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A Phase 1/2 Trial of TC-510 In Patients With Advanced Mesothelin-Expressing Cancer

ABSTRACT: TC-510 is a novel cell therapy that consists of autologous genetically engineered T cells expressing two synthetic constructs: first, a single-domain antibody that recognizes human Mesothelin, fused to the CD3-epsilon subunit which, upon expression, is incorporated into the endogenous T cell receptor (TCR) complex and second, a PD-1:CD28 switch receptor, which is expressed on the surface of the T cell, independently from the TCR. The PD-1:CD28 switch receptor comprises the PD-1 extracellular domain fused to the CD28 intracellular domain via a transmembrane domain. Thus, the switch is designed to produce a costimulatory signal upon engagement with PD-L1 on cancer cells.

DISEASE(S): Adenocarcinoma,Tnbc - Triple-negative Breast Cancer,Pancreatic Adenocarcinoma,Triple Negative Breast Neoplasms,Colorectal Cancer,Non Small Cell Lung Cancer,Mesothelioma,Triple Negative Breast Cancer,Pancreatic Cancer,Breast Neoplasms,Neoplasms,Ovarian Cancer,Mesothelioma Peritoneum,Mesotheliomas Pleural,Colorectal Neoplasms,Mesothelioma, Malignant,Cystadenocarcinoma, Serous,Ovarian Neoplasms,Ovarian Serous Adenocarcinoma,Pancreatic Neoplasms,Cholangiocarcinoma,Ovarian Adenocarcinoma

PROVIDER: 2740481 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Mukhopadhyay2013 - T cell receptor proximal signaling reveals emergent ultrasensitivity This model is described in the article: Systems model of T cell receptor proximal signaling reveals emergent ultrasensitivity. Mukhopadhyay H, Cordoba SP, Maini PK, van der Merwe PA, Dushek O. PLoS Comput. Biol. 2013; 9(3): e1003004 Abstract: Receptor phosphorylation is thought to be tightly regulated because phosphorylated receptors initiate signaling cascades leading to cellular activation. The T cell antigen receptor (TCR) on the surface of T cells is phosphorylated by the kinase Lck and dephosphorylated by the phosphatase CD45 on multiple immunoreceptor tyrosine-based activation motifs (ITAMs). Intriguingly, Lck sequentially phosphorylates ITAMs and ZAP-70, a cytosolic kinase, binds to phosphorylated ITAMs with differential affinities. The purpose of multiple ITAMs, their sequential phosphorylation, and the differential ZAP-70 affinities are unknown. Here, we use a systems model to show that this signaling architecture produces emergent ultrasensitivity resulting in switch-like responses at the scale of individual TCRs. Importantly, this switch-like response is an emergent property, so that removal of multiple ITAMs, sequential phosphorylation, or differential affinities abolishes the switch. We propose that highly regulated TCR phosphorylation is achieved by an emergent switch-like response and use the systems model to design novel chimeric antigen receptors for therapy. This model is hosted on BioModels Database and identified by: MODEL1604100000. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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A Phase 1/2 Trial of TC-510 In Patients With Advanced Mesothelin-Expressing Cancer

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