Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that locate in peripheral organs. It has been thought that a systemic immune response does not play a role in regression of central nervous system (CNS) tumors, because the CNS is an immunologically privileged site. However, recent advances in immunology have led to the possibility of immunotherapy using peripheral DCs against CNS tumors. Here, we investigated whether DCs pulsed with tumor extract could induce an antitumor effect against malignant glioma. Furthermore, we also investigated whether the antitumor effect become higher by pulsation with tumor extract-liposome complex, compared to pulsation with tumor extract alone. As a liposome, we used cationic small unilamellar vesicles composed of N-(alpha-trimethylammonioacetyl)-didodecyl-D-glutamate chloride (TMAG), dilauroylphosphatidylcholine (DLPC), and dioleoylphosphatidylethanolamine (DOPE) in a molar ratio of 1:2:2. After intracerebral inoculation of mouse malignant glioma GL261 cells into syngeneic C57BL/6 mice, DCs pulsed with extract from the glioma cells by sonication were administered intraperitoneally thrice weekly on days 7, 14 and 21. Tumor growth inhibition was evaluated by measuring the tumor size 1 month after the tumor inoculation. The group treated with DCs pulsed by tumor extract was inhibited in tumor progression compared with the control non-pulsed DCs group, and the group treated with DCs pulsed by tumor extract and liposomes showed substantial tumor volume reductions in all the mice. Among the mice, there were several with no visible masses in their brains. Immunohistochemical study showed that the CD8-positive cytotoxic T cells (CTLs) were strongly recognized among the almost disappearing tumor cells of pulsed DCs groups. The CTLs showed a specific antitumor activity for GL261 mouse glioma cells. These findings indicated that DCs pulsed with tumor extract and liposomes might play an important role in the activation of an immune response in malignant glioma.

Background Approximately 70% of lower-grade gliomas harbor isocitrate dehydrogenase 1 (IDH1) mutations, resulting in accumulation of oncometabolite D-2-hydroxyglutarate (D-2-HG); this leads to epigenetic dysregulation, oncogenesis, and subsequent clonal expansion. DS-1001 is an oral brain-penetrant mutant IDH1 selective inhibitor. This first-in-human study investigated the safety, pharmacokinetics, pharmacodynamics, and efficacy of DS-1001. Methods This was a multicenter, open-label, dose-escalation, phase I study of DS-1001 for recurrent/progressive IDH1-mutant (R132) glioma (N = 47) (NCT03030066). DS-1001 was administered orally at 125–1400 mg twice daily. Dose escalation used a modified continual reassessment method. Results The maximum tolerated dose was not reached. Eight patients were continuing treatment at the data cut-off. Most adverse events (AEs) were grade 1–2. Twenty patients (42.6%) experienced at least one grade 3 AE. No grade 4 or 5 AEs or serious drug-related AEs were reported. Common AEs (>20%) were skin hyperpigmentation, diarrhea, pruritus, alopecia, arthralgia, nausea, headache, rash, and dry skin. The objective response rates were 17.1% for enhancing tumors and 33.3% for non-enhancing tumors. Median progression-free survival was 10.4 months (95% confidence interval [CI], 6.1 to 17.7 months) and not reached (95% CI, 24.1 to not reached) for the enhancing and non-enhancing glioma cohorts, respectively. Seven on-treatment brain tumor samples showed a significantly lower amount of D-2-HG compared with pre-study archived samples. Conclusions DS-1001 was well-tolerated with a favorable brain distribution. Recurrent/progressive IDH1-mutant glioma patients responded to treatment. A study of DS-1001 in patients with chemotherapy- and radiotherapy-naïve IDH1-mutated WHO grade 2 glioma is ongoing (NCT04458272).

Background The Delphi consensus statements on the management of germ cell tumors (GCTs) failed to reach agreements on the statement that the cases with 1) pineal and neurohypophyseal bifocal lesion, 2) with diabetes insipidus, and 3) with negative tumor markers can be diagnosed as germinoma without histological verification. To answer this, multicenter retrospective analysis was performed. Methods A questionnaire on clinical findings, histological diagnosis, and details of surgical procedures was sent to 86 neurosurgical and 35 pediatrics departments in Japan. Results Fifty-one institutes reported 132 cases that fulfilled the three criteria. Tissue sampling was performed in 91 cases from pineal (n = 44), neurohypophyseal (n = 32), both (n = 6) and distant (n = 9) lesions. Histological diagnosis was established in 89 cases: pure germinoma or germinoma with syncytiotrophoblastic giant cells in 82 (92.1%) cases, germinoma and mature teratoma in two cases, and granulomatous inflammation in two cases. Histological diagnosis was not established in two cases. Although no tumors other than GCTs were identified, three (3.4%) patients had non-germinomatous GCTs (NGGCTs). None of the patients developed permanent complications after endoscopic or stereotactic biopsy. Thirty-nine patients underwent simultaneous procedure for acute hydrocephalus without permanent complications, and hydrocephalus was controlled in 94.9% of them. Conclusion All patients who fulfilled the three criteria had GCTs or granulomatous inflammation, but not other types of tumors. However, no less than 3.4% of the patients had NGGCTs. Considering the safety and the effects of simultaneous procedures for acute hydrocephalus, biopsy was recommended in such patients.

