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Nature Communications Apr 2024Hematopoietic stem cell gene therapy (GT) using a γ-retroviral vector (γ-RV) is an effective treatment for Severe Combined Immunodeficiency due to Adenosine Deaminase...
Hematopoietic stem cell gene therapy (GT) using a γ-retroviral vector (γ-RV) is an effective treatment for Severe Combined Immunodeficiency due to Adenosine Deaminase deficiency. Here, we describe a case of GT-related T-cell acute lymphoblastic leukemia (T-ALL) that developed 4.7 years after treatment. The patient underwent chemotherapy and haploidentical transplantation and is currently in remission. Blast cells contain a single vector insertion activating the LIM-only protein 2 (LMO2) proto-oncogene, confirmed by physical interaction, and low Adenosine Deaminase (ADA) activity resulting from methylation of viral promoter. The insertion is detected years before T-ALL in multiple lineages, suggesting that further hits occurred in a thymic progenitor. Blast cells contain known and novel somatic mutations as well as germline mutations which may have contributed to transformation. Before T-ALL onset, the insertion profile is similar to those of other ADA-deficient patients. The limited incidence of vector-related adverse events in ADA-deficiency compared to other γ-RV GT trials could be explained by differences in transgenes, background disease and patient's specific factors.
Topics: Humans; Adenosine Deaminase; Genetic Therapy; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Mas; Severe Combined Immunodeficiency; Genetic Vectors; Hematopoietic Stem Cell Transplantation; Agammaglobulinemia; Male; Retroviridae
PubMed: 38688902
DOI: 10.1038/s41467-024-47866-5 -
Medicina Clinica Apr 2024
PubMed: 38688737
DOI: 10.1016/j.medcli.2024.01.020 -
Immunogenetics Jun 2024Hypogammaglobulinemia without B-cells is a subgroup of inborn errors of immunity (IEI) which is characterized by a significant decline in all serum immunoglobulin...
Hypogammaglobulinemia without B-cells is a subgroup of inborn errors of immunity (IEI) which is characterized by a significant decline in all serum immunoglobulin isotypes, coupled with a pronounced reduction or absence of B-cells. Approximately 80 to 90% of individuals exhibit genetic variations in Bruton's agammaglobulinemia tyrosine kinase (BTK), whereas a minority of cases, around 5-10%, are autosomal recessive agammaglobulinemia (ARA). Very few cases are grouped into distinct subcategories. We evaluated phenotypically and genetically 27 patients from 13 distinct families with hypogammaglobinemia and no B-cells. Genetic analysis was performed via whole-exome and Sanger sequencing. The most prevalent genetic cause was mutations in BTK. Three novel mutations in the BTK gene include c.115 T > C (p. Tyr39His), c.685-686insTTAC (p.Asn229llefs5), and c.163delT (p.Ser55GlnfsTer2). Our three ARA patients include a novel homozygous stop-gain mutation in the immunoglobulin heavy constant Mu chain (IGHM) gene, a novel frameshift mutation of the B-cell antigen receptor complex-associated protein (CD79A) gene, a novel bi-allelic stop-gain mutation in the transcription factor 3 (TCF3) gene. Three patients with agammaglobulinemia have an autosomal dominant inheritance pattern, which includes a missense variant in PIK3CD, a novel missense variant in PIK3R1 and a homozygous silent mutation in the phosphoinositide-3-kinase regulatory subunit (RASGRP1) gene. This study broadens the genetic spectrum of hypogammaglobulinemia without B-cells and presented a few novel variants within the Iranian community, which may also have implications in other Middle Eastern populations. Notably, disease control was better in the second affected family member in families with multiple cases.
Topics: Humans; Agammaglobulinemia; Male; B-Lymphocytes; Female; Agammaglobulinaemia Tyrosine Kinase; Registries; Child; Child, Preschool; Mutation; Adolescent; Infant; Pedigree; Class Ia Phosphatidylinositol 3-Kinase
PubMed: 38683392
DOI: 10.1007/s00251-024-01342-y -
Anticancer Research May 2024The treatment for chronic lymphocytic leukemia (CLL) has changed dramatically over the last two decades. The current study aimed to investigate the impact on overall...
