A Phase I/II Study of the Safety and Feasibility of Administering T Cells Expressing Anti-EGFRvIII Chimeric Antigen Receptor to Patients With Malignant Gliomas Expressing EGFRvIII

Background:
The National Cancer Institute (NCI) Surgery Branch has developed an experimental therapy for treating patients with gliomas that involves taking white blood cells from the patient, growing them in the laboratory in large numbers, genetically modifying these specific cells with a type of virus (retrovirus) to attack only the tumor cells, and then giving the cells back to the patient. This type of therapy is called gene transfer. In this protocol, we are modifying the patient's white blood cells with a retrovirus that has the gene for epidermal growth factor receptor (EGFR) vIII incorporated in the retrovirus.
Objective:
The purpose of this study is to determine a safe number of these cells to infuse and to see if these particular tumor-fighting cells (anti-EGFRvIII cells) are a safe and effective treatment for advanced gliomas.
Eligibility:
- Adults age 18-70 with malignant glioma expressing the EGFRvIII molecule.
Design:
Work up stage: Patients will be seen as an outpatient at the National Institutes of Health (NIH) clinical Center and undergo a history and physical examination, scans, x-rays, lab tests, and other tests as needed
Leukapheresis: If the patients meet all of the requirements for the study they will undergo leukapheresis to obtain white blood cells to make the anti-EGFRvIII cells. {Leukapheresis is a common procedure, which removes only the white blood cells from the patient.}
Treatment: Once their cells have grown, the patients will be admitted to the hospital for the conditioning chemotherapy, the anti-EGFRvIII cells, and aldesleukin. They will stay in the hospital for about 4 weeks for the treatment.
Follow up: Patients will return to the clinic for a physical exam, review of side effects, lab tests, and scans every month for the first year, and then every 1-2 months as long as their tumors are shrinking. Follow up visits will take up to 2 days.

Start Date16 May 2012

Sponsor / Collaborator

National Cancer Institute

100 Clinical Results associated with Anti-EGFRvIII-CAR(Kite Pharma)

100 Translational Medicine associated with Anti-EGFRvIII-CAR(Kite Pharma)

100 Patents (Medical) associated with Anti-EGFRvIII-CAR(Kite Pharma)

Literatures (Medical) associated with Anti-EGFRvIII-CAR(Kite Pharma)

15 Feb 2023·Science translational medicineQ1 · MEDICINE

Small-molecule toosendanin reverses macrophage-mediated immunosuppression to overcome glioblastoma resistance to immunotherapy

Q1 · MEDICINE

Article

Author: Yang, Fan ; Zhang, Duo ; Jiang, Haowen ; Ye, Jiangbin ; Winkler, Jeffery ; Gong, Yanqing ; Fan, Yi ; Zhang, Lin ; Bagley, Stephen J.

T cell–based immunotherapy holds promise for treating solid tumors, but its therapeutic efficacy is limited by intratumoral immune suppression. This immune suppressive tumor microenvironment is largely driven by tumor-associated myeloid cells, including macrophages. Here, we report that toosendanin (TSN), a small-molecule compound, reprograms macrophages to enforce antitumor immunity in glioblastoma (GBM) in mouse models. Our functional screen of genetically probed macrophages with a chemical library identifies that TSN reverses macrophage-mediated tumor immunosuppression, leading to enhanced T cell infiltration, activation, and reduced exhaustion. Chemoproteomic and structural analyses revealed that TSN interacts with Hck and Lyn to abrogate suppressive macrophage immunity. In addition, a combination of immune checkpoint blockade and TSN therapy induced regression of syngeneic GBM tumors in mice. Furthermore, TSN treatment sensitized GBM to Egfrviii chimeric antigen receptor (CAR) T cell therapy. These findings suggest that TSN may serve as a therapeutic compound that blocks tumor immunosuppression and circumvents tumor resistance to T cell–based immunotherapy in GBM and other solid tumors that warrants further investigation.

