Scientists at the University of Glasgow developed a bioengineered bone marrow (BM) model that helped them to evaluate potential use of a combined CRISPR-CAR T cell therapy in the treatment of acute myeloid leukemia.
The team claims the model, which incorporates human cells in a synthetic peptide hydrogel, allows researchers to generate new insights into potential therapies for the disease, and represents an important step forward in being able to carry out medical research without the use of animals. They suggest that the new bioengineered model delivered the kind of human-relevant insights and information that current research methods that rely on animal models have so far been unable to achieve.
Hannah Donnelly, PhD, a 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.”
Donnelly is co-senior author on the team’s published paper in Biomaterials, titled “Synthetic peptide hydrogels as a model of the bone marrow niche demonstrate efficacy of a combined CRISPR-CAR T-cell therapy for acute myeloid leukemia.”
Leukemias are cancers caused by mutations in hematopoietic stem cells (HSCs), which then rely on interactions with the bone marrow for their growth and survival. “Leukemic malignancy is commonly driven by mutated hematopoietic stem cells (HSCs), which become chemoresistant leukemia stem cells (LSCs) and represent a major contributor to disease progression and relapse,” the authors explained.
Healthy HSCs interact with their microenvironment, including other cell types such as mesenchymal stromal cells (MSCs), and the extracellular matrix (ECM) of the bone marrow where they reside. This microenvironment, known as the bone marrow niche (BMN), is also relied on by LSCs, the researchers continued. “LSCs depend on the BM niche; during leukemic transformation, the niche is remodeled to facilitate LSC growth and survival and has been shown to play a role in chemoresistance.”
Studying HSCs outside of the body is particularly challenging. Once removed from the bone marrow, HSCs quickly change or die, making them challenging, or impossible, to work with in the lab. As a result, until now, research teams have had to rely on animal models to test new drugs that could target blood cancers.
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 prior to clinical trial has been hampered by the differences between humans and animal models.
“Currently, preclinical testing of CAR T-cell therapies relies on simplified in vitro systems and in vivo models that fail to sufficiently predict efficacy or adverse events that occur in patients, demonstrating a significant translational gap,” the investigators noted.
Now, a team led by scientists at the University of Glasgow has been able to successfully carry out research on leukemic HSCs by inserting them into bioengineered jelly-like 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 treat the disease.
Using their bioengineered stem cell model the researchers were able to gain key new information on the efficacy and safety of the CAR T-cell therapy for AML. They found that conventional testing methods, typically cells in a Petri dish, both overestimated the effectiveness of the treatment 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. “In conclusion, we have successfully developed a simple, synthetic BM model which replicates some of the complexity of the endogenous niche,” the authors wrote. “Our niche facilitated testing of a CRISPR-CAR T-cell therapy for AML which has been researched extensively but has yet to reach clinical trial…These results highlight the usefulness of in vitro organ models as a cruelty-free, fully human alternative for bridging the gap between pre-clinical research and clinical trials.”
Donnelly commented, “Our results highlight the potential of non-animal technologies for studying and developing new leukemia 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.”
While this is an early-stage study, the approach opens the door to more accurate pre-clinical testing, which—over the next decade—could help improve the development of safer and more effective therapies.
