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.
