Current issues and perspectives in PD-1 blockade cancer immunotherapy

Programmed cell death 1 (PD-1) signal receptor blockade has revolutionized the field of cancer therapy. Despite their considerable potential for treating certain cancers, drugs targeting PD-1 still present two main drawbacks: the substantial number of unresponsive patients and/or patients showing recurrences, and side effects associated with the autoimmune response. These drawbacks highlight the need for further investigation of the mechanisms underlying the therapeutic effects, as well as the need to develop novel biomarkers to predict the lack of treatment response and to monitor potential adverse events. Combination therapy is a promising approach to improve the efficacy of PD-1 blockade therapy. Considering the increasing number of patients with cancer worldwide, solving the above issues is central to the field of cancer immunotherapy. In this review, we discuss these issues and clinical perspectives associated with PD-1 blockade cancer immunotherapy

B cell-derived GABA elicits IL-10⁺ macrophages to limit anti-tumour immunity

GABAを標的とする抗腫瘍免疫機構 --代謝産物を介した免疫細胞間制御の一端を解明--. 京都大学プレスリリース. 2021-11-10.Small, soluble metabolites not only are essential intermediates in intracellular biochemical processes, but can also influence neighbouring cells when released into the extracellular milieu1-3. Here we identify the metabolite and neurotransmitter GABA as a candidate signalling molecule synthesized and secreted by activated B cells and plasma cells. We show that B cell-derived GABA promotes monocyte differentiation into anti-inflammatory macrophages that secrete interleukin-10 and inhibit CD8⁺ T cell killer function. In mice, B cell deficiency or B cell-specific inactivation of the GABA-generating enzyme GAD67 enhances anti-tumour responses. Our study reveals that, in addition to cytokines and membrane proteins, small metabolites derived from B-lineage cells have immunoregulatory functions, which may be pharmaceutical targets allowing fine-tuning of immune responses

Update on Chemotherapeutic Approaches and Management of Bevacizumab Usage for Glioblastoma.

Glioblastoma, the most common primary brain tumor in adults, has one of the most dismal prognoses in cancer. In 2009, bevacizumab was approved for recurrent glioblastoma in the USA. To evaluate the clinical impact of bevacizumab as a first-line drug for glioblastoma, two randomized clinical trials, AVAglio and RTOG 0825, were performed. Bevacizumab was found to improve progression-free survival (PFS) and was reported to be beneficial for maintaining patient performance status as an initial treatment. These outcomes led to bevacizumab approval in Japan in 2013 as an insurance-covered first-line drug for glioblastoma concurrently with its second-line application. However, prolongation of overall survival was not evinced in these clinical trials; hence, the clinical benefit of bevacizumab for newly diagnosed glioblastomas remains controversial. A recent meta-analysis of randomized controlled trials of bevacizumab combined with temozolomide in recurrent glioblastoma also showed an effect only on PFS, and the benefit of bevacizumab even for recurrent glioblastoma is controversial. Here, we discuss the clinical impact of bevacizumab for glioblastoma treatment by reviewing previous clinical trials and real-world evidence by focusing on Japanese experiences. Moreover, the efficacy and safety of bevacizumab are summarized, and we provide suggestions for updating the approaches and management of bevacizumab

Complex DNA repair pathways as possible therapeutic targets to overcome temozolomide resistance in glioblastoma

Many conventional chemotherapeutic drugs exert their cytotoxic function by inducing DNA damage in the tumor cell. Therefore, a cell-inherent DNA repair pathway, which reverses the DNA-damaging effect of the cytotoxic drugs, can mediate therapeutic resistance to chemotherapy. The monofunctional DNA-alkylating agent temozolomide (TMZ) is a commonly used chemotherapeutic drug and the gold standard treatment for glioblastoma. Although the activity of DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) has been described as the main modulator to determine the sensitivity of glioblastoma to TMZ, a subset of glioblastoma does not respond despite MGMT inactivation, suggesting that another DNA repair mechanism may also modulate the tolerance to TMZ. Considerable interest has focused on MGMT, mismatch repair (MMR), and the base-excision repair (BER) pathway in the mechanism of mediating TMZ resistance, but emerging roles for the DNA strand-break repair pathway have been demonstrated. In the first part of this review article, we briefly review the significant role of MGMT, MMR, and the BER pathway in the tolerance to TMZ; in the last part, we review the recent publications that demonstrate possible roles of DNA strand-break repair pathways, such as single-strand break (SSB) repair and double-strand break (DSB) repair, as well as the Fanconi anemia pathway in the repair process after alkylating agent-based therapy. It is possible that all of these repair pathways have a potential to modulate the sensitivity to TMZ and aid in overcoming the therapeutic resistance in the clinic

Pediatric Glioma: An Update of Diagnosis, Biology, and Treatment

Recent research has promoted elucidation of the diverse biological processes that occur in pediatric central nervous system (CNS) tumors. Molecular genetic analysis is essential not only for proper classification, but also for monitoring biological behavior and clinical management of tumors. Ever since the 2016 World Health Organization classification of CNS tumors, molecular profiling has become an indispensable step in the diagnosis, prediction of prognosis, and treatment of pediatric as well as adult CNS tumors. These molecular data are changing diagnosis, leading to new guidelines, and offering novel molecular targeted therapies. The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) makes practical recommendations using recent advances in CNS tumor classification, particularly in molecular discernment of these neoplasms as morphology-based classification of tumors is being replaced by molecular-based classification. In this article, we summarize recent knowledge to provide an overview of pediatric gliomas, which are major pediatric CNS tumors, and describe recent developments in strategies employed for their diagnosis and treatment

Pediatric Glioma: An Update of Diagnosis, Biology, and Treatment.

