Nuclear medicine treatment is a treatment in which RI is administered to patients, and hematopoietic tumors were treated with 90Y-conjugated anti-CD20 antibodies for low-grade B-cell lymphoma from 2008 to 2021. Targeted α-particle therapy has attracted attention because they have a remarkable therapeutic effect and is effective in cases refractory to β-particle therapy. In Japan, astatine-211(211At)-labeled drugs are being developed due to the restriction of the production and supply of actinium-225(225Ac). Because hematopoietic tumors are sensitive to radiation and suitable for nuclear medicine therapy, the authors have been developing therapy with α radionuclides that target CD82, which is highly expressed in hematopoietic tumor stem cells. Overseas, the development of nuclear medicine treatment is progressing, and new drugs are being applied clinically one after another. In Japan, corporate clinical trials have been conducted and approved earlier than before. As a result, there will be a shortage of radiotherapy rooms that provide treatment and specialized medical personnel engaged in the treatment. In this article, we look at the future of conventional nuclear medicine therapies for hematopoietic tumors, the development of targeted α-particle therapy, and the problems as mentioned above.

The cancer-immunity cycle has been proposed, and immunotherapeutic approaches, such as vaccines using self-antigens and adjuvant, have been employed for a long time, but their therapeutic effects have been limited. However, recent studies have demonstrated that immune checkpoint inhibitors(ICIs)are able to achieve high therapeutic efficacy, in a variety of cancer types. Today, advances in multi-omics technologies, including single-cell RNA sequencing(scRNA-seq), spatial transcriptomics, and multicolor immunostaining technologies, have made it possible to analyze immune cell dynamics at the single-cell level in a greater detail. While CD8+ T cells play a central role in the antitumor immune response, recent findings have revealed the existence of various subsets within the CD8+ T cell population. During the research on T cell exhaustion, the in vivo dynamics of T progenitor exhausted cells(Tpex cells)/stem cell memory T cells(TSCM)have also been elucidated. Tpex/TSCM cells are present in tumor-draining lymph nodes and within tumors and have reported to be an important target for ICIs. Furthermore, interactions between CD4+ T cells, dendritic cells(DCs), B cells, and CD8+ T cells within the tumor microenvironment are crucial for the induction of cytotoxic CD8+ effector T cells. In human tumor tissues, cancer cells exhibit heterogeneous characteristics and the tumor microenvironment varies depending on cancer type, subtypes, and individual patients. To enhance the anti-tumor effects of CD8+ T cells in immunotherapy, it is essential to achieve a more precise understanding of the in vivo dynamics of CD8+ T cells in each patient and to develop strategies for their effective intervention. This knowledge will then be applied to the development of vaccine therapies, combination immunotherapies, and cellular immunotherapy.

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.

Allogeneic hematopoietic stem cell transplantation is a curative treatment for hematological malignancies and bone marrow failure syndromes, but appropriate donor selection is important to reduce the risk of complications such as graft-versus-host disease (GVHD) and poor engraftment. Use of HLA-matched sibling donors has been decreasing, which has led to increased use of unrelated donors, cord blood, and haploidentical donors. In haplo-transplantation, outcomes are influenced by HLA epitope compatibility (which depends on the method of GVHD prophylaxis) and the number of CD34+ cells infused. In cord blood transplantation, the number of CD34+ cells and CFU-GM are important. In unrelated bone marrow transplantation, HLA-DPB1 and HLA epitope level compatibility are also considered important. In the future, comprehensive donor selection that considers not only HLA compatibility but also epitope compatibility and donor characteristics might be required. The use of new evaluation indices such as the PIRCHE score should improve the safety and success rate of transplantation.

