Aside from leukemia, brain tumors represent the most common type of malignant tumors encountered in pediatric patients. Recent advances in genetic analysis techniques have changed how pediatric brain tumors are diagnosed and classified, and some molecular-targeted therapies have proven to be more effective against particular tumor types. However, many types of pediatric brain tumors still carry poor prognoses, even though they are treated using intensive therapies. Effective molecular targeted therapies are warranted, but have not yet been developed for most of these tumors. Recently, CAR T-cell therapy has been used to effectively treat CD19+ acute lympho­blastic leukemia. However, this therapy has not yet been well established against other types of pediatric malignancies in clinical settings. In particular, suitable antigens for molecular-targeted therapies against pediatric brain tumors have not yet been established. Although flow cytometry (FCM) has been conventionally applied in clinical settings for treating leukemia, the confirmation of brain tumor antigen expression typically relies on immunohistochemistry—the results of which largely relate to diagnostic significance rather than identifying therapeutic targets. Therefore, we chose to separate and analyze pediatric brain tumor samples obtained surgically via FCM, to identify which surface antigens were most widely expressed, regardless of the tumor type. We also obtained several samples of exceedingly rare tumor types, from which we established both in vitro cell lines and in vivo murine disease models.

Although most leukemic cells can be eradicated by chemotherapy, a subset acquires resistance to treatment through metabolic reprogramming. Recent studies have identified mitochondrial oxidative phosphorylation (OXPHOS) as being essential for energy maintenance and drug resistance in leukemic stem cells (LSCs), which highlights mitochondrial metabolism as a promising therapeutic target in acute myeloid leukemia (AML). Therapeutic strategies have focused on targeting the oxidative phosphorylation (OXPHOS), mitochondrial DNA, apoptosis, mitophagy, and the electron transport chain (ETC). The BCL-2 inhibitor venetoclax, approved in 2021, improves survival in combination with 5-azacitidine by promoting apoptosis and suppressing mitochondrial respiration. We are currently exploring novel therapeutic strategies that target mitochondrial metabolism, including: (1) development of novel kinase inhibitors that suppress mitochondrial metabolism, (2) inhibition of mitochondrial fission regulators (DNM1L and MFF) to downregulate OXPHOS, and (3) metabolic inhibition using mannose, a monosaccharide that competes with glucose metabolism. This review outlines recent advances in the understanding of mitochondrial metabolism in AML treatment resistance, highlights key molecular targets, and discusses future perspectives on innovative therapies based on these findings.

The chimeric antigen receptor (CAR) is an artificial receptor that employs single-chain antibodies or natural ligand/receptor binding as its specific antigen-binding sites. CAR T-cell therapies have demonstrated remarkable efficacy in clinical trials for relapsed and refractory hematological malignancies. In contrast, CAR T-cell therapy application for solid tumors lags significantly behind that for hematological malignancies. Key challenges include overcoming heterogeneous target antigen expression and the multiple immune escape mechanisms mediated by the tumor tissue microenvironment.

This article discusses the current clinical development in CAR T-cell therapy for brain tumors, which are unique because of the presence of a blood-brain barrier in comparison with extracranial solid tumors. Intraventricular or intratumoral administration via catheters is frequently used in clinical trials. Tumor inflammation-associated neurotoxicity (TIAN) is a reported complication. Clinical development has focused primarily on glioblastomas in adults and pediatric tumors, including diffuse intrinsic pontine gliomas, ependymomas, and other pediatric tumor types. Although some cases have shown neurological symptoms improvement and tumor shrinkage (radiographically confirmed), durable responses remain limited. Therefore, further research and improvements in target antigen selection, receptor structure, and T-cell function are needed.

Immune cells survey and eliminate cancer cells. With this capability, cell therapy using engineered immune cells, which involves ex vivo activation, expansion, and genetic modification of immune cells, has emerged as a promising approach for cancer treatment.

Natural killer (NK) cells are a key source of therapeutic cell products owing to their potent anticancer activity. At the National University of Singapore, we have conducted clinical studies employing expanded and activated NK cells, with or without antibodies targeting tumor antigens, in patients with solid tumors, including sarcoma, breast cancer, and neuroblastoma. These studies demonstrated the clinical benefits of NK cell-based therapy and highlighted the potential for enhanced efficacy by prolonged persistence and target specificity.

To enhance the efficacy, we have developed several constructs to be introduced into NK or T cells using gene modification technology. Examples include membrane-bound interleukin-15 that prolongs NK cell survival, chimeric antigen receptors (CARs) targeting tumor-specific antigens, and a construct enabling T cells to mediate antibody-dependent cellular cytotoxicity. These technologies have been translated into clinical applications, and further investigation is warranted to evaluate their efficacy.

A comparison of CAR-T cell therapy efficacy in hematological malignancies versus solid tumors revealed several factors limiting its effectiveness in solid tumors. Strategies under investigation to overcome these challenges include CAR modification, multiple tumor antigen-targeting, combination therapies with drugs or radiation, tumor microenvironment modulation, and alternative immune cell sources. These may serve as viable strategies to improve the prognosis of patients with solid tumors.

Inborn errors of immunity (IEIs) encompass a spectrum of inherited immune system disorders, including increased susceptibility to infections, autoimmune and autoinflammatory diseases, malignancies, and allergies. IEIs include > 550 diseases, most of which have specific monogenic causes. For proper management, new diagnostic and treatment strategies, including clinical sequencing, have been developed. Identifying the genetic background enables the development of disease-specific treatments targeting the affected pathway. Furthermore, expanded newborn screening programs have been initiated for severe combined immunodeficiency and B-cell deficiency. Previously, most patients with these diseases were diagnosed only after the onset of infectious complications. However, early diagnosis before infection can significantly improve patient outcomes and quality of life.

Introduction: Several reports on coronavirus disease 2019 (COVID-19) in pediatric patients with cancer have been published in Europe and the United States. However, detailed studies on this topic from Japan are lacking.

Objective: This study aimed to assess the clinical characteristics of COVID-19 among pediatric patients with cancer and their impact on therapeutic strategies.

Patients and methods: Data on the clinical course and outcomes in nine pediatric patients with cancer infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) between January 2020 and December 2022 were retrospectively collected from the patients’ medical records and analyzed.

Results: Of the nine patients with SARS-CoV-2 infection during chemotherapy, four developed COVID-19. The route of transmission was identified in six patients (intrafamilial transmission in all six). The main symptoms were fever and cough. No patient required hospitalization for oxygen therapy. Chemotherapy was delayed in two patients, one of whom was unable to participate in the clinical trial because of tumor growth during treatment interruption.

Conclusion: Although the risk of severe COVID-19 in pediatric patients with cancer is not markedly high, treatment delays due to COVID-19 are problematic. Therefore, balancing the risk of severe COVID-19 with that of disease progression or recurrence is important when determining treatment strategies for pediatric patients with cancer and COVID-19.

A 13-year-old girl was diagnosed with acute promyelocytic leukemia (APL) and treated with multi-agent chemotherapy, including all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). The patient was unsuccessfully treated with ATO induction therapy for relapsed APL 19 months later. However, the subsequent tamibarotene chemotherapy resulted in complete remission. During the second remission period, the patient underwent bone marrow transplantation from an HLA 8/8 allele-matched sibling with a myeloablative conditioning regimen comprising busulfan 11.2 mg/kg and melphalan 180 mg/m². After engraftment on day 21, the patient experienced no acute graft-versus-host disease or other serious complications, and was discharged 96 days after transplantation.

Tamibarotene may be effective for patients with ATRA- and ATO-resistant relapsed APL, although reports in children are limited.