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

Periodic Reporting for period 1 - Exh-Res-CART (Exhaustion-resistant CAR-T cells for the treatment of solid tumours)

Reporting period: 2019-06-01 to 2021-05-31

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.
In this project, we have generated a CAR-T cell therapy targeting Her-2 for the treatment of breast and ovarian cancer. We have tested this therapy in mice with ovarian cancer tumours and found that large ovarian tumours can be completely eliminated when using high doses of CAR-T cells. However, when using lower CAR-T cell doses, that are more clinically relevant, CAR-T cells can cause tumour regressions, but eventually they fail to control tumour growth. Analysis of the tumours at the end of the experiments showed robust and uniform expression of the targeted antigen (Her2), therefore excluding loss of antigen expression as the main cause of tumour escape. The observation that relapsed tumours were highly infiltrated with CAR-T cells suggested that T cell dysfunction was the more plausible cause of treatment failure. We next analysed the phenotype of T cells infiltrating tumours during the phase of effective tumour elimination and during the phase of tumour relapse. We found that, during the phase of tumour relapse, T cells isolated from tumours display some features of T cell exhaustion, such as loss of proliferative capacity and increased expression of inhibitory receptors. In conclusion, we have developed an animal model to study CAR-T cell dysfunction. Using this model, we plan to obtain CAR-T cells from different normal donors at the different stages of T cell treatment an study the genes responsible for effective T cell treatment versus loss of effector T cell function. Understanding and manipulating the mechanistic pathways that lead to CAR-T cell dysfunction may pave the way towards effective tumor elimination.
During these first months of the project, we have developed a mouse model of solid tumours to study CAR-T cell dysfunction. Using this model, we will be able to generate new knowledge on the dysfunction of tumour-infiltrating CAR-T cells. Next steps will allow the definition of molecular signatures of CAR-T cells with either positive or negative effects on antitumour T cell responses. We will exploit this new knowledge to generate long-lived CAR-T cells resistant to T cell exhaustion.
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