Granulocyte transfusion therapy (GTX) is a treatment for severe infections in patients with neutropenia, but is not widely used because it requires repeated apheresis from healthy donors to harvest sufficient neutrophils. Induced pluripotent stem cell (iPSC)-derived neutrophils are considered a promising solution to this problem, and several groups have reported methods for differentiating iPSCs into neutrophils. However, the differentiation process takes more than 14 days, and an expansion culture method that yields sufficient neutrophils for effective GTX must be developed. We have recently established iPSC-derived granulocyte progenitor cell lines that can be expanded in vitro, which could serve as a starting point for supplying sufficient iPSC-derived neutrophils in 4 days when GTX treatment is required. However, before this manufacturing method is ready for clinical use, its efficacy and safety must be evaluated and the method must be improved to comply with quality control standards for regenerative medicine products.

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.

Danicopan (brand name: Voydeya® tablets) is a new oral small molecule complement factor D inhibitor that was approved in Japan in January 2024 for paroxysmal nocturnal hemoglobinuria (PNH). PNH is a rare, chronic hematologic disorder caused by acquired mutations of hematopoietic stem cells in the PIGA gene. These mutations cause deficiencies in complement regulatory proteins CD55 and CD59 that may lead to uncontrolled terminal complement activation, intravascular hemolysis, thrombosis, and premature mortality. Complement C5 inhibitors (C5i; eculizumab and ravulizumab) are the current standard of care of PNH treatment, and control intravascular hemolysis (IVH) by inhibiting terminal complement pathway activation. However, extravascular hemolysis (EVH) with persistent symptoms, such as anemia, occurs in some C5i-treated patients with PNH. EVH is caused by the accumulation of proximal complement C3 fragment on the membrane of surviving PNH-type red blood cells. These cells subsequently undergo phagocytosis in the spleen or liver. Danicopan was developed to control EVH by targeting complement factor D involved in alternative pathway activation. Preclinical studies showed that danicopan selectively inhibits alternative complement pathway activation by reversibly binding to factor D and inhibiting its serine protease activity. A global phase III study (ALPHA study: ALXN2040-PNH-301 [NCT04469465]) investigated danicopan as add-on therapy to ravulizumab or eculizumab in patients with PNH and clinically significant EVH. Danicopan achieved statistically significant, clinically meaningful increases in hemoglobin levels, reduced transfusion, and reduced fatigue, while maintaining control of IVH. No new safety concerns were observed. Danicopan makes it possible to control EVH while controlling IVH with C5i.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative treatment for hematologic malignancies. However, graft-versus-host disease (GVHD) and disease relapse negatively impact prognosis. Chronic GVHD significantly affects both prognosis and quality of life, making its prevention crucial. The current standard GVHD prophylaxis, using calcineurin inhibitors (CNIs) and methotrexate (MTX), is effective against acute GVHD but its effect on chronic GVHD is limited. The mechanism by which CNIs fail to prevent chronic GVHD has long been unclear. Recently, we conducted single-cell RNA sequencing of donor T cells after mouse HCT and found that CNIs inhibit donor T-cell exhaustion while inducing effector-like exhausted T cells. These cells contribute to the development of chronic GVHD after allo-HCT and play a role in enhancing graft-versus-leukemia (GVL) effects after post-HCT PD-1 blockade. We are currently accumulating and analyzing patient samples to validate our findings from the mouse HCT models.

Cord blood, which is rich in hematopoietic stem/progenitor cells, is now an important cell source for allogeneic hematopoietic cell transplantation (HCT). Although cord blood transplantation (CBT) was initially only performed in pediatric patients due to the limited number of cells, it now accounts for around 30% of allogeneic HCT for adults in Japan. It has overcome the shortage of donors caused by the declining birthrate and aging population. Although the greatest disadvantage of CBT is the high incidence of Engraftment failure, it has been shown that even in HLA-incompatible recipients, graft-versus-host disease (GVHD) is less frequent and less severe in CBT, whereas the graft-versus-leukemia (GVL) effect is stronger. CBT in Japan differs from that in other countries in that a single-unit is used in adult patients, and CBT is actively performed in elderly patients and patients with advanced hematopoietic disease. Based on the Japanese analysis, the usefulness of intensified conditioning regimen, the survival-improving effect on mild acute or chronic GVHD, and the strong GVL effect are all characteristic of CBT, which is an important source of cells for allogeneic HCT.

