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Journal of Hematology & Oncology Jul 2023The rapidly increasing use of high-throughput screening had produced a plethora of expanding knowledge on the molecular basis of natural killer/T-cell lymphoma (NKTCL),... (Review)
Review
The rapidly increasing use of high-throughput screening had produced a plethora of expanding knowledge on the molecular basis of natural killer/T-cell lymphoma (NKTCL), which in turn has revolutionized the treatment. Specifically, the use of asparaginase-containing regimens has led to substantial improvement in survival outcomes in NKTCL patients. Novel treatment strategies that are currently under development include cell-surface-targeted antibodies, immune checkpoint inhibitors, Epstein-Barr virus targeted cytotoxic T lymphocyte, immunomodulatory agents, chimeric antigen receptor T cells, signaling pathway inhibitors and epigenetic targeted agents. In almost all cases, initial clinical studies of newly developed treatment are conducted in patients relapsed, and refractory NKTCL due to very limited treatment options. This review summarizes the results of these novel treatments for NKTCL and discusses their potential for likely use in NKTCL in a wider setting in the future.
Topics: Humans; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Lymphoma; Lymphoma, T-Cell; Killer Cells, Natural
PubMed: 37480137
DOI: 10.1186/s13045-023-01483-9 -
Nature Cancer Jan 2024In pancreatic ductal adenocarcinoma (PDAC), glutamine is a critical nutrient that drives a wide array of metabolic and biosynthetic processes that support tumor growth....
In pancreatic ductal adenocarcinoma (PDAC), glutamine is a critical nutrient that drives a wide array of metabolic and biosynthetic processes that support tumor growth. Here, we elucidate how 6-diazo-5-oxo-L-norleucine (DON), a glutamine antagonist that broadly inhibits glutamine metabolism, blocks PDAC tumor growth and metastasis. We find that DON significantly reduces asparagine production by inhibiting asparagine synthetase (ASNS), and that the effects of DON are rescued by asparagine. As a metabolic adaptation, PDAC cells upregulate ASNS expression in response to DON, and we show that ASNS levels are inversely correlated with DON efficacy. We also show that L-asparaginase (ASNase) synergizes with DON to affect the viability of PDAC cells, and that DON and ASNase combination therapy has a significant impact on metastasis. These results shed light on the mechanisms that drive the effects of glutamine mimicry and point to the utility of cotargeting adaptive responses to control PDAC progression.
Topics: Humans; Glutamine; Asparagine; Cell Line, Tumor; Asparaginase; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Neoplastic Processes
PubMed: 37814011
DOI: 10.1038/s43018-023-00649-1 -
Science Advances Dec 2023Myeloid/natural killer (NK) cell precursor acute leukemia (MNKPL) has been described on the basis of its unique immunophenotype and clinical phenotype. However, there is...
Myeloid/natural killer (NK) cell precursor acute leukemia (MNKPL) has been described on the basis of its unique immunophenotype and clinical phenotype. However, there is no consensus on the characteristics for identifying this disease type because of its rarity and lack of defined distinctive molecular characteristics. In this study, multiomics analysis revealed that MNKPL is distinct from acute myeloid leukemia, T cell acute lymphoblastic leukemia, and mixed-phenotype acute leukemia (MPAL), and and activation and down-regulation are hallmarks of MNKPL. Although NK cells have been classically considered to be lymphoid lineage-derived, the results of our single-cell analysis using MNKPL cells suggest that NK cells and myeloid cells share common progenitor cells. Treatment outcomes for MNKPL are unsatisfactory, even when hematopoietic cell transplantation is performed. Multiomics analysis and in vitro drug sensitivity assays revealed increased sensitivity to l-asparaginase and reduced levels of asparagine synthetase (ASNS), supporting the clinically observed effectiveness of l-asparaginase.
Topics: Humans; Asparaginase; Leukemia, Myeloid, Acute; Acute Disease; Killer Cells, Natural; Treatment Outcome; Repressor Proteins; Tumor Suppressor Proteins
PubMed: 38091391
DOI: 10.1126/sciadv.adj4407 -
IScience Nov 2023Natural killer (NK)/T cell lymphoma (NKTCL) is a rare subtype of Epstein-Barr virus (EBV)-associated non-Hodgkin lymphoma characterized by poor clinical outcomes. It is... (Review)
Review
Natural killer (NK)/T cell lymphoma (NKTCL) is a rare subtype of Epstein-Barr virus (EBV)-associated non-Hodgkin lymphoma characterized by poor clinical outcomes. It is more common in East Asian and Latin American countries. Despite the introduction of asparaginase/pegaspargase-based chemotherapy, the prognosis of patients with advanced NKTCL needs to be improved, and few salvage treatment options are available for relapsed/refractory patients who fail chemotherapy. Although many unknowns remain, novel treatment strategies to further improve outcomes are urgently needed. Immunotherapy has emerged and shown favorable antitumor activity in NKTCL, including monoclonal antibodies targeting immune checkpoint inhibitors, other receptors on the cellular membrane, and cellular immunotherapy, which could enhance immune cells attack on tumor cells. In this review, we provide an overview of recent immunotherapy in NKTCL, focusing on programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1), cytotoxic T lymphocyte-associated protein 4 (CTLA-4), chimeric antigen receptor (CAR) T cells, EBV-specific cytotoxic T lymphocytes, immunomodulatory agents, and other targeted agents, as well as the current progress and challenges in the field.
PubMed: 38026157
DOI: 10.1016/j.isci.2023.108192 -
Leukemia Sep 2023Polyethylene glycol (PEG)-asparaginase (pegaspargase) is a key agent in chemotherapy for acute lymphoblastic leukemia (ALL), but recipients frequently experience... (Randomized Controlled Trial)
Randomized Controlled Trial
Polyethylene glycol (PEG)-asparaginase (pegaspargase) is a key agent in chemotherapy for acute lymphoblastic leukemia (ALL), but recipients frequently experience allergic reactions. We hypothesized that by decreasing antibody-producing CD20-positive B cells, rituximab may reduce these reactions. Children and adolescents (aged 1-18 years) with newly diagnosed B-ALL treated on the St. Jude Total XVII study were randomized to induction therapy with or without rituximab on day 3 (cohort 1) or on days 6 and 24 (cohort 2). Patient clinical demographics, CD20 expression, minimal residual disease (MRD), rituximab reactions, pegaspargase allergy, anti-pegaspargase antibodies, and pancreatitis were evaluated. Thirty-five patients received rituximab and 37 did not. Among the 35 recipients, 16 (45.7%) experienced a grade 2 or higher reaction to rituximab. There were no differences between recipients and non-recipients in the incidence of pegaspargase reactions (P > 0.999), anti-pegaspargase antibodies (P = 0.327), or pancreatitis (P = 0.480). CD20 expression on day 8 was significantly lower in rituximab recipients (P < 0.001), but there were no differences in MRD levels on day 8, 15, or at the end of induction. Rituximab administration during induction in pediatric patients with B-ALL was associated with a high incidence of infusion reactions with no significant decrease in pegaspargase allergies, anti-pegaspargase antibodies, or MRD.
Topics: Adolescent; Child; Humans; Rituximab; Asparaginase; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Polyethylene Glycols; Pancreatitis; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Antineoplastic Combined Chemotherapy Protocols; Antineoplastic Agents
PubMed: 37543655
DOI: 10.1038/s41375-023-01992-z