Scientists at the University of Glasgow have successfully used the first bioengineered bone marrow model to carry out vital cancer research, offering new insights into potential therapies for the disease.
The research is an important step forward in being able to carry out medical research without the use of animals.
In a study published in the journal Biomaterials, the researchers detail the efficacy of CAR T-cell therapy – a promising new blood cancer treatment – in targeting acute myeloid leukaemia (AML), the most common leukaemia in adults.
The scientists say their new bioengineered model has been able to deliver the kind of human-relevant insights and information that current research methods that rely on animal models have so far been unable to achieve.
Leukaemia cancers are caused by mutations in hematopoietic stem cells (HSCs), which then rely on interactions with the bone marrow for their growth and survival.
However, studying these stem cells outside of the body is particularly challenging, as once they are removed from the bone marrow, HSCs quickly change or die, making them challenging to work with in laboratories.
Thus, until now, research teams have had to rely on animal models to test new drugs that could target blood cancers.
Now, a team led by scientists at the University of Glasgow has been able to successfully carry out research on leukaemic HSCs by inserting them into bioengineered jelly-like substances, called hydrogels, that mimic the natural bone marrow environment.
The team then targeted the cancer cells with CAR T-cell therapy to find out if it could effectively target the disease.
While this is an early-stage study, the approach opens the door to more accurate pre-clinical testing, which, during the next decade, could help improve the development of safer and more effective therapies.
While CAR T-cell therapy has shown promise for other blood cancers, its application to AML has been hindered by a number of issues, including toxicity to local healthy cells.
Researchers have suggested that combining CRISPR-Cas9 gene editing with CAR T-cell therapy might have the potential for selectively targeting AML cells while sparing healthy tissue, by essentially making healthy cells ‘invisible’ to CAR T cells.
However, so far, validating the effectiveness of this combination of treatments before a clinical trial has been hampered by the differences between humans and animal models.
Using their bioengineered stem cell model, the team were able to provide key new information on the efficacy and safety of CAR T-cell therapy for AML.
They found that conventional testing methods, which are typically cells in a Petri dish, both overestimated the effectiveness of CAR T-cell therapy and failed to predict its harmful effects on healthy cells — issues that were detected using the bioengineered tissue model.
The new findings have clear implications not only for future research on CAR T-cell therapy for AML, but also on approaches to pre-clinical CAR T-cell testing.
Dr Hannah Donnelly, a lead author of the study and research fellow at the University of Glasgow, said: “There is a major translational gap in cell therapy development — conventional, over-simplified testing methods often fail to predict how therapies will behave in humans."
"This gap leads to high failure rates in clinical trials, driving up costs and delaying treatments for patients."
"By using human cells combined with hydrogels to mimic the complex structure of the bone marrow in the lab, we’ve shown that it’s possible to assess both the effectiveness of therapies and detect off-target effects much earlier — well before they reach the expensive clinical trial stage.
“Our results highlight the potential of non-animal technologies for studying and developing new leukaemia therapies."
"This approach could reduce reliance on animal models in drug testing over time, ultimately paving the way for more efficient and effective development of therapies for patients.”