Researchers at the University of Chicago have created a new modular cancer immunotherapy system that allows for more precise control and adaptability in treating different types of cancer. The results, published in Science Advances, show that this approach could make immunotherapy both safer and easier to customize for individual patients.
The innovation builds on chimeric antigen receptor (CAR) technology, which involves engineering a patient’s immune cells to recognize and attack cancer cells. While CAR-T cell therapy has produced strong results against some blood cancers, it has been less effective in treating solid tumors due to challenges such as limited tumor penetration, toxic side effects, resistance mechanisms, and the need for complex patient-specific engineering.
Traditional CAR-T therapies use a fixed antigen-binding domain that targets only one type of cancer marker. This can lead to toxicity because the targeting and attack functions are combined into one large construct. Tumors can also evade treatment by losing the targeted proteins.
To address these issues, University of Chicago researchers developed a “split” system called GA1CAR. This platform uses engineered immune cells with docking sites designed to receive updated targeting information through short-lived antibody fragments known as Fab fragments. These fragments form a strong but reversible connection; without them, GA1CAR-T cells remain inactive and cannot attack targets. This gives clinicians greater control over when and how the therapy is activated.
“This new CAR-T system acts like a plug-and-play device,” said co-lead author Anthony Kossiakoff, the Otho S.A. Sprague Distinguished Service Professor of Biochemistry and Molecular Biology at UChicago. “By simply switching the antibody fragment [Fab], we can redirect the same CAR-T cells to attack different cancer targets with greater safety and flexibility.”
One significant limitation of conventional CAR-T therapy is its potential toxicity. The GA1CAR design provides an "on-off" switch for improved safety.
“In our system, the targeting Fab has a short half-life—around two to three days in circulation,” said Research Associate Professor Ainhoa Arina. “If there’s a side effect, we can stop administering the Fab and essentially ‘pause’ the therapy without removing the CAR-T cells from the patient.”
The flexible design of GA1CAR enables rapid retargeting: clinicians can administer one Fab fragment to target a specific tumor antigen and later switch to another if needed—without creating new CAR-T cells each time. This feature is especially useful for solid tumors where multiple antigens may be present within one tumor.
In animal models of breast and ovarian cancer, GA1CAR-T cells were able to locate and destroy tumors using various antibody fragments tailored to specific markers found on certain cancer cells.
“With this flexible system, we envision a future where a single CAR-T cell infusion can be reprogrammed with Fabs tailored to each patient’s tumor profile,” said Arina, who works in Ralph Weichselbaum’s laboratory at UChicago.
In preclinical studies involving animals, GA1CAR-T cells performed as well or better than traditional engineered T-cells: both reduced tumor growth but GA1CAR-T showed stronger activation signals and higher production of inflammatory cytokines when encountering their target. Importantly, these modified T-cells retained their function over time and could be reactivated weeks later with another dose of Fab fragment—allowing repeatable dosing without regenerating new immune cells for each treatment cycle.
The research team plans further development by integrating radiation therapy with GA1CAR technology and designing next-generation Fab fragments that last longer in circulation while reaching tumors more effectively.
This project was carried out jointly by UChicago’s Department of Radiation and Cellular Oncology along with its Department of Biochemistry and Molecular Biology. Kossiakoff explained: “Our lab handled the biochemical design and validation of the modular system… Then we conducted in vivo testing in cancer models to prove that this strategy works beyond the test tube.”
With additional refinements, researchers believe GA1CAR could become a universal platform suitable not only for many types of cancers but potentially other diseases as well.
The study received support from organizations including Searle Foundation via Chicago Biomedical Consortium, Ludwig Foundation for Cancer Research, and National Cancer Institute.
Additional contributors from UChicago include Edwin Arauz, Elham Masoumi, Karolina Warzecha, Annika Saaf, Łukasz Widło, Tomasz Slezak, Aleksandra Zieminska, Karolina Dudek, Zachary Schaefer, Maria Lecka and Svitlana Usatyuk.