PMID- 35205800 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220301 IS - 2072-6694 (Print) IS - 2072-6694 (Electronic) IS - 2072-6694 (Linking) VI - 14 IP - 4 DP - 2022 Feb 18 TI - Interstitial Control-Released Polymer Carrying a Targeting Small-Molecule Drug Reduces PD-L1 and MGMT Expression in Recurrent High-Grade Gliomas with TMZ Resistance. LID - 10.3390/cancers14041051 [doi] LID - 1051 AB - In recurrent glioblastoma, Gliadel wafer implantation after surgery has been shown to result in incomplete chemical removal of residual tumor and development of brain edema. Furthermore, temozolomide (TMZ) resistance caused by O(6)-methylguanine-DNA-methyltransferase (MGMT) activation and programmed cell death-ligand 1 (PD-L1) expression leads to immune-cold lesions that result in poorer prognosis. Cerebraca wafer, a biodegradable polymer containing (Z)-n-butylidenephthalide (BP), is designed to eliminate residual tumor after glioma resection. An open-label, one-arm study with four dose cohorts, involving a traditional 3 + 3 dose escalation clinical trial, of the Cerebraca wafer combined with TMZ on patients with recurrent high-grade glioma, was conducted. Of the 12 patients who receive implantation of Cerebraca wafer, there were no drug-related adverse events (AEs) or serious AEs (SAEs). The median overall survival (OS) of patients receiving low-dose Cerebraca wafer was 12 months in the group with >25% wafer coverage of the resected tumor, which is longer than OS duration in previously published studies (Gliadel wafer, 6.4 months). Patients who received high-dose Cerebraca wafer treatment had not yet died at the data cut-off date; a 100% progression-free survival (PFS) rate at six month was achieved, indicating the median OS of cohort IV was more than 17.4 months. In vitro study of the primary cells collected from the patients revealed that the IC(50) of BP against tumor stem cells was four times lower than that of bis-chloroethylnitrosourea (BCNU). A synergistic effect between BP and TMZ was demonstrated by a reduction in MGMT expression. Furthermore, BP inhibited PD-L1 expression, thereby activating T-cell cytotoxicity and increasing interferon-gamma (IFN-gamma) secretion. The better therapeutic effect of Cerebraca wafer on recurrent high-grade glioma could occur through re-sensitization of TMZ and reduction of PD-L1. FAU - Liu, Ching-Ann AU - Liu CA AD - Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien 97002, Taiwan. AD - Department of Medical Research, Hualien Tzu Chi Hospital, Hualien 97002, Taiwan. AD - Department of Neurosurgery, Neuro-Medical Scientific Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 97002, Taiwan. FAU - Liu, Wei-Hsiu AU - Liu WH AD - Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan. AD - Department of Surgery, School of Medicine, National Defense Medical Center, Taipei 11490, Taiwan. FAU - Ma, Hsin-I AU - Ma HI AD - Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan. AD - Department of Surgery, School of Medicine, National Defense Medical Center, Taipei 11490, Taiwan. FAU - Chen, Yuan-Hao AU - Chen YH AUID- ORCID: 0000-0002-0570-4328 AD - Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan. FAU - Hueng, Dueng-Yuan AU - Hueng DY AD - Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan. AD - Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11490, Taiwan. AD - Department of Biochemistry, National Defense Medical Center, Taipei 11490, Taiwan. FAU - Tsai, Wen-Chiuan AU - Tsai WC AD - Department of Pathology; Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan. FAU - Lin, Shinn-Zong AU - Lin SZ AD - Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien 97002, Taiwan. AD - Department of Neurosurgery, Neuro-Medical Scientific Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 97002, Taiwan. AD - School of Medicine, Tzu Chi University, Hualien 97002, Taiwan. FAU - Harn, Horng-Jyh AU - Harn HJ AD - Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien 97002, Taiwan. AD - Department of Pathology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien 97002, Taiwan. FAU - Chiou, Tzyy-Wen AU - Chiou TW AD - Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, Hualien 974, Taiwan. FAU - Liu, Jen-Wei AU - Liu JW AD - Everfront Biotech Inc., New Taipei City 221, Taiwan. FAU - Lee, Jui-Hao AU - Lee JH AUID- ORCID: 0000-0001-5907-7246 AD - Everfront Biotech Inc., New Taipei City 221, Taiwan. FAU - Chiu, Tsung-Lang AU - Chiu TL AUID- ORCID: 0000-0002-5717-8104 AD - Department of Neurosurgery, Neuro-Medical Scientific Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 97002, Taiwan. AD - School of Medicine, Tzu Chi University, Hualien 97002, Taiwan. LA - eng GR - 106-EC-17-A-22-I5-0-008/Department of Industrial Technology, Ministry of Economic Affairs, Taiwan/ PT - Journal Article DEP - 20220218 PL - Switzerland TA - Cancers (Basel) JT - Cancers JID - 101526829 PMC - PMC8870243 OTO - NOTNLM OT - (Z)-n-butylidenephthalide OT - Cerebraca wafer OT - MGMT OT - PD-L1 OT - clinical trial OT - intraparenchymal implantation OT - recurrent glioblastoma OT - target therapy OT - temozolomide resistance COIS- S.-Z.L., H.-J.H., and T.-W.C. are the patent inventors of the core technique utilized in Cerebraca wafer. This clinical trial is sponsored by Everfront Biotech Inc (Taiwan). J.-W.L. and J.-H.L. are employees of Everfront Biotech Inc. and they report receiving grants from the Department of Industrial Technology, Ministry of Economic Affairs. EDAT- 2022/02/26 06:00 MHDA- 2022/02/26 06:01 PMCR- 2022/02/18 CRDT- 2022/02/25 01:07 PHST- 2021/12/13 00:00 [received] PHST- 2022/02/08 00:00 [revised] PHST- 2022/02/13 00:00 [accepted] PHST- 2022/02/25 01:07 [entrez] PHST- 2022/02/26 06:00 [pubmed] PHST- 2022/02/26 06:01 [medline] PHST- 2022/02/18 00:00 [pmc-release] AID - cancers14041051 [pii] AID - cancers-14-01051 [pii] AID - 10.3390/cancers14041051 [doi] PST - epublish SO - Cancers (Basel). 2022 Feb 18;14(4):1051. doi: 10.3390/cancers14041051.