Non-clinical pharmacological safety studies are conducted using cells and animals to ensure the safety of pharmaceuticals in humans. Following these studies, drug candidates are administered to humans during clinical trials. Safety must be sufficiently confirmed in non-clinical studies to ensure that test participants suffer no adverse health effects. However, due to species differences, low ability to extrapolate from in vitro to in vivo evaluation methods, and other problems, health hazards may unfortunately still occur. Therefore, sophisticated in vitro evaluation systems using human cells are actively being pursued. The main challenge remains the lack of a reliable methodology for extrapolating in vitro results to in vivo settings. We have attempted to extract parameters that can be predictably translated from in vitro [contractile evaluation in three-dimensional (3D) heart tissue] to in vivo (guinea pig echocardiography) conditions, using cardiac contractile dysfunction induced by anticancer drugs as an example. In this review, we introduce the in vitro methods developed to date to evaluate this cardiac contractile dysfunction, analyze the factors enabling highly accurate prediction of torsades de pointes in humans based on past proarrhythmic risk prediction methods using human induced pluripotent stem cell-derived cardiomyocytes, and apply them to evaluate cardiac contractile dysfunction caused by anticancer drugs using three-dimensional heart tissue. We also introduce the proposed strategy for this evaluation method in this section.

To increase success rates of clinical studies, preclinical evaluation systems have been expected to improve human predictability. In addition, future preclinical studies need to become more sophisticated and efficient on the back ground of the adoption of FDA Modernization Act 2.0 and the 3R principle promotion of animal tests. In this review, we will discuss about the efficiency of in vivo imaging in preclinical studies taking 'an attempt to establishment of in vitro in vivo extraporation (IVIVE) model for seizure risk assessment using microphysiological system (MPS) and magnetic resonance imaging (MRI)', and 'an attempt to predict drug delivery to the alveoli' as examples. In the seizure risk assessment of new drugs so far, primary cultures of rodent neurons and in vivo behavioral observation have been mainly used, however, since the human induced pluripotent stem cell (iPSC) technology was reported, the need for IVIVE model is more and more increasing to improve human predictability. As an MPS, we here introduce microelectrode array (MEA) system recording of primary culture of rodent neurons, while as in vivo experiments, we here introduce the measurement of cerebrospinal fluid (CSF) concentrations and MRI imaging of forebrains of the rats i.p. injected with seizurogenic compounds. In case of inhalation drugs, it has been difficult to confirm whether or not the drugs surely reach alveoli. We visualized two-dimensional spatial localization of inhaled ciclesonide (CIC) in rat lungs after administration of a single dose of a CIC aerosol using by desorption electrospray ionization-time of flight mass spectrometry imaging (DESI-MSI).

The development of new in vitro cell culture systems, the microphysiological systems(MPSs), is progressing rapidly around the world. MPS is a biomimetic cell culture system that recapitulate tissue biology(patho)physiologically using clinically derived specimens, organoids, or differentiated cells from stem cells on a culture device with circulation and detection devices. New disease model systems are being constructed using MPS and are used as proof-of-concept and drug evaluation systems, and are attracting attention as an approach to addressing unmet medical needs. In conventional anti-cancer drug research, in vitro culture systems are mainly used to evaluate the growth inhibitory potential of cancer cell line monocultures. On the other hand, MPS has made it possible to monitor cancer pathology, malignant traits, and pharmacological activity, such as reproduction of the cancer niche, interactions between cancer cells and various stroma in the tumor microenvironment, cancer cell movement, and immune cell accumulation in cancer tissue. MPS is also used to evaluate safety and adverse effects and pharmacokinetics, which are essential for anticancer drug development. Various MPSs have been developed and reported for these purposes also in Japan, MPS technology is being developed, including for use in the regulatory process for non-clinical studies. Through these efforts, it is expected to lead to innovation in drug discovery in the field of oncology.

