[Development of off-the-shelf universal T cell therapies from ES/iPS cells: applications in cancer and viral infection].

Methods in which patient-derived T cells are genetically modified in vitro and administered to patients have been demonstrated effective in the area of cancer immunotherapy. However, these methods have some unresolved issues such as cost, time, and unstable quality. Several groups have developed strategies to overcome these barriers by regenerating T cells from iPSCs.

A Chimeric IL-7Rα/IL-2Rβ Receptor Promotes the Differentiation of T Cell Progenitors into B Cells and Type 2 Innate Lymphoid Cells.

IL-7 and IL-2 are evolutionarily related cytokines that play critical roles in the development and expansion of immune cells. Although both IL-7R and IL-2R activate similar signaling molecules, whether their signals have specific or overlapping functions during lymphocyte differentiation remains unclear. To address this question, we generated IL-7R α-chain (IL-7Rα)/IL-2R β-chain (IL-24β) (72R) knock-in mice expressing a chimeric receptor consisting of the extracellular domain of IL-7Rα and the intracellular domain of IL-2Rβ under the control of the endogenous IL-7Rα promoter.

Phase 2 study of glucarpidase in patients with delayed methotrexate elimination after high-dose methotrexate therapy.

Purpose: High-dose methotrexate therapy (HD-MTX) is a standard treatment for various malignant tumors, but approximately 1-10% of patients experience delayed MTX elimination (DME) that can induce organ damage. Glucarpidase can hydrolyze MTX and thereby lower the level of active MTX in the blood. A multicenter, open-label, phase II investigator-initiated trial (CPG2-PII study) was conducted to evaluate glucarpidase rescue therapy in Japanese patients who showed DME after HD-MTX treatment.

Development of Immune Cell Therapy Using T Cells Generated from Pluripotent Stem Cells.

In the field of cancer immunotherapy, the effectiveness of a method in which patient-derived T cells are genetically modified ex vivo and administered to patients has been demonstrated. However, problems remain with this method, such as (1) time-consuming, (2) costly, and (3) difficult to guarantee the quality. To overcome these barriers, strategies to regenerate T cells using iPSC technology are being pursued by several groups in the last decade.

Trends in cell medicine: from autologous cells to allogeneic universal-use cells for adoptive T-cell therapies.

In currently ongoing adoptive T-cell therapies, T cells collected from patients are given back to them after ex vivo activation and expansion. In some cases, T cells are transduced with chimeric antigen receptor (CAR) or T-cell receptor (TCR) genes during the ex vivo culture period in order to endow T cells with the desired antigen specificity. Although such strategies are effective in some types of cancer, there remain issues to be solved: (i) the limited number of cells, (ii) it is time-consuming, (iii) it is costly, and (iv) the quality can be unstable.

Evolutionary reversion in tumorigenesis.

Cells forming malignant tumors are distinguished from those forming normal tissues based on several features: accelerated/dysregulated cell division, disruption of physiologic apoptosis, maturation/differentiation arrest, loss of polarity, and invasive potential. Among them, accelerated cell division and differentiation arrest make tumor cells similar to stem/progenitor cells, and this is why tumorigenesis is often regarded as developmental reversion. Here, in addition to developmental reversion, we propose another insight into tumorigenesis from a phylogeny viewpoint.

Regulation of lymphoid-myeloid lineage bias through regnase-1/3-mediated control of Nfkbiz.

Regulation of lineage biases in hematopoietic stem and progenitor cells (HSPCs) is pivotal for balanced hematopoietic output. However, little is known about the mechanism behind lineage choice in HSPCs. Here, we show that messenger RNA (mRNA) decay factors regnase-1 (Reg1; Zc3h12a) and regnase-3 (Reg3; Zc3h12c) are essential for determining lymphoid fate and restricting myeloid differentiation in HSPCs.

SETBP1 is dispensable for normal and malignant hematopoiesis.

SETBP1 is a potential epigenetic regulator whose hotspot mutations preventing proteasomal degradation are recurrently detected in myeloid malignancies with poor prognosis. It is believed that the mutant SETBP1 exerts amplified effects of wild-type SETBP1 rather than neomorphic functions. This indicates that dysregulated quantitative control of SETBP1 would result in the transformation of hematopoietic cells.

[Development of "Off the Shelf" T Cells for Cancer Immunotherapy].

In the area of cancer immunotherapy, the efficacy of strategies in which patient derived T cells are genetically modified ex vivo and administered to patients has been demonstrated. However, some issues have remained to be addressed; the method using autologous T cells is costly and time consuming, and their quality is unstable. The time consuming problem can be solved by preparing allogeneic T cells in advance.

Pharmacokinetics and Pharmacodynamics of Glucarpidase Rescue Treatment After High-dose Methotrexate Therapy Based on Modeling and Simulation.

Background: Model-informed approaches are important in drug development, including for dose optimization and the collection of evidence in support of efficacy.

Materials And Methods: We developed a modified Michaelis-Menten pharmacokinetics/pharmacodynamics model and used it to conduct simulations of glucarpidase at doses between 10 and 80 U/kg rescue treatment after high-dose methotrexate therapy. We carried out a dose-finding modeling and simulation study before a phase II study of glucarpidase.

Characteristic differences in the abundance of tumor-infiltrating lymphocytes and intratumoral developing T cells in thymoma, with special reference to PD-1 expression.

