A team of researchers at NYU Tandon School of Engineering has created the first laboratory device that replicates both the structural and immune features of human bone marrow, allowing scientists to study how CAR T-cell immunotherapies interact with leukemia in real time. The microscope slide sized “leukemia on a chip” device uses patient-derived bone marrow cells that self-organize to produce their own cellular matrix, which could significantly accelerate preclinical testing of immunotherapy candidates. Details of the new device are published in Nature Biomedical Engineering.
“We can now watch cancer treatments unfold as they would in a patient, but under completely controlled conditions without animal experimentation,” said senior author Weiqiang Chen, PhD, a professor of mechanical and aerospace engineering at NYU.
The platform incorporates engineered tissue that mimics three key regions of the bone marrow environment: the blood vessels, the marrow cavity, and the outer bone lining to create a physiologically relevant and immunocompetent microenvironment. The researchers wrote that the chip “recapitulates microarchitectural and pathophysiological characteristics of human leukemia bone marrow stromal and immune niches for CAR T cell therapy modeling.”
In earlier research, the Chen lab had developed a leukemia-on-a-chip device to investigate chemoresistance, using single-cell RNA sequencing to study immune dynamics in the leukemia microenvironment. The current platform integrates the biological insights gained from this earlier work with an engineered three-dimensional vascularized structure, enabling real-time live-cell imaging and high-throughput molecular analysis.
CAR T-cell therapy has been an effective treatment for many people, but nearly half of patients relapse or experience toxic side effects such as cytokine release syndrome, an overactive response to the immunotherapy that can be life-threatening. Improvements in CAR T therapies have been difficult in part because existing testing methods using either 2D cell cultures or animal models do not accurately simulate the human immune system or tumor microenvironment.
The NYU team believe their chip represents an important advance that overcomes these preclinical testing hurdles. The chip “empowers real-time spatiotemporal monitoring of CAR T cell functionality, including T cell extravasation, recognition of leukemia, immune activation, cytotoxicity and killing,” the investigators wrote.
“We observed immune cells patrolling their environment, making contact with cancer cells, and killing them one by one,” Chen added.
Significantly, the chip allowed researchers to recreate common clinical scenarios observed in patients including complete remission, treatment resistance, and initial response followed by relapse. The researchers reported that their model “reproduces clinical refractory cases driven by both inadequate CAR T cell expansion and exhaustion in CAR T cell products,” as well as relapse scenarios caused by clonal selection of CD19-negative cancer cells.
To assess performance, the researchers developed a matrix-based analytical and integrative index to evaluate different CAR T cell designs. This included comparing second-generation CAR T designs manufactured under different protocols and testing fourth-generation CAR T cells with IL-18-enhanced signaling. They found the newer generation cells performed better, especially at lower doses and that shorter T cell manufacturing methods (3-day vs. 9-day cultures) also resulted in more effective immune responses.
The chip also revealed a bystander activation effect, where CAR T cells stimulated additional immune activity beyond their primary targets—a factor that may affect both efficacy and side effect.
One strength of the platform is speed at which the chip can be produced and available to for testing. Animal models can take months to prepare, while the leukemia chip can be assembled in half a day and supports two-week experiments. “This technology could eventually allow doctors to test a patient’s cancer cells against different therapy designs before treatment begins,” Chen said. “Instead of a one-size-fits-all approach, we could identify which specific treatment would work best for each patient.”
Development of the new chip also comes at a time when new FDA is revamping their testing requirements with an eye toward phasing out preclinical animal studies.
Continuing their research, the NYU team will now incorporate patient-derived stroma and iPSC-derived cells to model additional immune microenvironmental factors such as hypoxia and extracellular matrix stiffness, and to gain a better understanding of the role of clonal hematopoiesis in CAR T response and toxicity.
“Our tissue-engineered immune-oncology model offers an ideal precision medicine platform for preclinical evaluation of CAR T cell immunotherapies,” the researchers wrote, “which can accelerate preclinical CAR T cell development, bridge up biological and technical gaps between preclinical studies and clinical trials, and ultimately pave ways to reliably screen responders and non-responders and develop optimal CAR T cell therapy.”
