Expanding the benefits of immunotherapy for cancer patients
Immune checkpoint blockade (ICB) is a revolutionary cancer treatment, which uses drugs to block proteins known as immune checkpoints. These checkpoints stop immune cells from targeting cancerous tissue. Yet despite strong results, the therapy only benefits a small percentage of cancer patients. ICB is generally only effective in tumours that are highly visible to the immune system, such as lung cancers in smokers and melanomas caused by UV exposure. And the mechanism of ICB involves rescuing previously activated T-cells or boosting T-cell responses. However, these therapies can in theory target any T-cells in the body, including those responding to viruses. “This lack of selectivity is why ICB treatment often results in immune-related adverse effects,” explains Noel de Miranda(opens in new window), associate professor of Cancer Immunogenomics at Leiden University Medical Center(opens in new window). “Unfortunately, we currently lack a reliable way to predict whether, in a given patient, ICB will primarily enhance tumour-specific T-cells or affect other T-cell populations,” he adds. In the RARITY project, which was funded by the European Research Council(opens in new window), researchers led by de Miranda aimed to develop strategies that complement ICB activity, to expand the benefits of immunotherapy to a broader patient population. “This can be seen as adding new tools to the immunotherapy toolbox, which is particularly crucial for cancers that do not respond to ICB therapy,” says de Miranda.
Identifying cancer-reactive immune cells
Through the RARITY project, the researchers combined fundamental (preclinical) and translational research, making use of clinical trial data and samples. First the team investigated whether specific markers pinpoint cancer-specific T-cells, which could then be used as therapeutic products. In collaboration with clinical partners, the researchers also sought to identify new cellular effectors of immunotherapy response, by analysing samples from patients treated with ICB. “This bidirectional exchange between the lab and the clinical setting is the ideal research setting for our research group,” notes de Miranda.
Contributing to innovative and alternative immunotherapies
RARITY successfully demonstrated that tumour-specific T-cells are also present in patients who are not currently benefiting from checkpoint blockade immunotherapy. “This is a significant finding, as it suggests that these patients could eventually be treated with immunotherapy once the optimal approach to harnessing these cells is identified,” explains de Miranda. The team also showed that tumour-specific T-cells can be distinguished from other T-cells, opening the possibility for their targeted isolation and use in immunotherapy. RARITY also highlighted the significance of lesser-known immune cell subsets, and demonstrated their role in immune responses in patients undergoing checkpoint blockade immunotherapy. While most immunotherapy research has traditionally focused on conventional T-cells, this provides alternative avenues for therapies to eliminate cancer cells. Finally, RARITY helped in the development of numerous technological approaches currently operational in de Miranda’s lab, providing unprecedented insights into cancer biology and the interactions between cancer cells and immune cells. “These technologies place us in a privileged position to dissect the mechanisms underlying therapeutic responses in patients, ultimately leading to the design of novel strategies to enhance treatment efficacy,” adds de Miranda.
A deepening knowledge of cancer biology
The work under RARITY will continue in de Miranda’s lab, supporting the development of novel immunotherapies and dissecting the mechanisms of response in patients undergoing immunotherapy. “Additionally, we continue to leverage advanced technologies to deepen our understanding of cancer biology,” says de Miranda.
Keywords
RARITY, cancer, immunotherapy, cancer-reactive immune cells, innovative, immunotherapies, biology