01 Feb 2020·European journal of medicinal chemistry

Design, synthesis and biological evaluation of 2-amino-4-(1,2,4-triazol)pyridine derivatives as potent EGFR inhibitors to overcome TKI-resistance

Review

Author: Zhang, Tingting ; Yan, Ruohong ; Wu, Xiaoyun ; Yang, Zichao ; Zhou, Mingfeng ; Zhang, Jiajie ; Yang, Haikui ; Jiang, Ying ; Zhang, Xingmei

A new class of 2-amino-4-(1,2,4-triazol)pyridine derivatives were designed and synthesized as potent epidermal growth factor receptor inhibitors. In particular, compound 10c exhibited significant inhibitory against EGFR^L858R/T790M, and also displayed potent anti-proliferative activity against non-small cell lung cancer cell line H1975. Besides, compound 10j showed potent inhibitory activity against glioblastoma cell line U87-EGFRvⅢ, which was at least 3-fold more potent than Osimertinib and 25-fold superior to Lazertinib. Moreover, molecular modeling and molecular dynamics simulations disclosed the binding model of the most active compound to the domain of EGFR. This contribution provides 2-amino-4-(1,2,4-triazol)pyridines as a new scaffold for EGFR^T790M and/or EGFRvⅢ inhibitor.

01 May 2019·Journal of immunotherapy (Hagerstown, Md. : 1997)Q4 · MEDICINE

Pilot Trial of Adoptive Transfer of Chimeric Antigen Receptor–transduced T Cells Targeting EGFRvIII in Patients With Glioblastoma

Q4 · MEDICINE

Article

Author: Sherry, Richard M ; Fine, Howard A ; Xi, Liqiang ; Robbins, Paul F ; Rosenberg, Steven A ; Epstein, Monica ; Goff, Stephanie L ; Lu, Yong-Chen ; Zheng, Zhili ; Malekzadeh, Parisa ; McIntyre, Lori S ; Lu, Lily ; Morgan, Richard A ; Restifo, Nicholas P ; Feldman, Steven A ; Raffeld, Mark ; Yang, James C

A deletion variant of epidermal growth factor receptor (EGFRvIII) is a known driver mutation in a subset of primary and secondary glioblastoma multiforme. Adoptive transfer of genetically modified chimeric antigen receptor (CAR) lymphocytes has demonstrated efficacy in hematologic malignancies but is still early in development for solid cancers. The surface expression of the truncated extracellular ligand domain created by EGFRvIII makes it an attractive target for a CAR-based cancer treatment. Patients with recurrent glioblastoma expressing EGFRvIII were enrolled in a dose escalation phase I trial, using a third-generation CAR construct derived from a human antibody. Transduced cells were administered after lymphodepleting chemotherapy and supported posttransfer with intravenous interleukin-2. The dose escalation proceeded at half-log increments from 107 to >1010 cells. Primary endpoints were safety and progression-free survival. Eighteen patients were treated with final infusion products ranging from 6.3×106 to 2.6×1010 anti-EGFRvIII CAR+ T cells. Median progression-free survival was 1.3 months (interquartile range: 1.1–1.9), with a single outlier of 12.5 months. Two patients experienced severe hypoxia, including one treatment-related mortality after cell administration at the highest dose level. All patients developed expected transient hematologic toxicities from preparative chemotherapy. Median overall survival was 6.9 months (interquartile range: 2.8–10). Two patients survived over 1 year, and a third patient was alive at 59 months. Persistence of CAR+ cells correlated with cell dose, but there were no objective responses. Administration of anti-EGFRvIII CAR-transduced T cells did not demonstrate clinically meaningful effect in patients with glioblastoma multiforme in this phase I pilot trial.