Purpose: Though programmed cell death-1 (PD-1) inhibitors mainly target tumor-infiltrating lymphocytes (TILs) expressing PD-1, developing T cells in thymus also express PD-1 in their process of maturation. To predict the therapeutic effect of PD-1 inhibitors for thymoma, it is necessary to clarify the proportions of TILs and intratumoral developing T cells.

Methods: The expressions of CD4, CD8, and PD-1 on T cells were analyzed by flow cytometry in 31 thymomas.

Development of a population pharmacokinetics and pharmacodynamics model of glucarpidase rescue treatment after high-dose methotrexate therapy.

Introduction: Glucarpidase (CPG2) reduces the lethal toxicity of methotrexate (MTX) by rapid degradation.

Methods: In this study, a CPG2 population pharmacokinetics (popPK) analysis in healthy volunteers (phase 1 study) and a popPK-pharmacodynamics (popPK-PD) analysis in patients (phase 2 study, = 15) who received 50 U/kg of CPG2 rescue for delayed MTX excretion were conducted. In the phase 2 study, the first CPG2 treatment at a dose of 50 U/kg was intravenously administered for 5 min within 12 h after the first confirmation of delayed MTX excretion.

Murine breast cancers disorganize the liver transcriptome in a zonated manner.

The spatially organized gene expression program within the liver specifies hepatocyte functions according to their relative distances to the bloodstream (i.e., zonation), contributing to liver homeostasis.

Tracing the evolutionary history of blood cells to the unicellular ancestor of animals.

Blood cells are thought to have emerged as phagocytes in the common ancestor of animals followed by the appearance of novel blood cell lineages such as thrombocytes, erythrocytes, and lymphocytes, during evolution. However, this speculation is not based on genetic evidence and it is still possible to argue that phagocytes in different species have different origins. It also remains to be clarified how the initial blood cells evolved; whether ancient animals have solely developed de novo programs for phagocytes or they have inherited a key program from ancestral unicellular organisms.

Remote solid cancers rewire hepatic nitrogen metabolism via host nicotinamide-N-methyltransferase.

Cancers disrupt host homeostasis in various manners but the identity of host factors underlying such disruption remains largely unknown. Here we show that nicotinamide-N-methyltransferase (NNMT) is a host factor that mediates metabolic dysfunction in the livers of cancer-bearing mice. Multiple solid cancers distantly increase expression of Nnmt and its product 1-methylnicotinamide (MNAM) in the liver.

Propionic Acid, Induced in Gut by an Inulin Diet, Suppresses Inflammation and Ameliorates Liver Ischemia and Reperfusion Injury in Mice.

Liver ischemia and reperfusion injury (IRI) is one of the obstacles in liver surgery such as liver resection and transplantation. In this study, we investigated the preventive effect on mouse liver IRI by feeding mice with inulin, which is a heterogeneous blend of indigestible fructose polymer. Mice were fed either a control ordinary diet (CD) or an inulin diet (ID) containing 5% inulin in the CD, for 14 days before the ischemia and reperfusion (IR) maneuver.

Increase in the incidence of acute inflammatory reactions to injectable fillers during COVID-19 era.

Background: Acute inflammatory reactions (AIRs) are a rare complication following esthetic treatment with hyaluronic acid (HA) and/or human collagen fillers. However, a substantial increase in the frequency of AIRs was observed in the first author's clinic since May 2020.

Aims: To report AIR cases, we experienced and discuss potential underlying mechanisms.

Isolation of TCR genes with tumor-killing activity from tumor-infiltrating and circulating lymphocytes in a tumor rejection cynomolgus macaque model.

To develop effective adoptive cell transfer therapy using T cell receptor (TCR)-engineered T cells, it is critical to isolate tumor-reactive TCRs that have potent anti-tumor activity. In humans, tumor-infiltrating lymphocytes (TILs) have been reported to contain CD8PD-1 T cells that express tumor-reactive TCRs. Characterization of tumor reactivity of TILs from non-human primate tumors could improve anti-tumor activity of TCR-engineered T cells in preclinical research.

Regeneration of antigen-specific T cells by using induced pluripotent stem cell (iPSC) technology.

In currently ongoing adoptive T-cell therapies, T cells collected from the patient are given back to the patient after ex vivo cell activation and expansion. In some cases, T cells are transduced with chimeric antigen receptor (CAR) or T-cell receptor (TCR) genes during the ex vivo culture period. Although such strategies have been shown to be effective in some types of cancer, there remain issues to be solved; these methods (i) are time-consuming, (ii) are costly and (iii) it is difficult to guarantee the quality because the products depend on patient-derived T cells.

A Dose-Confirmation Phase 1 Study to Evaluate the Safety and Pharmacology of Glucarpidase in Healthy Volunteers.

Glucarpidase rapidly decomposes methotrexate. A phase 1 study of glucarpidase in an open-label, randomized parallel group was conducted to evaluate the safety, pharmacokinetics, and other pharmacologic effects in Japanese healthy volunteers without methotrexate treatment. A dose of 50 U/kg (n = 8) or 20 U/kg (n = 8) of glucarpidase was administered as an intravenous injection, with 1 repeated dose at 48 hours after the first dose.

[The origin of blood cells and myeloid cells].

In human hematopoiesis, cells of various lineages exist, such as neutrophils, lymphocytes, and erythrocytes. Unveiling the pathway from stem cells to the various lineages helps us understand the blood disorders and develop therapies for them. We have studied the developmental pathway of hematopoiesis for decades and found that myeloid potential is retained just before the differentiation into each lineage of the various lineage progenitors.