Paroxysmal nocturnal hemoglobinuria (PNH) is a hematopoietic stem cell disease that results from clonal expansion of hematopoietic stem cells with gene mutations. Patients with PNH are known to have an increased risk of developing myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We report a case of a 42-year-old woman diagnosed with AML 13 years after a diagnosis of PNH. Gene mutations associated with MDS were detected. She did not achieve complete remission (CR) after induction therapy with idarubicin and cytarabine. Unrelated bone marrow transplantation was performed with a myeloablative conditioning regimen with cyclophosphamide (120 mg/kg) and total body irradiation (12 Gy). Ravulizumab was administered until 47 days after transplantation. She achieved CR after transplantation with complete donor engraftment. The transplantation was successful without severe complications such as graft-versus-host disease or sinusoidal obstruction syndrome. Further accumulation of cases is necessary to determine the efficacy and safety of anti-complement inhibitors in allogeneic hematopoietic stem cell transplantation.

A 46-year-old woman developed chronic skin graft-versus-host disease (GVHD) with bilateral axillary lymph node (LN) swelling 7 months after cord blood transplantation for acute myeloid leukemia. Histological examination of the LNs revealed dermatopathic lymphadenopathy (DL). After treatment with topical steroids, GVHD improved and lymphadenopathy subsided.DL typically occurs associated with chronic dermatologic disorders, and its pathology is characterized by paracortical LN hyperplasia by Langerhans cells and interdigitating cell infiltration. LN swelling rarely occurs with GVHD, and the clinical course in this patient suggests that her DL was caused by chronic skin GVHD. Interestingly, chimerism analysis of the Langerhans cells indicated donor origin.

A 41-year-old woman with myelodysplastic syndrome underwent unrelated bone marrow transplantation following conditioning with fludarabine, busulfan, total body irradiation, and anti-thymocyte globulin. She received tacrolimus and short-term methotrexate for graft-versus-host disease (GVHD) prophylaxis. After engraftment, she developed acute GVHD involving the skin, gut, and liver. Even after treatment with glucocorticoids, human mesenchymal stem cells, and ruxolitinib, skin GVHD progressed and caused extensive epidermolysis and erosions with persistent bleeding. The patient was started on a daily skin care regimen, which included washing, application of dimethyl isopropylazulene and betamethasone ointment, and topical trafermin and hydrogel wound dressing for bleeding sites. A multi-disciplinary team consisting of hematologists, plastic surgeons, and nurses, and physical therapists, psychiatrists/clinical psychologists, and palliative care providers for physical, mental, and pain supportive care managed the patient's care. After 4 months of treatment under this team, complete epithelial regeneration was achieved. This case demonstrates the efficacy of local skin care and multi-disciplinary collaboration in acute GHVD causing extensive skin damage.

Based on the perspectives of the environment, food, and health, this review reflects on previous research examining stem cells for the early detection of chemical hazards and the development of preventive health tools. The risks posed by endocrine-disrupting chemicals in the environment are investigated, including studies on 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), phthalate esters, and bisphenol A. Building on the findings of these studies, this review identifies emerging challenges in the field of endocrine-disrupting chemical research. Moreover, this paper explores innovative testing methods aimed at accurately evaluating the impact of chemicals on human health. The key topics covered include the implementation of developmental neurotoxicity testing methods, the species-specific effects of methylmercury, nanomaterials and the application of human pluripotent cells to assess the effects of low-dose radiation. Additionally, this review highlights transformative approaches in chemical health impact assessment that integrate cell science and artificial intelligence, and addresses challenges related to the application of multi-omics technologies in environmental health and toxicology.

Primary bone marrow lymphoma (PBML) is a malignant lymphoma characterized by proliferation of lymphoma cells exclusively in the bone marrow without lymphadenopathy. Despite the dismal prognosis of PBML, it is a very rare lymphoma with limited evidence concerning its pathophysiology, making accumulation of cases important. We herein report three cases of PBML at our institution. The first patient was an 80-year-old man who presented with hemophagocytic syndrome and pancytopenia at admission, and died of septic shock during initial chemotherapy. The second patient was a 64-year-old man who achieved complete remission with intensive chemotherapies, but relapsed shortly after completing the final chemotherapy course. The third patient was a 66-year-old woman who underwent chemotherapies and allogeneic hematopoietic stem cell transplantation, only to relapse shortly after transplantation. Although early intervention with chemotherapy is essential for PBML treatment, diagnosis of PBML is very challenging due to the absence of lymph node involvement. Moreover, treatment outcomes of existing chemotherapy and transplantation therapies for PBML are still poor. Further accumulation of cases and development of new treatment strategies are desirable.

