Research into immunotherapy against cancer typically focuses on better recognition of cancer cells by the body's own immune system. Researchers at Amsterdam UMC and Moffitt Cancer Center have taken a different approach. They investigated how cancer affects the energy management of a patient's T cells and showed for the first time that contact with chronic lymphocytic leukaemia (CLL) cells leads to a serious energy crisis in these cells. These findings are published today in Cellular & Molecular Immunology, building on a publication earlier this month in Blood Advances.
CLL is the most common type of leukaemia in the Western world and mainly affects the elderly. Despite new therapies, the disease remains incurable, and treatments are becoming increasingly expensive.
Some cancers, like acute B-cell leukemia, can now be treated by redirecting a patient's own T cells against cancer cells, known as CAR-T cell therapy. However, in many others, including chronic B-cell leukemia (CLL), immune cells fail to eliminate tumors effectively. While it can be lifesaving, it works in only 15% of CLL patients and costs more than $250,000 per patient.
"Our research revealed two things to us: firstly, that healthy T cells greatly increase their absorption of cholesterol and fats after they have identified their targets. Without this fuel, they are unable to proliferate. Secondly, and crucially, that this doesn't happen when T cells come into close contact with leukemia cells," says Arnon Kater, professor of Translational Haematology at Amsterdam UMC. This second finding is in line with the results of another study, published last month in Blood Advances, by the Amsterdam UMC research team and Moffit Cancer Center. In that study, researchers found that the 'engine' of T cells – the mitochondria, small structures in the cell that provide energy – does not function properly in CLL patients. In CLL, these mitochondria become damaged, causing T cells to lose their power to attack cancer cells.
"Just like when a battery is overcharged, we tried to rejuvenate T cells. This was very successful. We demonstrated that an existing drug, which affects energy management, greatly improved the effectiveness of CAR T-cell therapy. We hope this discovery will lead to improved success of CAR T-cell treatment in the future," says Javier Pinilla-Ibarz, MD, Ph.D a senior member at Moffitt Cancer Center
"This discovery brings us one step closer to making CAR T-cell treatment more successful for a greater number of patients. More importantly, it opens the door for exploring similar strategies in other cancers where immune cells struggle to sustain their attack. By addressing the energy crisis in T cells, we hope to enhance immunotherapy across a wider range of cancers," he adds.
New treatment options
The researchers are now working on ways to modify specific genes so that T cells become more resistant to the disruptive effects of CLL on the uptake, processing and use of fuel and building materials. This should ensure that both the fuel supply and the engine of T cells continue to function properly. If this approach is successful, it may also be possible to apply it to other forms of cancer, as immunotherapy with the body's own immune cells does not yet work optimally in many types of cancer.
In addition, an international clinical trial ( HOVON study ) is underway, in which the first results show that combining a drug that weakens and reduces the number of leukaemia cells and greatly improves the effectiveness of a treatment that attracts T cells to cancer cells. This opens the door to combination therapies in which the cancer cells are tackled first, so that the energy management of the immune system is not first weakened by the cancer, and it can therefore function better.
"These findings, combined with our ongoing research, underscore the profound impact of cancer-immune cell crosstalk on metabolism, disrupting the efficient energy supply necessary for immune function. Restoring T cell energy has the potential to significantly enhance the effectiveness of current treatments," concludes Kater.
