Boosting metabolism in T cells: a tool to improve T cell therapy for chronic lymphocytic leukemia patients

Project Information

BOOTCAMP

Grant agreement ID: 864815

DOI

10.3030/864815

EC signature date 15 July 2020

Start date 1 August 2020

End date 31 January 2027

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 997 662,00

EU contribution

€ 1 997 662,00

Coordinated by

STICHTING AMSTERDAM UMC
Netherlands

Periodic Reporting for period 3 - BOOTCAMP (Boosting metabolism in T cells: a tool to improve T cell therapy for chronic lymphocytic leukemia patients)

Reporting period: 2023-08-01 to 2025-01-31

Summary of the context and overall objectives of the project

What is the problem/issue being addressed?
Chronic lymphocytic leukemia (CLL) is still uncurable. the most common type of leukemia and mainly affects the elderly. The disease can rarely be cured, causing ~40,000 deaths globally per year. Recent global phase 3 trials (including landmark studies we have been leading) compared novel targeted agents, with chemo-immunotherapeutic regimes and paved the way for novel chemotherapy-free therapies. Nevertheless, these treatments are not curative, and as inevitable result, increasing numbers of patients emerge with resistant disease that has a very poor outcome. Hence, despite recent advances in the therapeutic landscape of CLL, an unmet need exists for additional therapeutic strategies with curative potential. Novel autologous T cell-based therapies engage patient's own T cells to combat tumor cells. In contrast to aggressive B-cell leukemia, current autologous T cell-based therapies are far less effective in CLL, causing most patients to relapse within 2 years. The limited responses of autologous T cell-based therapy in CLL is due to acquired and progressive T-cell dysfunction,
Within the ERC consolidator BOOTCAM grant, I aim to improve the understanding of T-cell dysfunction, in order to develop novel T-cell based strategies for CLL. Preliminary data pointed to alterations in T-cell metabolism as possible driver of immune dysfunction imposed by CLL cells.

Why is it important for society?
CLL is the most common type of leukemia and mainly affects the elderly. The disease can rarely be cured, causing ~40,000 deaths globally per year. Due to increasing ages, this number is expected to increase in the years to come. Targeted agents are effective, but are to be taken for prolonged periods of time, causing a high financial burden for society.
Despite successes of T cell-based therapies, it is not yet active in many other diseases than CLL as well.
Findings obtained in BOOTCAMP will not only improve therapeutic options, and outcome for patients with CLL, but potentially also for patients with other malignancies with dismal outcome, also on autologous-based T cell therapies.

What are the overall objectives?
The short-term objectives are:
1. Characterize the molecular mechanism of metabolic and functional alterations in CLL-derived T cells
2. Elucidate how CLL cells reprogram T cells
3. Increase (mitochondrial biogenesis and) fitness in (CAR-_T cells to improve therapeutic efficacy
The long-term objective is to improve efficacy of autologous T cell-based strategies by reversing metabolic dysfunction in CLL T cells as a step towards a cure.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

So far we discovered at what levels metabolism is altered in T cells from CLL patients, we partly understand how CLL cells impact T cell metabolism and function.
We found that acquired T cell dysfunction is highly regulated at the epigenetic level, making it attractive for therapeutic interventions.
We discovered that uptake and use of key fuels of both CLL and T cells is disturbed, also providing novel clinical exploitable pathways.
Against the current dogma that T cells in CLL are at a (pseudo) exhausted state, we foumd that these T cells suffer from a heavily disturbed T cell receptor/CD3 signaling pathway. We now found highly promising tools that provide alternative activation which rescues these cells from dysfunction.

Data obtained so far were presented at conferences in more than 15 scientific abstracts and have resulted in 6 published scientific manuscripts. A patent application will be filed in the next period.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Data thus far, provides clues for novel treatment strategies that are actively being pursued. Such therapies are at the level of gene editing and the generation of novel CAR and bispecific constructs.