H2020Индивидуална стипендия2021–2023

TRAP-CART · Tumor targeting through a TME-specific regulatory code and programmable CAR T cells

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2021-04-01 → 2023-03-31
Финансиране от ЕС: 174 167 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Генното инженерство на CAR T клетките и анализът на макрофагите в туморната среда помагат за създаването на по-прецизна и специфична имунотерапия. Това е важно, за да се подобрят методите за лечение на рака, който е една от водещите причини за смърт в света.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Tumor targeting through a TME-specific regulatory code and programmable CAR T cells

This project aimed at potentiate cancer immunotherapies by modifying cells of the immune system and improve current cell therapies based on CAR T cells. The project is very important for society since cancer is one of the leading cause of death and suffering worldwide, and new strategies to improve cancer treatment are urgently needed. The overall objectives of the project are to generate a publicly available database of sequences which could be exploited to render immunotherapies more cancer-specific and provide a proof-of-concept for our new strategy based on gene engineering. During the action we were able to accumulate data concerning chromatin and epigenetic signatures of tumor associated macrophages (TAM) associated to enhancers specifically active in this context. We have developed a strategy to set up the screening of these enhancers and promoters for their activity within the tumor. And we have developed ways to couple TAM engineering

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

Two major issues hamper successful treatment of solid cancers with CAR T cells. First, immunosuppression imposed by the tumor microenvironment (TME) can compromise CAR T cell function. Second, CAR T cells require specific antigens for precise tumor recognition to limit/avoid toxicities associated with on-target/off-tumor activity. Initial attempts to overcome these challenges included immune checkpoint blockade and tunable CAR T cells. Here, we propose to develop a conceptually new framework for solid tumor therapy that introduces genetically modified, blood-derived TME cells as Trojan horses to deliver inflammation and broadcast “intratumor” signals that activate programmable CAR T cells. Overall, we will design a hematopoietic stem cell (HSC)-directed strategy for Tumor microenvironment-Regulated Activation of Programmable CAR T (TRAP-CART). This project builds on the host lab’s expertise in high-throughput genomics, bioinformatics, and CAR T cells, and on my own background in HSC engineering.Through epigenome/transcriptome profiling, we will systematically identify gene-regulatory elements that are specific to blood-derived cells in the TME. We will use such regulatory sequences for HSC-directed gene therapy, such that their progeny will express a programmed transgene only in the immediate vicinity of tumor cells. This TME-regulated transgene will induce inflammation (to help overcome the hostile immune environment of many solid tumors) and/or release localized activatory signals for CAR T-cells (making it possible to use weakly specific CARs while avoiding on-target/off-tumor activity elsewhere in the body). We will focus on melanoma as our “model cancer”, which has a high mutational burden, good mouse models and is widely used for testing cutting-edge immunotherapies. Specific Objectives:1)Develop a promoter/enhancer toolbox for HSC gene therapy targeting the TME2)Induce a CAR T-supportive TME that activates programmable CAR T-cells in situ

Оригинален текст от CORDIS (на английски).

Участници

CEMM - FORSCHUNGSZENTRUM FUER MOLEKULARE MEDIZIN GMBH · WienКоординаторАвстрия