Delving into the Latest Updates on Ad-SGE-DKK3 gene therapy(KYORIN Pharmaceutical Co. Ltd.) with Synapse

Overview

Basic Info

Drug Type

Gene therapy

Synonyms

AD-SGE-REIC

Target

DKK3

Mechanism

DKK3 gene transference, Apoptosis stimulants

Therapeutic Areas

NeoplasmsRespiratory DiseasesOther Diseases

Active Indication

Malignant Pleural MesotheliomaMesothelioma

Inactive Indication-

Originator Organization

KYORIN Pharmaceutical Co., Ltd.

Active Organization

Momotaro-Gene, Inc.

KYORIN Pharmaceutical Co., Ltd.

Okayama University

Inactive Organization-

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Author: Ninomiya, Kiichiro ; Ichihara, Eiki ; Tabata, Masahiro ; Hirabae, Atsuko ; Takada, Kenji ; Watanabe, Hiromi ; Ando, Chihiro ; Makimoto, Go ; Hotta, Katsuyuki ; Okawa, Sachi ; Ohashi, Kadoaki ; Kumon, Hiromi ; Nishii, Kazuya ; Tomonobu, Nahoko ; Fujii, Masanori ; Kubo, Toshio ; Kiura, Katsuyuki ; Maeda, Yoshinobu ; Nakasuka, Takamasa

OBJECTIVESNo immunotherapeutic protocol has yet been established in never-smoking patients with lung cancer harboring driver oncogenic mutations, such as epidermal growth factor receptor (EGFR) mutations. The immunostimulatory effect of Ad-REIC, a genetically engineered adenovirus vector expressing a tumor suppressor gene, reduced expression in immortalized cells (REIC), has been investigated in clinical trials for various solid tumors. However, the immunostimulatory effect of the Ad-REIC in EGFR-mutant lung cancer with a non-inflamed tumor microenvironment (TME) has not been explored.MATERIALS AND METHODSWe used a syngeneic mouse model developed by transplanting Egfr-mutant lung cancer cells into single or double flanks of C57BL/6J mice. Ad-SGE-REIC, a 2nd-generation vector with an enhancer sequence, was injected only into the tumors from one flank, and its antitumor effects were assessed. Tumor-infiltrating cells were evaluated using immunohistochemistry or flow cytometry. The synergistic effects of Ad-SGE-REIC and PD-1 blockade were also examined.RESULTSInjection of Ad-SGE-REIC into one side of the tumor induced not only a local antitumor effect but also a bystander abscopal effect in the non-injected tumor, located on the other flank. The number of PD-1⁺CD8⁺ T cells increased in both injected and non-injected tumors. PD-1 blockade augmented the local and abscopal antitumor effects of Ad-SGE-REIC by increasing the number of CD8⁺ T cells in the TME of Egfr-mutant tumors. Depletion of CD8⁺ cells reverted the antitumor effect, suggesting they contribute to antitumor immunity.CONCLUSIONAd-SGE-REIC induced systemic antitumor immunity by modifying the TME status from non-inflamed to inflamed, with infiltration of CD8⁺ T cells. Additionally, in Egfr-mutant lung cancer, this effect was enhanced by PD-1 blockade. These findings pave the way to establish a novel combined immunotherapy strategy with Ad-SGE-REIC and anti-PD-1 antibody for lung cancer with a non-inflamed TME.

24 Jun 2020·Current Gene TherapyQ4 · MEDICINE

Promising Gene Therapy Using an Adenovirus Vector Carrying REIC/Dkk-3 Gene for the Treatment of Biliary Cancer

Q4 · MEDICINE

Article

Author: Iwamuro, Masaya ; Watanabe, Masami ; Tanaka, Emi ; Kato, Hironari ; Okada, Hiroyuki ; Ohyama, Atsushi ; Uchida, Daisuke ; Shiraha, Hidenori ; Kumon, Hiromi

Background:We previously demonstrated that the reduced expression in immortalized cells (REIC)/dikkopf-3 (Dkk-3) gene was downregulated in various malignant tumors, and that an adenovirus vector carrying the REIC/Dkk-3 gene, termed Ad-REIC induced cancer-selective apoptosis in pancreatic cancer and hepatocellular carcinoma.Objective:In this study, we examined the therapeutic effects of Ad-REIC in biliary cancer using a second- generation Ad-REIC (Ad-SGE-REIC).Methods:Human biliary cancer cell lines (G-415, TFK-1) were used in this study. The cell viability and apoptotic effect of Ad-SGE-REIC were assessed in vitro using an MTT assay and Hoechst staining. The anti-tumor effect in vivo was assessed in a mouse xenograft model. We also assessed the therapeutic effects of Ad-SGE-REIC therapy with cisplatin. Cell signaling was assessed by Western blotting.Results:Ad-SGE-REIC reduced cell viability, and induced apoptosis in biliary cancer cell lines via the activation of the c-Jun N-terminal kinase pathway. Ad-SGE-REIC also inhibited tumor growth in a mouse xenograft model. This effect was further enhanced in combination with cisplatin.Conclusions:Ad-SGE-REIC induced apoptosis and inhibited tumor growth in biliary cancer cells. REIC/Dkk-3 gene therapy using Ad-SGE-REIC is an attractive therapeutic tool for biliary cancer.

01 Feb 2020·Future Oncology

Study Protocol of a Phase I/IIa Clinical Trial of Ad-SGE-REIC for Treatment of Recurrent Malignant Glioma

Article

Author: Kumon, Hiromi ; Kurozumi, Kazuhiko ; Tomita, Yusuke ; Date, Isao ; Sasaki, Tatsuya ; Shimazu, Yosuke ; Fujii, Kentaro ; Hishikawa, Tomohito ; Kameda, Masahiro ; Yasuhara, Takao

Malignant glioma is one of the most common brain cancers in humans, which is very devastating. The expression of reduced expression in immortalized cells/Dickkopf-3 (REIC/Dkk-3) is decreased in various human cancers. Lately, we have developed a novel second-generation adenoviral vector that expresses REIC/Dkk-3 (Ad-SGE-REIC) and revealed its antiglioma efficacy. The present investigator-initiated clinical trial is a single-arm, prospective, nonrandomized, noncomparative, open-label, single-center trial performed at Okayama University Hospital, Okayama, Japan. The primary end points are dose-limiting toxicities and the incidence of adverse events. The secondary end points are the objective response rate and immunological assessment. Use of Ad-SGE-REIC will help to improve the prognosis of patients with malignant brain tumors.

100 Deals associated with Ad-SGE-DKK3 gene therapy(KYORIN Pharmaceutical Co. Ltd.)

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Malignant Pleural Mesothelioma	Phase 2	JP	KYORIN Pharmaceutical Co., Ltd.	03 Aug 2018
Mesothelioma	Phase 2	-	Momotaro-Gene, Inc.	-
Mesothelioma	Phase 2	-	Okayama University	-