is important to understand how the development of IL-4– versus interferon (IFN)-γ–producing NKT cells is regulated. Here, we show that NKT cells from adult blood and those from cord blood undergo massive expansion in cell numbers (500–70,000-fold) during a 4-wk culture with IL-2, IL-7, phytohemagglutinin, anti-CD3, and anti-CD28 mAbs. Unlike adult NKT cells that preferentially produce both IL-4 and IFN-γ, neonatal NKT cells preferentially produce IL-4 after polyclonal activation. Addition of type 2 dendritic cells (DC2) enhances the development of neonatal NKT cells into IL-4+IFN-γ− NKT2 cells, whereas addition of type 1 dendritic cells (DC1) induces polarization towards IL-4−IFN-γ+ NKT1 cells. Adult NKT cells display limited plasticity for polarization induced by DC1 or DC2. Thus, newly generated NKT cells may possess the potent ability to develop into IL-4+IFN-γ− NKT2 cells in response to appropriate stimuli and may thereafter acquire the tendency to produce both IL-4 and IFN-γ

Dendritic Cells—A Conductor of T Cell Differentiation—

Induction of different types of adaptive immune responses depending on the nature of antigens and the environmental context is crucial to cope with a variety of pathogens and concurrently to avoid pathological reaction to self antigens. Recent studies have been elucidating that the diversity of immune responses is critically controlled by dendritic cells (DCs). Two DC subsets have been identified in humans: myeloid DCs and plasmacytoid DCs. The DC subsets induce different types of adaptive immune responses depending on environmental factors. Interleukin (IL)-12 from myeloid DCs is a dominant factor for the induction of a Th1 response, whereas OX40 ligand on myeloid DCs is important for the induction of a Th2 response. Furthermore, inducible costimulator (ICOS) ligand on plasmacytoid DCs is critical for the induction of IL-10-producing regulatory T cells. Elucidating cellular and molecular mechanisms by which functions of the two DC subsets are modulated will lead to understanding the pathogenesis of various immune-related diseases and to developing novel immunological therapies