Recent research has promoted elucidation of the diverse biological processes that occur in pediatric central nervous system (CNS) tumors. Molecular genetic analysis is essential not only for proper classification, but also for monitoring biological behavior and clinical management of tumors. Ever since the 2016 World Health Organization classification of CNS tumors, molecular profiling has become an indispensable step in the diagnosis, prediction of prognosis, and treatment of pediatric as well as adult CNS tumors. These molecular data are changing diagnosis, leading to new guidelines, and offering novel molecular targeted therapies. The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) makes practical recommendations using recent advances in CNS tumor classification, particularly in molecular discernment of these neoplasms as morphology-based classification of tumors is being replaced by molecular-based classification. In this article, we summarize recent knowledge to provide an overview of pediatric gliomas, which are major pediatric CNS tumors, and describe recent developments in strategies employed for their diagnosis and treatment

Liquid Biopsy for Glioma Using Cell-Free DNA in Cerebrospinal Fluid

Glioma is one of the most common primary central nervous system (CNS) tumors, and its molecular diagnosis is crucial. However, surgical resection or biopsy is risky when the tumor is located deep in the brain or brainstem. In such cases, a minimally invasive approach to liquid biopsy is beneficial. Cell-free DNA (cfDNA), which directly reflects tumor-specific genetic changes, has attracted attention as a target for liquid biopsy, and blood-based cfDNA monitoring has been demonstrated for other extra-cranial cancers. However, it is still challenging to fully detect CNS tumors derived from cfDNA in the blood, including gliomas, because of the unique structure of the blood–brain barrier. Alternatively, cerebrospinal fluid (CSF) is an ideal source of cfDNA and is expected to contribute significantly to the liquid biopsy of gliomas. Several successful studies have been conducted to detect tumor-specific genetic alterations in cfDNA from CSF using digital PCR and/or next-generation sequencing. This review summarizes the current status of CSF-based cfDNA-targeted liquid biopsy for gliomas. It highlights how the approaches differ from liquid biopsies of other extra-cranial cancers and discusses the current issues and prospects

Giant cranial angiolipoma with arteriovenous fistula: A case report.

BACKGROUND: Angiolipomas are benign mesenchymal tumors comprising mature adipocytes and abnormal blood vessels, commonly found in the subcutaneous tissue of the trunk and rarely in the skull. Furthermore, sporadic cases of angiolipoma with arteriovenous fistula (AVF) have been reported. CASE DESCRIPTION: We reported the case of a 72-year-old woman who presented with head swelling, seizures, and cognitive dysfunction. Computed tomography and magnetic resonance imaging revealed a right frontal bone tumor exceeding a sagittal suture of up to 10.7 cm. Angiography revealed AVF and varices formation. Endovascular embolization was performed to treat the AVF and reduce blood loss during surgical resection. Two days after the embolization, a craniotomy was performed; however, uncontrollable bleeding was observed at the time of tumor resection. Postoperatively, the patient was symptom-free and has been stable for 2 years without recurrence. CONCLUSION: Despite careful preoperative evaluation and treatment planning, the patient in this case report was difficult to treat. Such cases require adequate preparation

Current trend in treatment of glioblastoma in Japan: a national survey using the diagnostic procedure combination database (J-ASPECT study-glioblastoma).

BACKGROUND: In the treatment for glioblastoma (GBM), treatment modalities, such as bevacizumab (BEV) and carmustine wafers implants have been approved in Japan since 2013. However, it is unclear whether such a trend in treatment complexity can accelerate treatment centralization. The aim of this study was to reveal the current trend in the treatment of GBM in Japan. METHODS: We used diagnostic procedure combination (DPC) database to analyze the data of 1,774 patients from 305 institutions between April 2016 and March 2019. To analyze the situations associated with first-line BEV use during concurrent TMZ (temozolomide)-radiotherapy, we compared TMZ alone and TMZ-BEV groups. RESULTS: Of the 1,774 patients with GBM, tumor removal by craniotomy was performed in 1,572 (88.6%) patients, and stereotactic biopsy was performed in 156 (8.8%) patients. A total of 1,229 (69.3%) patients underwent radiotherapy, and 1,287 (72.5%) patients underwent chemotherapy. TMZ alone was administered to 878 (68.2%) and TMZ combined with BEV in 381 (29.6%) patients. In the TMZ-BEV group, as compared to the TMZ-alone group, the rate of discharge to home was significantly lower (P = 0.0044), and the rate of stereotactic biopsy was significantly higher (P < 0.0001). No significant difference was observed in the distribution of patients between the TMZ alone and TMZ-BEV groups depending on the scale of institution (P = 0.1240). CONCLUSION: First-line BEV administration seems to be selected properly regardless of the institutional scale. This Japan-wide study of GBM treatment revealed that high level and newly introduced treatments have been steadily generalized in Japanese institutions