AdCD40L(AdCD40L) - 药物靶点：CD40L_在研适应症：膀胱癌，黑色素瘤_专利_临床

概要

基本信息

药物类型

基因疗法

别名-

靶点

CD40L

作用机制

CD40L抑制剂(CD40配体抑制剂)

治疗领域

肿瘤皮肤和肌肉骨骼疾病泌尿生殖系统疾病

在研适应症

膀胱癌黑色素瘤

非在研适应症

晚期癌症非肌层浸润性膀胱肿瘤

原研机构

Uppsala University Hospital

在研机构

Uppsala University Hospital

非在研机构

University of Uppsala

最高研发阶段临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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关联

3

项与 AdCD40L 相关的临床试验

NCT01455259 / Completed临床1/2期

Phase I/IIa AdCD40L Immunogene Therapy for Patients With Advanced Malignant Disease.

In this phase I/II trial, immunostimulatory gene therapy (AdCD40L) will be investigated. In Part 1 patients with melanoma will receive AdCD40L as mono therapy. In Part 2A, patients with melanoma and patients with other solid tumors will receive AdCD40L in combination with low dose cyclophosphamide. In Part 2B, patients with melanoma will receive AdCD40L in combination with one local radiotherapy and cyclophosphamide.

开始日期2011-09-01

申办/合作机构

University of Uppsala

[+1]

EUCTR2010-023103-94-SE / Not yet recruitingN/A

PHASE I/IIa AdCD40L IMMUNOGENE THERAPY FOR MALIGNANT MELANOMA PATIENTS WITH DISSEMINATED DISEASE - 002:CD40L

开始日期2011-07-04

申办/合作机构

University of Uppsala

NCT00891748 / Completed临床1/2期

A Phase I/IIa Study of Dose-escalating Intravesical AdCD40L Instillation in Urinary Bladder Carcinoma

The study objective is to evaluate the feasibility of three instillations of immunostimulating gene therapy (AdCD40L) in patients with urinary bladder cancer. Tolerance, toxicity and immunological parameters will be evaluated during and post treatment.

开始日期2006-11-01

申办/合作机构

University of Uppsala

[+1]

100 项与 AdCD40L 相关的临床结果

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100 项与 AdCD40L 相关的转化医学

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100 项与 AdCD40L 相关的专利（医药）

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23

项与 AdCD40L 相关的文献（医药）

2021-11-01·Cancer Gene Therapy1区 · 医学

Intratumoral immunostimulatory AdCD40L gene therapy in patients with advanced solid tumors

1区 · 医学

Article

作者: Irenaeus, Sandra ; Sundin, Anders ; Tötterman, Thomas H ; Hellström, Vivan ; Loskog, Angelica ; Krause, Johan ; Ullenhag, Gustav J ; Wenthe, Jessica ; Tufveson, Gunnar ; Ahlström, Håkan

AdCD40L is a replication-deficient virus carrying the gene for CD40 ligand which has previously been evaluated in patients with urothelial cancer and malignant melanoma. Herein, we present the results of repeated intratumoral injections of AdCD40L in seven patients with metastatic solid cancer. One patient who developed urothelial cancer derived from a renal transplant was treated with repeated injections of AdCD40L alone. The remaining patients suffered from cholangiocarcinoma, kidney, breast, rectal, or ovarian cancer and received AdCD40L repeatedly (4x) in combination with cyclophosphamide. The treatment was safe and generally well-tolerated. Two patients had clinical benefit of the treatment and one of them was accepted for re-treatment. Circulating proinflammatory cytokines were commonly increased after treatment, but save for TNFα, significances were not reached which could be due to the low number of patients. Similar to earlier findings in AdCD40L-treated melanoma patients, IL8 plasma levels were high in the present study. In conclusion, gene therapy by repeated intratumoral AdCD40L injections alone, or in combination with cyclophosphamide, is feasible and safe in patients with solid cancers. The potential of intratumoral CD40L gene transfer as treatment of cancer was illustrated by the clinical improvement in two out of seven patients.

