Immunotherapy that enhances T-cells has not been particularly successful to date for chronic lymphocytic leukaemia (CLL) patients. An international research collaboration led by scientists from Cancer Center Amsterdam takes on the daunting task of understanding why – with the hope of improving this therapy option for patients. Recently, their research was published in Leukemia.
Chronic lymphocytic leukaemia is the most common type of leukaemia in adults. Many patients live with the disease symptom-free for years, however as disease progresses patients must consider their treatment options. One new option is immunotherapy, where the body’s own immune system is given a boost to fight disease. For CLL patients, this involves harvesting their cells and adding a cancer-detection receptor before transfusion back to the patient (chimeric antigen receptor (CAR) T-cell therapy). This treatment is very effective against acute lymphoblastic leukemia (ALL), but CLL patients have not experienced the same success. Researchers in Amsterdam tried to find out why.
For a CAR-T treatment to succeed, the modified immune cells, specifically T-cells, need to persist long enough in the body to fight disease. Certain types of T-cells survive longer than others, and in CLL patients, the T-cell population is unusually skewed toward short-lived T-cells. The reason for this shift in T-cell population is not yet known. To understand the epigenetic, transcriptional, and functional mechanisms driving this skew, researchers need to conduct long term T-cell studies on patient-derived samples, and this is difficult.
Despite the challenges, an international collaboration led by Dr. Fleur Peters and Prof. Arnon Kater set out to explain how CLL cells might skew T-cell differentiation in favor of short-lived T-cells. Their aim: (1) to determine if the presence of CLL cells directly affects epigenetic programming resulting in irregular T-cell differentiation, or (2) if CLL is causing the T-cell population to skew independent of CLL-antigen recognition.
The team began by first conducting in vitro studies with CLL cells from patients. “The in vitro studies confirm that CLL cells dysregulate T-cell differentiation to preferentially become short-lived effector T-cells at the expense of more persistent memory T-cells,” says Dr. Fleur Peters.
To gain more mechanistic insight into this dysregulation, the team developed a unique in vivo CLL-like mouse model. This allowed them to observe the impact of antigen-specific T-cell behavior in healthy mice versus mice with CLL-like disease.
“The in vivo studies show that the presence of CLL induces a short-lived effector T-cell phenotype and impaired T-cell memory responses through strong epigenetic reprogramming,” Dr. Peters says. This resulted in an immune system that is less equipped to react in the presence of CLL.
The knowledge gained from this study, recently published in the respected journal Leukemia, helps demystify the lack of CAR T treatment success in CLL patients to date. “Our results imply that CLL-like disease hampers optimal memory T-cell formation,” Dr. Peters explains. “With this knowledge, we can better understand how CLL may impact the immune response in patients and eventually improve T-cell-based therapies for this group.”
Martens, A.W.J., Kavazović, I., Krapić, M. et al. Chronic lymphocytic leukemia presence impairs antigen-specific CD8+ T-cell responses through epigenetic reprogramming towards short-lived effectors. Leukemia (2023). https://doi.org/10.1038/s41375-023-01817-z