[Rinsho ketsueki] The Japanese journal of clinical hematology最新文献

Sideroblastic anemias (SAs) represent a diverse group of congenital and acquired disorders, characterized by anemia and the presence of ring sideroblasts in the bone marrow. Congenital sideroblastic anemia (CSA) arises from genetic mutations that disrupt heme and iron metabolism within mitochondria. The most common form of CSA is X-linked sideroblastic anemia (XLSA), caused by mutations in the erythroid-specific aminolevulinate synthase 2 (ALAS2) gene, a key enzyme in the heme biosynthesis pathway in erythroid cells. On the other hand, the most common form of acquired SA is myelodysplastic syndrome with ring sideroblasts (MDS-RS). The review explores the current understanding and emerging perspectives on the pathophysiology of SAs, with a particular focus on XLSA and MDS-RS.

My research group developed cytotoxic T lymphocytes (CTLs) redifferentiated from iPS cells (iPSC) established from antigen-specific CTLs that are rejuvenated, exhibiting a younger memory T cell phenotype with robust tumor-killing activity, and can be produced in unlimited quantities. We later introduced a chimeric antigen receptor (CAR) into these iPSC-derived rejuvenated CTLs (rejTs) to mitigate tumor antigen escape. These dual-antigen receptor rejTs can recognize both CD19 via CAR and MHC class I-presented LMP2 antigen via endogenous T cell receptors, and show a synergistic antitumor effect against EBV-associated lymphomas and longer persistence in vivo. We also generated HLA class I-edited virus-specific rejTs using CRISPR/Cas9 genome editing technology. These rejTs not only minimize recipient immune rejection, but also retain more robust cytotoxicity against virus-associated tumors compared to the original CTLs. We believe that these next-generation T cells offer a sustainable and promising approach to "off-the-shelf" T cell therapy.

Autoimmune hemolytic anemia (AIHA), which is caused by autoantibodies for red blood cell membrane antigens, is categorized into two forms: warm AIHA, which involves warm antibodies, and cold agglutinin disease (CAD), which involves hemolysis and red blood cell agglutination due to cold agglutinins. The first-line therapy for wAIHA is corticosteroids. Clinical guidelines by the British Society for Haematology recommend rituximab as second-line therapy, but Japanese national health insurance does not cover rituximab for wAIHA. Several new drugs with different mechanisms of action are in clinical development for refractory cases. Some of these drugs inhibit antibody production or promote antibody clearance, while others inhibit erythrophagocytosis. In CAD, anti-complement drugs targeting C1s improve anemia but do not treat peripheral circulatory failure due to erythrocyte aggregation. B-cell-targeted therapies should be used for patients with severe symptoms of these conditions.

Bone marrow examination is essential for the definitive diagnosis of myelodysplastic neoplasms (MDS). However, non-invasive diagnostic approaches are needed for patients who cannot tolerate the procedure, especially elderly patients. This study aimed to validate the diagnostic accuracy of non-invasive gradient-boosted models (GBMs) in Japanese patients with MDS. When used alone, GBMs had sensitivity of 63.2% and specificity of 43.9% for diagnosis of MDS. When combined with WT1 mRNA expression levels (WT1 levels)(cutoff: 150 copies/µg RNA), specificity remained similar at 50.0%, while sensitivity improved to 81.6%. MDS was correctly diagnosed in 87.2% of patients with probable or indeterminate MDS by GBMs who had WT1 levels higher than 150 copies/µg RNA. When patients with vitamin B12 deficiency were excluded from analysis, this percentage increased to 91.9%. These findings suggest that the combination of GBMs, WT1 levels, and vitamin B12 deficiency could non-invasively identify patients likely to have MDS.

Gene therapies for hemophilia A and B were approved in the US and EU in 2022. A single infusion of adeno-associated virus vector containing FVIII and FIX gene increases clotting factor levels within a few weeks. Around 90% of hemophilia patients treated with gene therapy no longer need clotting factor injections and show a reduced annual bleeding rate. Gene therapy vectors for hemophilia have strong liver tropism and use liver-specific promoters. This review discusses the history of hemophilia gene therapy, phase 3 trials, and unmet needs.

The iPLAT1 study was conducted from 2019 to 2020 as the first-in-human clinical trial of iPS cell-derived platelet products (iPSC-PLTs). The subject was a patient with aplastic anemia refractory to anti-HPA-1a antibody-induced platelet transfusions who had no matched HPA-1b/1b donor. Autologous iPSC-PLTs were manufactured from a megakaryocyte cell line, imMKCL, established from the patient's iPSCs. High-efficiency manufacturing of iPSC-PLTs was achieved by incorporating the concept of turbulent flow in bioreactor tanks to mimic in vivo conditions. After comprehensive non-clinical studies, the iPLAT1 study was conducted as a dose-escalation study and achieved the primary endpoint of safety. However, an increase in the platelet count after transfusion was not observed, raising the possibility of a failure in post-transfusion measurement or defective circulation of transfused iPSC-PLTs. Since then, my research team and I have been conducting reverse-translational research to improve imMKCLs and developing a larger-scale manufacturing system to improve turbulent flow in bioreactor tanks. We have also recently demonstrated properties of subset of immune megakaryocytes in imMKCLs. Building upon such efforts, we have newly begun R&D for next-generation iPSC-PLTs.

Hematopoietic stem cells have the ability to self-renew and differentiate into multilineage cells. Therefore, hematopoietic stem cell gene therapy, which involves introducing therapeutic genes into these cells, could be an effective treatment for hereditary diseases currently targeted by hematopoietic cell transplantation. In fact, gene therapies using lentiviral vectors have already received manufacturing and sales approvals for several hereditary diseases. However, there are issues with this approach, such as tumorigenesis associated with the insertion of the vector genome and insufficient response to gain-of-function diseases caused by proteins derived from mutant genes. For this reason, the development of gene therapy using genome editing technology has become an active area of research in recent years. Nevertheless, because these technologies may cause permanent changes to the human genome, it is essential to proceed carefully with clinical development, based on social consensus.

Ethics in clinical research are indispensable for participant protection and ensuring research quality, and constitute essential knowledge for all healthcare professionals involved in clinical practice. Learning from historical case studies of unethical research, such as the Nazi human experiments and the Tuskegee Syphilis Study has led to progressive development of ethical guidelines like the Nuremberg Code, the Declaration of Helsinki, and the Belmont Report-which presents the three core principles of respect for persons, beneficence, and justice. In Japan, incidents including the Diovan case prompted the enactment of the Clinical Research Act. The 8 requirements set forth by the U.S. National Institutes of Health (social/scientific value, scientific validity, fair subject selection, favorable risk-benefit ratio, independent review, informed consent, and respect for subjects) serve as a key framework for modern research practice. In Japan, regulations such as the Pharmaceuticals and Medical Devices Act/Good Clinical Practice, the Clinical Research Act, and associated guidelines have been established, and require compliance tailored to the specific type of research. The practice of clinical research adhering to ethical principles forms the foundation for the advancement of medicine built on trust.