H2020Индивидуална стипендия2019–2021

Exh-Res-CART · Exhaustion-resistant CAR-T cells for the treatment of solid tumours

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

Период: 2019-06-01 → 2021-05-31
Финансиране от ЕС: 160 932 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Модифицираните Т-клетки (CAR-T) се изследват, за да се разбере защо те губят ефективността си при борба със солидни тумори. Това е важно, за да се подобри действието и издръжливостта на тези клетки при лечението на тежки форми на рак.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Exhaustion-resistant CAR-T cells for the treatment of solid tumours

Despite considerable improvements in the variety and effectiveness of therapeutic agents in recent years, advanced metastatic cancers remain largely incurable. Therefore, the development of novel therapeutic agents is needed. Chimeric Antigen Receptor-modified T cells (CAR-T) have shown tremendous success in haematological malignancies. However, the outcome of CAR-T cells in patients with solid tumours remains poor. Clinical trials conducted with CAR-T cells targeting solid tumours suggest that CAR-T cells can traffic to tumours and respond to antigen, but fail to expand, persist and mediate objective responses. Thus, a key question remaining is: How can we improve the activity of CAR-T cell responses in solid tumours? In order to answer this question, we need to understand the mechanisms and obstacles preventing effective CAR-T cell activity in solid tumours. In solid tumours, infused engineered T cells need to undertake a long journey to reach the tumour, survive in a rough tumour microenvironment capable of inactivating their effector functions, and be fit enough to eliminate the whole tumour mass. But what is the main mechanism behind this lack of potency and persistence? The premise of our studies is that CAR-T cells become dysfunctional once they reach the tumour, similarly to what occurs with the natural tumour-specific T cells that fail to control tumour growth, and that this dysfunction is in part due to chronic antigen-exposure. The general aim of this project is to enhance the persistence and function of CAR-T cells in solid tumours by overcoming T-cell dysfunction. Our general goal is divided in the following aims: (1) Elucidate the T-cell intrinsic mechanisms by which CAR-T cells become unresponsive to solid tumours, (2) Design new approaches to enable infused T cells to effectively function and persist within the tumour microenvironment. My ultimate goal is to develop a technology to be used in clinical trials, giving a new opportunity to patients that have incurable cancer.

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

Цел на проекта

Adoptive transfer of T-cells collected from patient’s blood and engineered to express chimeric antigen receptors (CARs) has produced unprecedented clinical responses in patients with cancer. CAR-T cells targeting CD19 were recently approved by the US food and drug administration (FDA) and the European Commission (EC) for the treatment of leukemia and lymphoma, heralding a new era for cancer treatment. However, despite the stunning results of CAR-T cells in patients with hematologic malignancies, results with CAR-T cells in patients with solid tumors are far from expected. Although CAR-T cells are able to infiltrate solid tumors and exert antigen directed activity, observed responses in patients with solid tumors have been minor and transient. But what are the mechanisms behind the poor T-cell activity in solid tumors? Are CAR-T cells susceptible to dysfunction in a similar way as the endogenous tumor-specific T cells that fail to eliminate the tumors in treatment-naïve cancer patients? My central hypothesis is that CAR-T cells become exhausted in the tumor microenvironment mainly due to continuous antigen encounter, and that this process can be prevented or delayed. My general aim for this project is to enhance the persistence and function of CAR-T cells by overcoming T-cell dysfunction while promoting T-cell stemness. By using animal models and a combination of innovative technologies, including next-generation sequencing and genome editing I will: 1) elucidate the T-cell intrinsic mechanisms by which CAR-T cells become unresponsive to solid tumors, 2) design new approaches to enable infused T cells to overcome dysfunction and persist within the tumor microenvironment.

Оригинален текст от CORDIS (на английски).

Участници

FUNDACIO DE RECERCA CLINIC BARCELONA-INSTITUT D INVESTIGACIONS BIOMEDIQUES AUGUST PI I SUNYER · BarcelonaКоординаторИспания