BACKGROUND/AIM
The treatment for chronic lymphocytic leukemia (CLL) has changed dramatically over the last two decades. The current study aimed to investigate the impact on overall survival (OS) and time to next treatment (TTT) among CLL patients from 1998 to 2022.
PATIENTS AND METHODS
The cohort was based on data obtained from electronic medical records of Maccabi, the second largest healthcare organization in Israel. All included patients were diagnosed with CLL based on the IWCLL criteria and complete clinical, laboratory, and treatment data were available. The study encompassed 3,964 patients diagnosed with CLL during the specified study period.
RESULTS
Patients with CLL who required therapy were divided into three eras based on the dominant treatment approach: chemotherapy alone before 2010, therapy with chemotherapy and anti-CD20 between 2010 and 2017, and therapy with targeted agents between 2017 and 2022. Median OS was 4.1 years, 7.5 years, and not reached, respectively. The six-year OS rates were 40%, 55%, and 69%, respectively, (p=0.0001). The median time to the next treatment improved from 5.5 years before 2010, to 8.3 between 2010-2017, to not reached after 2017 (p=0.0021).
CONCLUSION
Marked improvements in survival subsequent to fundamental changes in first-line therapy were found in patients with CLL from before 2010 to after 2017.
Topics: Female; Humans; Male; Agammaglobulinaemia Tyrosine Kinase; Israel; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Targeted Therapy; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Retrospective Studies
PubMed: 38677726
DOI: 10.21873/anticanres.17016 -
Journal of Clinical Immunology Apr 2024A patient with X-linked agammaglobulinemia (XLA) and severe tick-borne encephalitis (TBE) was treated with TBE virus (TBEV) IgG positive plasma. The patient's clinical...
PURPOSE
A patient with X-linked agammaglobulinemia (XLA) and severe tick-borne encephalitis (TBE) was treated with TBE virus (TBEV) IgG positive plasma. The patient's clinical response, humoral and cellular immune responses were characterized pre- and post-infection.
METHODS
ELISA and neutralisation assays were performed on sera and TBEV PCR assay on sera and cerebrospinal fluid. T cell assays were conducted on peripheral blood the patient and five healthy vaccinated controls.
RESULTS
The patient was admitted to the hospital with headache and fever. He was not vaccinated against TBE but receiving subcutaneous IgG-replacement therapy (IGRT). TBEV IgG antibodies were low-level positive (due to scIGRT), but the TBEV IgM and TBEV neutralisation tests were negative. During hospitalisation his clinical condition deteriorated (Glasgow coma scale 3/15) and he was treated in the ICU with corticosteroids and external ventricular drainage. He was then treated with plasma containing TBEV IgG without apparent side effects. His symptoms improved within a few days and the TBEV neutralisation test converted to positive. Robust CD8 T cell responses were observed at three and 18-months post-infection, in the absence of B cells. This was confirmed by tetramers specific for TBEV.
CONCLUSION
TBEV IgG-positive plasma given to an XLA patient with TBE without evident adverse reactions may have contributed to a positive clinical outcome. Similar approaches could offer a promising foundation for researching therapeutic options for patients with humoral immunodeficiencies. Importantly, a robust CD8 T cell response was observed after infection despite the lack of B cells and indicates that these patients can clear acute viral infections and could benefit from future vaccination programs.
Topics: Humans; Encephalitis, Tick-Borne; Male; Agammaglobulinemia; Encephalitis Viruses, Tick-Borne; Genetic Diseases, X-Linked; Immunoglobulin G; Antibodies, Viral; T-Lymphocytes; Treatment Outcome; Adult; Immunization, Passive
PubMed: 38676861
DOI: 10.1007/s10875-024-01718-5 -
Journal of Clinical Immunology Apr 2024Patients with adenosine deaminase 1 deficient severe combined immunodeficiency (ADA-SCID) are initially treated with enzyme replacement therapy (ERT) with polyethylene...