2020-12-18·Neuro-Oncology1区 · 医学

Ad-CD40L mobilizes CD4 T cells for the treatment of brainstem tumors

1区 · 医学

Article

作者: Stone, Cathy ; Parker, Alan L ; Tonne, Jason ; Evgin, Laura ; Vile, Richard G ; Wetmore, Cynthia ; Huff, Amanda L ; Thompson, Jill M ; Driscoll, Christopher B ; Wongthida, Phonphimon ; Davies, James A ; Schuelke, Matthew R ; Kottke, Timothy

AbstractBackgroundDiffuse midline glioma, formerly DIPG (diffuse intrinsic pontine glioma), is the deadliest pediatric brainstem tumor with median survival of less than one year. Here, we investigated (i) whether direct delivery of adenovirus-expressing cluster of differentiation (CD)40 ligand (Ad-CD40L) to brainstem tumors would induce immune-mediated tumor clearance and (ii) if so, whether therapy would be associated with a manageable toxicity due to immune-mediated inflammation in the brainstem.MethodsSyngeneic gliomas in the brainstems of immunocompetent mice were treated with Ad-CD40L and survival, toxicity, and immune profiles determined. A clinically translatable vector, whose replication would be tightly restricted to tumor cells, rAd-Δ24-CD40L, was tested in human patient–derived diffuse midline gliomas and immunocompetent models.ResultsExpression of Ad-CD40L restricted to brainstem gliomas by pre-infection induced complete rejection, associated with immune cell infiltration, of which CD4+ T cells were critical for therapy. Direct intratumoral injection of Ad-CD40L into established brainstem tumors improved survival and induced some complete cures but with some acute toxicity. RNA-sequencing analysis showed that Ad-CD40L therapy induced neuroinflammatory immune responses associated with interleukin (IL)-6, IL-1β, and tumor necrosis factor α. Therefore, to generate a vector whose replication, and transgene expression, would be tightly restricted to tumor cells, we constructed rAd-Δ24-CD40L, the backbone of which has already entered clinical trials for diffuse midline gliomas. Direct intratumoral injection of rAd-Δ24-CD40L, with systemic blockade of IL-6 and IL-1β, generated significant numbers of cures with readily manageable toxicity.ConclusionsVirus-mediated delivery of CD40L has the potential to be effective in treating diffuse midline gliomas without obligatory neuroinflammation-associated toxicity.

2017-12-01·Journal of Translational Medicine2区 · 医学

Adenovirus-mediated CD40L gene transfer increases Teffector/Tregulatory cell ratio and upregulates death receptors in metastatic melanoma patients

2区 · 医学

ArticleOA

作者: Nilsson, Anders ; Mangsbo, S ; Schiza, A ; Eriksson, E ; Ullenhag, G ; Wenthe, J ; Loskog, A ; Tötterman, T H

AbstractBackground and aimsMalignant melanoma is an aggressive tumor sensitive for immunotherapy such as checkpoint blockade antibodies. Still, most patients with late stage disease do not respond, and the side effects can be severe. Stimulation of the CD40 pathway to initiate anti-tumor immunity is a promising alternative. Herein, we demonstrate immune profiling data from melanoma patients treated with an adenovirus-based CD40 ligand gene therapy (AdCD40L).MethodsPeripheral blood mononuclear cells and plasma were collected from malignant melanoma patients (n = 15) enrolled in a phase I/IIa study investigating intratumoral delivery of AdCD40L with or without low dose cyclophosphamide. Cells were analyzed by flow cytometry while plasma samples were analyzed by a multi-array proteomics.ResultsAll patients had an increased Teffector/Tregulatory cell ratio post therapy. Simultaneously, the death receptors TNFR1 and TRAIL-R2 were significantly up-regulated post treatment. Stem cell factor (SCF), E-selectin, and CD6 correlated to enhanced overall survival while a high level of granulocytic myeloid-derived suppressor cells (gMDSCs), IL8, IL10, TGFb1, CCL4, PlGF and Fl3t ligand was highest in patients with short survival.ConclusionsAdCD40L intratumoral injection induced desirable systemic immune effects that correlated to prolonged survival. Further studies using CD40 stimulation in malignant melanoma are warranted.Trial registration The 002:CD40L trial “Phase I/IIa AdCD40L Immunogene Therapy for Malignant Melanoma and Other Solid Tumors” (clinicalTrials.gov identifier: NCT01455259) was registered at September 2011

100 项与 AdCD40L 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
膀胱癌	临床2期	-	Uppsala University Hospital	-
黑色素瘤	临床2期	-	Uppsala University Hospital	-
晚期癌症	药物发现	瑞典	University of Uppsala	2011-09-01
非肌层浸润性膀胱肿瘤	药物发现	瑞典	University of Uppsala	2006-11-01