News (Medical) associated with Anti-EGFRvIII-CAR(Kite Pharma)

23 Jan 2024

·www.biospace.com

PharmAbcine Announces First Patient Dosed in Phase 1a/b Clinical Trial of PMC-309 in Combination with KEYTRUDA® (pembrolizumab) in Patients with Advanced or Metastatic Solid Tumors

[23-January-2024] Initiation of Phase 1a/b clinical trial exploring MTD, RP2D, safety and tolerability of PMC-309 monotherapy and combination therapy with KEYTRUDA® The clinical trial aims to enroll a total of 67 patients across four institutions in Australia DAEJEON, South Korea, Jan. 23, 2024 /PRNewswire/ -- PharmAbcine Inc. (KOSDAQ: 208340ks), a clinical-stage biotech company focusing on next-generation antibody therapeutics, announced today the initiation of patient dosing in the Phase 1a/b clinical trial of PMC-309 in patients with advanced or metastatic solid tumors. PMC-309 is an IgG1 monoclonal antibody with specific binding to VISTA in immunosuppressive cells, exhibiting excellent binding affinity at various pH conditions within the tumor microenvironment (TME). By inhibiting VISTA, PMC-309 presents a differentiated mechanism of action contributing to anti-cancer effects through activation of T cells, activation of monocytes, and proliferation of M1 macrophages. This open-label clinical trial comprises two phases, Phase 1a and Phase 1b. Phase 1a involves PMC-309 monotherapy and combination therapy with KEYTRUDA® (pembrolizumab), determining the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D). In Phase 1b, safety and tolerability of PMC-309 monotherapy and combination therapy with KEYTRUDA® at the RP2D will be evaluated. The clinical trial, spanning four institutions in Australia, aims to enroll a total of 67 patients. Dr. Jin-San Yoo, President and Chief Executive Officer of PharmAbcine, stated, "This clinical trial aims to assess the human safety of PMC-309 and explore the potential of both monotherapy and combination therapy with KEYTRUDA®. We are committed to developing new therapeutic options for cancer patients facing high unmet needs, emphasizing our dedication to advancing oncology treatments." For more information on the clinical trial, please visit clinicaltrials.gov, identifier NCT 05957081. KEYTRUDA® is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. About PharmAbcine Inc. PharmAbcine is a clinical stage public company developing next generation IgG based therapeutics to treat cancer, neovascular eye diseases, and vascular related unmet needs. The Company's main pipeline include clinical assets olinvacimab, PMC-403, and PMC-309. Olinvacimab, the Company's lead asset, is undergoing a Phase 2 trial in combination with MSD's pembrolizumab for mTNBC patients in Australia. The Company entered the Phase 2 study to reconfirm the encouraging result from Phase 1b olinvacimab-pembrolizumab trial, delivering 50% ORR, 67% DCR, and clean safety profile. PMC-403 is a novel TIE2-activating antibody that stabilizes dysfunctional leaky disorganized pathological vessels and can be used for vascular-related eye disease, including wet AMD (Age-related Macular Degeneration). PMC-403 is currently undergoing Phase 1 trial for neovascular AMD patients in Korea. PMC-403 is also being explored to expand into wider therapeutic areas related to pathological vessels including vessel-related rare disease and chronic kidney disease. PMC-309, a novel anti-VISTA-antagonizing IgG in pan pH conditions, is an immune checkpoint regulator that targets MDSC (myeloid derived suppressor cells) and M2 macrophages which play pivotal role in maintaining immunosuppressive TME (Tumor Microenvironment). PMC-005, is an anti-EGFRviii IgG that only binds to EGFRviii expressed on cancer cells and can be applied to various modalities including CAR-T, CAR-NK, CAR-Macrophage, T cell/NK cell engager, and Radio-Immunotherapy. For additional information about PharmAbcine, visit or follow on Youtube and LinkedIn. Company Codes: Korea:208340

Phase 2Phase 1Immunotherapy

100 Deals associated with Anti-EGFRvIII-CAR(Kite Pharma)

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Gliosarcoma	Phase 2	US	National Cancer Institute	16 May 2012
Glioblastoma	Phase 2	US	National Cancer Institute	16 May 2012

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

Anti-EGFRvIII-CAR(Kite Pharma)

Overview

Basic Info

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation