An open-label, uncontrolled, single-arm pilot study to evaluate vascular interventional therapy mediated EGFRVIII-targeted chimeric antigen receptor T cells in advanced brain glioma

Start Date15 Apr 2016

Sponsor / Collaborator-

100 Clinical Results associated with EGFRVIII-targeted CAR-T(Shanghai Genechem)

100 Translational Medicine associated with EGFRVIII-targeted CAR-T(Shanghai Genechem)

100 Patents (Medical) associated with EGFRVIII-targeted CAR-T(Shanghai Genechem)

Literatures (Medical) associated with EGFRVIII-targeted CAR-T(Shanghai Genechem)

01 Oct 2020·Pathology & Oncology ResearchQ4 · MEDICINE

EGFRvIII-CAR-T Cells with PD-1 Knockout Have Improved Anti-Glioma Activity

Q4 · MEDICINE

Article

Author: You, Yongping ; Zhu, Haifeng ; Shen, Zhouming ; Shi, Lei

Glioblastoma multiforme (GBM) is the most malignant form of the brain tumors. EGFR variant III (EGFRvIII) is expressed in about 30% of GBM specimens, but not expressed in normal brain tissues. Therefore, EGFRvIII protein offers an ideal CAR-T therapeutic target for EGFRvIII-positive GBM patients. PD-L1 is expressed in a variety of cancer cells, including GBM. Tumor-associated PD-L1 can bind to PD-1 on T cells and promote apoptosis of T cells, thus suppressing the anti-cancer immune response. In our current studies, PD-1^WT EGFRvIII-CAR-T cells and PD-1^KD EGFRvIII-CAR-T cells were generated. Cytokine production and lytic activity of these two CAR-T cells against to PD-L1^WT EGFRvIII⁺ U373 cells or PD-L1^KO EGFRvIII⁺ U373 cells were evaluated. The results showed that PD-1^KD EGFRvIII-CAR-T cells and PD-1^WT EGFRvIII-CAR-T cells showed same levels of interferon-γ (IFN-γ) and interleukin-2 (IL-2) production as well as cytolytic activity against PD-L1^KO EGFRvIII⁺ U373 cells; however, PD-1^KD EGFRvIII-CAR-T cells exhibited higher levels of IFN-γ and IL-2 production as well as cytolytic activity against PD-L1⁺ EGFRvIII⁺ U373 cells than that of PD-1^WT EGFRvIII-CAR-T cells. PD-1^KD EGFRvIII-CAR-T cells also exhibited higher anti-glioma activity and longer survival in mice in vivo than that of PD-1^WT EGFRvIII-CAR-T cells. Taken together, our findings indicate that PD-1 knockout enhances lytic activity of EGFRvIII-CAR-T cells against PD-L1⁺ EGFRvIII⁺ GBM cells. These might provide a new insight into strategy of GBM CAR-T cell therapy.

01 Apr 2012·BioDrugsQ3 · MEDICINE

Targeting the Epidermal Growth Factor Receptor in Solid Tumor Malignancies

Q3 · MEDICINE

Review

Author: Mette K. Nedergaard ; Hans S. Poulsen ; Chris Juul Hedegaard

The epidermal growth factor receptor (EGFR) is over-expressed, as well as mutated, in many types of cancers. In particular, the EGFR variant type III mutant (EGFRvIII) has attracted much attention as it is frequently and exclusively found on many tumor cells, and hence both EGFR and EGFRvIII have been proposed as valid targets in many cancer therapy settings. Different strategies have been developed in order to either inhibit EGFR/EGFRvIII activity or to ablate EGFR/EGFRvIII-positive tumor cells. Drugs that inhibit these receptors include monoclonal antibodies (mAbs) that bind to the extracellular part of EGFR, blocking the binding sites for the EGFR ligands, and intracellular tyrosine kinase inhibitors (TKIs) that block the ATP binding site of the tyrosine kinase domain. Besides an EGFRvIII-targeted vaccine, conjugated anti-EGFR mAbs have been used in different settings to deliver lethal agents to the EGFR/EGFRvIII-positive cells; among these are radio-labelled mAbs and immunotoxins. This article reviews the current status and efficacy of EGFR/EGFRvIII-targeted therapies.

01 Mar 2011·Neuro-OncologyQ1 · MEDICINE

Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma

Q1 · MEDICINE

Article

Author: John H. Sampson ; Raymond Sawaya ; Henry S. Friedman ; Duane A. Mitchell ; Weiming Shi ; Annick Desjardins ; Allan H. Friedman ; Amy B. Heimberger ; James E. Herndon ; Darell D. Bigner ; James J. Vredenburgh ; Mark R. Gilbert ; Kenneth D. Aldape ; Gary E. Archer ; Roger E. McLendon ; David A. Reardon ; April Coan ; Robert Schmittling

Epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific mutation widely expressed in glioblastoma multiforme (GBM) and other neoplasms, but absent from normal tissues. Immunotherapeutic targeting of EGFRvIII could eliminate neoplastic cells more precisely but may be inhibited by concurrent myelosuppressive chemotherapy like temozolomide (TMZ), which produces a survival benefit in GBM. A phase II, multicenter trial was undertaken to assess the immunogenicity of an experimental EGFRvIII-targeted peptide vaccine in patients with GBM undergoing treatment with serial cycles of standard-dose (STD) (200 mg/m(2) per 5 days) or dose-intensified (DI) TMZ (100 mg/m(2) per 21 days). All patients receiving STD TMZ exhibited at least a transient grade 2 lymphopenia, whereas those receiving DI TMZ exhibited a sustained grade 3 lymphopenia (<500 cells/μL). CD3(+) T-cell (P = .005) and B-cell (P = .004) counts were reduced significantly only in the DI cohort. Patients in the DI cohort had an increase in the proportion of immunosuppressive regulatory T cells (T(Reg); P = .008). EGFRvIII-specific immune responses developed in all patients treated with either regimen, but the DI TMZ regimen produced humoral (P = .037) and delayed-type hypersensitivity responses (P = .036) of greater magnitude. EGFRvIII-expressing tumor cells were also eradicated in nearly all patients (91.6%; CI(95): 64.0%-99.8%; P < .0001). The median progression-free survival (15.2 months; CI(95): 11.0-18.5 months; hazard ratio [HR] = 0.35; P = .024) and overall survival (23.6 months; CI(95): 18.5-33.1 months; HR = 0.23; P = .019) exceeded those of historical controls matched for entry criteria and adjusted for known prognostic factors. EGFRvIII-targeted vaccination induces patient immune responses despite therapeutic TMZ-induced lymphopenia and eliminates EGFRvIII-expressing tumor cells without autoimmunity.

100 Deals associated with EGFRVIII-targeted CAR-T(Shanghai Genechem)

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Indication	Highest Phase	Country/Location	Organization	Date
Glioma	Phase 1	CN	Shanghai Genechem Co., Ltd.	-

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