Language：English   Publisher：Cancer Science  

Diffuse intrinsic pontine glioma (DIPG) is a very challenging-to-treat pediatric malignant tumor, with a median survival time of < 12 months. Convection-enhanced delivery (CED) allows for direct drug administration into the tumor site, showing potential as a novel therapeutic approach. This study evaluated the efficacy of CED of nimustine hydrochloride (ACNU) in children with DIPG. This phase 2, single-arm, multicenter study enrolled patients aged 3–21 years and diagnosed with DIPG. The investigational treatment commenced 1 month after completing radiotherapy (local 50–60 Gy). The treatment involved stereotactic brain surgery for catheter placement, followed by ACNU administration via a CED catheter at a concentration of 0.75 mg/mL for 2–3 days until a cumulative dose of 7 (±0.3) mL was achieved. The primary endpoint was the 1-year survival rate. From April 2018 to March 2020, 21 children were enrolled in the trial and treated, with 20 evaluable for the primary endpoint. The 1-year survival rate from the start of radiotherapy was 60%, and the median survival time was 15 months. The response rate was analyzed in 20 patients, with one complete response (CR), six partial responses (PR), nine stable diseases, and four progressive diseases, resulting in a response rate of 35% (CR + PR). The CED of ACNU in the brainstem of children with DIPG after radiotherapy appears to be an effective therapeutic strategy. This approach warrants further development as a treatment for children with DIPG. This study is registered with jRCT (No. jRCT2021190003).

DOI： 10.1111/cas.70054

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Web of Science

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PubMed

Language：English   Publisher：BMC Cancer  

Background: Glioblastoma (GB) is the most common and aggressive primary malignant brain tumor in adults. To date, no effective treatment has been reported for recurrent GB (rGB). Long noncoding RNA taurine upregulated gene 1 (TUG1), which is highly expressed in GB, resolves the formation of R-loops, thereby maintaining tumor growth. TUG1-targeting antisense oligonucleotide (ASO) (TUG1ASO) is a nucleotide therapeutic with drug delivery system that targets TUG1, demonstrating efficacy against GB in mouse models. This multicenter, first-in-human, phase I trial aims to investigate the safety and maximum tolerated dose (MTD) of TUG1ASO. Methods: This study will enroll patients aged 18–75 years with rGB following postoperative temozolomide plus radiation therapy. The primary endpoints will be the safety and tolerability of TUG1ASO and the MTD. The secondary endpoints will be the response rate, duration of response, progression-free survival, overall survival, and pharmacokinetics of TUG1ASO. Dose escalation will be performed utilizing a 3 + 3 design with four dose levels. Unless the discontinuation criteria are met, four cycles will be administered, with each cycle lasting 7 days. Administration of TUG1ASO will be possible until the discontinuation criteria are met. Discussion: TUG1ASO is the first oligonucleotide therapeutic with drug delivery system targeting TUG1, expected to show an efficacy in rGB patients. In this first-in-human study, safety, tolerability and MTD of this new targeted therapy will be confirmed to find the recommended dose for the further clinical trial. This study may contribute to develop a new treatment option for rGB patients. Trial registration: Japan Registry of Clinical Trials (jRCT) 2041230136, registration date May 17, 2024. Registry: jRCT2041230136. Registration date: May 17, 2024. Study dates: January 1, 2024, to present.

DOI： 10.1186/s12885-025-13623-0

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PubMed

Language：English   Publisher：Tohoku University Medical Press  

<p>Convection-enhanced delivery (CED) delivers agents directly into tumors and the surrounding parenchyma. Although a promising concept, clinical applications are often hampered by insufficient treatment efficacy. Toward developing an effective CED-based strategy for delivering drugs with proven clinical efficacy, we performed a basic characterization study to explore the locally delivered characteristics of the water soluble nitrosourea nimustine hydrochloride (ACNU). First, ACNU distribution after CED in rodent brain was studied using mass spectrometry imaging. Clearance of ¹⁴C-labeled ACNU after CED in striatum was also studied. ACNU was robustly distributed in rodent brain similar to the distribution of the hydrophilic dye Evans blue after CED, and locally delivered ACNU was observed for over 24 h at the delivery site. Subsequently, to investigate the potential of ACNU to induce an immunostimulative microenvironment, Fas and transforming growth factor-<i>β</i>1 (TGF-<i>β</i>1) was assessed <i>in vitro</i>. We found that ACNU significantly inhibited TGF-<i>β</i>1 secretion and reduced Fas expression. Further, after CED of ACNU in 9L-derived intracranial tumors, the infiltration of CD4/CD8 lymphocytes in tumors was evaluated by immunofluorescence.CED of ACNU in xenografted intracranial tumors induced tumor infiltration of CD4/CD8 lymphocytes. ACNU has a robust distribution in rodent brain by CED, and delayed clearance of the drug was observed at the local infusion site. Further, local delivery of ACNU affects the tumor microenvironment and induces immune cell migration in tumor. These characteristics make ACNU a promising agent for CED.</p>

DOI： 10.1620/tjem.2023.j069

Open Access

Web of Science

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PubMed

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