PURPOSE
Patients with adenosine deaminase 1 deficient severe combined immunodeficiency (ADA-SCID) are initially treated with enzyme replacement therapy (ERT) with polyethylene glycol-modified (PEGylated) ADA while awaiting definitive treatment with hematopoietic stem cell transplant (HSCT) or gene therapy. Beginning in 1990, ERT was performed with PEGylated bovine intestinal ADA (ADAGEN®). In 2019, a PEGylated recombinant bovine ADA (Revcovi®) replaced ADAGEN following studies in older patients previously treated with ADAGEN for many years. There are limited longitudinal data on ERT-naïve newborns treated with Revcovi.
METHODS
We report our clinical experience with Revcovi as initial bridge therapy in three newly diagnosed infants with ADA-SCID, along with comprehensive biochemical and immunologic data.
RESULTS
Revcovi was initiated at twice weekly dosing (0.2 mg/kg intramuscularly), and monitored by following plasma ADA activity and the concentration of total deoxyadenosine nucleotides (dAXP) in erythrocytes. All patients rapidly achieved a biochemically effective level of plasma ADA activity, and red cell dAXP were eliminated within 2-3 months. Two patients reconstituted B-cells and NK-cells within the first month of ERT, followed by naive T-cells one month later. The third patient reconstituted all lymphocyte subsets within the first month of ERT. One patient experienced declining lymphocyte counts with improvement following Revcovi dose escalation. Two patients developed early, self-resolving thrombocytosis, but no thromboembolic events occurred.
CONCLUSION
Revcovi was safe and effective as initial therapy to restore immune function in these newly diagnosed infants with ADA-SCID, however, time course and degree of reconstitution varied. Revcovi dose may need to be optimized based on immune reconstitution, clinical status, and biochemical data.
Topics: Animals; Female; Humans; Infant; Infant, Newborn; Male; Adenosine Deaminase; Agammaglobulinemia; Enzyme Replacement Therapy; Immune Reconstitution; Recombinant Proteins; Severe Combined Immunodeficiency; Treatment Outcome
PubMed: 38676811
DOI: 10.1007/s10875-024-01710-z -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Apr 2024Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) is a relatively inert B lymphocyte proliferative disease. In recent years with the launch of new... (Review)
Review
Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) is a relatively inert B lymphocyte proliferative disease. In recent years with the launch of new drugs, chemotherapy has been gradually replaced by targeted therapy, which significantly prolongs the survival of patients and reduces the side effects of treatment. At present, BTK inhibitors, PI3K inhibitors, spleen tyrosine kinase (SYK) inhibitors and BCL-2 inhibitors are the most studied targeted therapeutic drugs for CLL/SLL. This article reviews the research progress of different types of targeted therapeutic drugs in the treatment of CLL/SLL.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Targeted Therapy; Syk Kinase; Agammaglobulinaemia Tyrosine Kinase; Proto-Oncogene Proteins c-bcl-2; Protein Kinase Inhibitors; Antineoplastic Agents; Phosphoinositide-3 Kinase Inhibitors
PubMed: 38660880
DOI: 10.19746/j.cnki.issn.1009-2137.2024.02.049 -
Acta Neuropathologica Apr 2024In multiple sclerosis (MS), persisting disability can occur independent of relapse activity or development of new central nervous system (CNS) inflammatory lesions,...
In multiple sclerosis (MS), persisting disability can occur independent of relapse activity or development of new central nervous system (CNS) inflammatory lesions, termed chronic progression. This process occurs early and it is mostly driven by cells within the CNS. One promising strategy to control progression of MS is the inhibition of the enzyme Bruton's tyrosine kinase (BTK), which is centrally involved in the activation of both B cells and myeloid cells, such as macrophages and microglia. The benefit of BTK inhibition by evobrutinib was shown as we observed reduced pro-inflammatory activation of microglia when treating chronic experimental autoimmune encephalomyelitis (EAE) or following the adoptive transfer of activated T cells. Additionally, in a model of toxic demyelination, evobrutinib-mediated BTK inhibition promoted the clearance of myelin debris by microglia, leading to an accelerated remyelination. These findings highlight that BTK inhibition has the potential to counteract underlying chronic progression of MS.