Chronic obstructive pulmonary disease (COPD) is characterized by chronic bronchitis and emphysema, and current drug treatments is limited to symptomatic therapy. Thus, there is an urgent need for development of new treatments to repair alveolar destruction. To regenerate the destroyed alveoli, we focused on the differentiation of alveolar epithelial progenitor cells into type I or type II alveolar epithelial cells that constitute the alveoli. Our concept of alveolar regeneration therapy is based on developing a drug delivery system (DDS) and dry powder inhalation that can efficiently deliver new alveolar regeneration drugs, which were discovered using human alveolar epithelial progenitor cells, to stem cells present on the surface of the alveoli of COPD patients, thereby inducing alveolar regeneration. This review article summarizes our data on the discovery of the synthetic retinoid Am80 as a candidate drug for alveolar regeneration, the construction of a DDS that utilizes a biological mechanism that enhances its effect on alveolar regeneration, and the formulation design of a dry powder inhalation.

Currently, a variety of anticancer agents are used in the treatment of cancer. Since anticancer agents are used continuously over a long time, they carry the risk of side effects. One of the major side effects is cardiac dysfunction. For example, doxorubicin, an anthracycline-type anticancer agent, is clinically restricted because of its dose-dependent cardiotoxicity. Cardiotoxicity includes decreased ejection fraction, arrhythmias, and congestive heart failure, all of which are associated with high mortality rates. Therefore, it is important to assess the risk of cardiotoxicity of anticancer agents in advance. Cardiomyocytes require energy to beat and retain an abundance of mitochondria. We established quantitative measurements of mitochondrial length and respiratory activities using cardiomyocytes. We found that exposure of human iPS cell-derived cardiomyocytes (hiPSC-CMs) to anticancer agents with reported cardiotoxicity enhanced mitochondrial hyperfission and the oxygen consumption rate was significantly reduced. Knockdown of dynamin-related protein 1 (Drp1), mitochondrial fission-accelerating GTP-binding protein, suppressed mitochondrial hyperfission in hiPSC-CMs. This indicates that visualizing mitochondrial functions in hiPSC-CMs will be helpful in assessing the risk of cardiotoxicity caused by anticancer agents and that maintaining mitochondrial quality will become a new strategy to reduce anticancer agents-induced cardiotoxicity. In this review, we present the evaluation of cardiotoxicity targeting mitochondrial quality in anticancer agents, using osimertinib, a non-small cell lung cancer drug, as an example.

The delay and loss of drugs are serious problems in Japan. To overcome this issue, it is important to strengthen drug development capabilities. For drug development, the establishment and advancement of non-clinical testing methods are necessary for safe and effective clinical trials. Recently, the movement toward alternatives to animal testing has accelerated internationally. New Approach Methodologies (NAMs), such as human inducible pluripotent stem cell (hiPSC) technology and in silico modeling & simulation, are considered valuable for drug development. It has been demonstrated that hiPSC-derived cardiomyocytes (hiPSC-CMs) are useful tools to assess drug-induced cardiotoxicity, including arrhythmia and cardiac contractile dysfunction, leading to the use of hiPSC-CMs in the drug review process. Advancing hiPSC technologies have enabled the generation of mature hiPSC-CMs and engineered heart tissues, which are expected to provide novel information in drug safety and efficacy evaluation. Furthermore, it would be possible to establish the non-clinical evaluation that takes into account individual differences by developing hiPSCs bearing characteristics specific to certain populations, such as pediatrics or rare disease patients. Here, we present the recent findings and future perspectives on non-clinical evaluation using hiPSC technology.