2004 Background: WHO grade II/III gliomas frequently harbor isocitrate dehydrogenase 1 ( IDH1) mutations, resulting in intratumoral accumulation of oncometabolite 2-hydroxyglutarate (2-HG) and subsequent clonal expansion. DS-1001b is an oral selective inhibitor of mutant IDH1 R132X that was designed to penetrate the blood-brain barrier. Methods: In this first-in-human, multicenter, phase I study (NCT03030066), eligible patients (pts) with recurrent/progressive IDH1 mutant glioma received DS-1001b twice daily (bid), continuous. A modified continual reassessment method was used for dose escalation. RANO and RANO-LGG criteria were used to assess tumor response. Pts who planned to undergo salvage surgery after developing progressive disease (PD) and who provided informed consent received DS-1001b treatment until surgery. Tumor samples were also obtained from those pts to measure the free form of DS-1001b and 2-HG levels. Results: Between Jan 2017 and Oct 2018, DS-1001b (125-1400 mg bid) had administered for 45 pts (median age 44 yrs, prior radiation therapy 100%, prior chemotherapy 82%), and 17 pts were continuing treatment. Maximum tolerated dose (MTD) was not reached. Most AEs were Gr 1-2. Gr 3 AEs were observed in 42.2% of pts. No Gr 4 or 5 AEs or serious drug-related AEs were reported. One dose limiting toxicity was Gr 3 white blood cell count decreased (1000 mg bid). Common AEs ( > 20%) were skin hyperpigmentation, diarrhea, pruritus, nausea, rash, and headache. Of 29 evaluable pts with contrast enhancing gliomas, one, three and 10 achieved complete response, partial response and stable disease (SD), respectively. Of evaluable nine pts with contrast non-enhancing gliomas, two achieved minor response and seven achieved SD. Peak plasma concentration (Cmax) and area under the curve (AUC) increased dose-dependently. The brain/plasma ratio of free form of DS-1001b ranged 0.19‒0.77 in 3 pts. Conclusions: DS-1001b was well tolerated up to 1400 mg bid with favorable brain distribution, and MTD was not reached. Recurrent/progressive IDH1 mutant glioma pts responded to treatment. Investigation is ongoing to determine the recommended Phase II dose. Clinical trial information: NCT03030066.

Background/Aim: We previously established a novel type of epidermal growth factor receptor variant III (EGFRvIII)-specific chimeric antigen receptor (CAR)expressing natural killer (NK) cell line, designated EvCAR-KHYG-1, which inhibited the growth of glioblastoma (GBM) cells in vitro via apoptosis. Materials and Methods: We investigated the cytokine-producing effect of EvCAR-KHYG-1 cells on GBM-like cell lines and their antitumour effect using in vivo xenograft assays. Results: EvCAR-KHYG-1 cells produced interleukin-2, interferon-γ, and tumour necrosis factor-α on EGFRvIII-expressing U87MG cells. In vivo xenograft assays showed that EvCAR-KHYG-1 cells did not reduce the volume of subcutaneous tumours derived from EGFRvIII-expressing U87MG cells but did reduce tumour cell occupancy. Conclusion: EvCAR-KHYG-1 cells led to expression of cellular immunity-related cytokines on EGFRvIII-expressing U87MG in vitro but did not inhibit tumour progression due to the induction of a pseudo progression-like pathological feature. Future studies investigating the effect of different conditions in vivo are required to study the inhibition of tumour progression in GBM.Glioblastoma (GBM) is one of the most common and aggressive types of primary malignant central nervous system (CNS) tumours occurring in adults (1-3). Despite chemotherapy, radiation, with/without surgical resection, few patients survive for more than 5 years (1, 3). Thus, developing an effective therapy to treat GBM is warranted. Immunotherapy is a promising alternative to conventional treatments, with the possible long-term benefit of generating a sustained antitumour response and potentially targeting both localized and infiltrating tumour cells. Natural killer (NK) cells are potent effector cells in cell-based cancer immunotherapy. They respond rapidly to abnormal cells and represent a crucial effector cell population in adoptive immunotherapy (4). In addition, donor-derived NK cells such as NK-92 and KHYG-1 are being developed for clinical applications (5-8).Chimeric antigen receptor (CAR) is an artificially modified fusion protein consisting of an extracellular antigen-recognition domain fused to an intracellular signalling domain (9, 10). CAR redirects the specificity and function of T-lymphocytes and other immune cells. The general premise for the use of CAR cells in cancer immunotherapy is the rapid generation of tumour-targeted Tcells, bypassing the barriers and incremental kinetics of active immunization (11,12). CAR T-cells are effectively used to treat refractory chronic lymphocytic leukaemia and acute lymphoblastic leukaemia (ALL) (13,14). Specifically, CD19-targeting CAR T-cells have been reported to result in complete response rates of 70-90% in ALL patients (15). However, CAR T-cells exhibited poor therapeutic efficacy against solid tumours (16-18). A clinical trial showed that epidermal growth factor receptor variant III (EGFRvIII)targeted CAR T-cells infiltrated GBM but without objective 3231