Topics: Animals; Female; Mice; Agammaglobulinaemia Tyrosine Kinase; Biphenyl Compounds; Encephalomyelitis, Autoimmune, Experimental; Mice, Inbred C57BL; Microglia; Myelin Sheath; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Remyelination
PubMed: 38656399
DOI: 10.1007/s00401-024-02730-0 -
Frontiers in Immunology 2024Sepsis is a systemic inflammatory response to a severe, life-threatening infection with organ dysfunction. Although there is no effective treatment for this fatal...
Sepsis is a systemic inflammatory response to a severe, life-threatening infection with organ dysfunction. Although there is no effective treatment for this fatal illness, a deeper understanding of the pathophysiological basis of sepsis and its underlying mechanisms could lead to the development of new treatment approaches. Here, we demonstrate that the selective Bruton's tyrosine kinase (Btk) inhibitor acalabrutinib augments survival rates in a lipopolysaccharide (LPS)-induced septic model. Our and findings both indicate that acalabrutinib reduces IL-6 production specifically in marginal zone B (MZ B) cells rather than in macrophages. Furthermore, Btk-deficient MZ B cells exhibited suppressed LPS-induced IL-6 production . Nuclear factor-kappa B (NF-κB) signaling, which is the downstream signaling cascade of Toll-like receptor 4 (TLR4), was also severely attenuated in Btk-deficient MZ B cells. These findings suggest that Btk blockade may prevent sepsis by inhibiting IL-6 production in MZ B cells. In addition, although Btk inhibition may adversely affect B cell maturation and humoral immunity, antibody responses were not impaired when acalabrutinib was administered for a short period after immunization with T-cell-independent (TI) and T-cell-dependent (TD) antigens. In contrast, long-term administration of acalabrutinib slightly impaired humoral immunity. Therefore, these findings suggest that Btk inhibitors may be a potential option for alleviating endotoxic shock without compromising humoral immunity and emphasize the importance of maintaining a delicate balance between immunomodulation and inflammation suppression.
Topics: Animals; Mice; Agammaglobulinaemia Tyrosine Kinase; Benzamides; Interleukin-6; Lipopolysaccharides; NF-kappa B; Pyrazines; Shock, Septic; B-Lymphocytes
PubMed: 38638439
DOI: 10.3389/fimmu.2024.1388947 -
Journal of Medicinal Chemistry May 2024Cofactor mimicry represents an attractive strategy for the development of enzyme inhibitors but can lead to off-target effects due to the evolutionary conservation of...
Cofactor mimicry represents an attractive strategy for the development of enzyme inhibitors but can lead to off-target effects due to the evolutionary conservation of binding sites across the proteome. Here, we uncover the ADP-ribose (ADPr) hydrolase NUDT5 as an unexpected, noncovalent, off-target of clinical BTK inhibitors. Using a combination of biochemical, biophysical, and intact cell NanoBRET assays as well as X-ray crystallography, we confirm catalytic inhibition and cellular target engagement of NUDT5 and reveal an unusual binding mode that is independent of the reactive acrylamide warhead. Further investigation of the prototypical BTK inhibitor ibrutinib also revealed potent inhibition of the largely unstudied NUDIX hydrolase family member NUDT14. By exploring structure-activity relationships (SARs) around the core scaffold, we identify a potent, noncovalent, and cell-active dual NUDT5/14 inhibitor. Cocrystallization experiments yielded new insights into the NUDT14 hydrolase active site architecture and inhibitor binding, thus providing a basis for future chemical probe design.
Topics: Humans; Pyrophosphatases; Agammaglobulinaemia Tyrosine Kinase; Structure-Activity Relationship; Crystallography, X-Ray; Protein Kinase Inhibitors; Pyrazoles; Piperidines; Drug Discovery; Pyrimidines; Adenine; Models, Molecular; Enzyme Inhibitors
PubMed: 38635563
DOI: 10.1021/acs.jmedchem.4c00072