Researchers at the University of Chicago have developed a modular cancer immunotherapy that can be switched on, off or reprogramed to attack different cancers.
Promising initial testing results, published in Science Advances, demonstrate a “universal” function built on a chimeric antigen receptor (CAR) platform. This could make immunotherapy safer and easier to adapt to each patient—dramatically changing the treatment landscape for certain cancers.
With CAR-T cell therapy, a patient’s own immune cells are harvested and genetically engineered to recognize a specific tumor antigen and attack cancer cells. Although CAR-T cell therapy has shown remarkable outcomes in certain blood cancers, it has struggled to succeed in solid tumors. Its challenges include poor tumor penetration, toxic side effects, development of resistance mechanisms and the complex, patient-specific engineering process required for each treatment.
Traditional CAR-T cells rely on a fixed antigen-binding domain, which means they can only target one type of cancer antigen—a specific protein that marks tumor cells for attack. The potential toxicity of the therapy is also due to a single CAR-T cell packaging both targeting and attack machinery into a single large construct.
Moreover, tumors often display antigens in different degrees and may escape CAR-T cell therapy by losing the targeted proteins.
To make the therapy safer and more adaptable, UChicago researchers developed a new “split” system called GA1CAR. This uses engineered immune cells with a docking site that can receive updated tumor targeting information in the form of short-lived antibody pieces known as Fab fragments.
These Fab fragments are engineered to create a strong yet reversible connection. Without the Fab, GA1CAR-T cells stay inactive—unable to recognize or attack targets. This gives clinicians precise control over how, when and where the engineered cells attack cancer.
“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. “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 of the main limitations of traditional CAR-T cell therapy is toxicity. The GA1CAR system provides an “on-off” switch for enhanced safety.
“In our system, the targeting Fab has a short half-life—around two to three days in circulation,” said Research Assoc. Prof. 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.”
Multi-targeting and personalization of cancer immunotherapy
Beyond safety, the GA1CAR system’s flexible design offers rapid retargeting. Clinicians can administer one Fab to attack a specific tumor antigen and later switch to another if the tumor evolves or develops resistance—without generating new CAR-T cells.
This flexibility is particularly valuable in solid tumors, where tumor heterogeneity—the presence of multiple antigens within the same tumor—has limited the effectiveness of single-target therapies.
In animal models of breast and ovarian cancer, GA1CAR-T cells were able to find and attack tumors by using different antibody pieces that target specific markers on cancer cells. These markers are often found in high amounts on certain cancer cells, so targeting them helps the cells recognize and destroy the tumors more effectively.
“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 the laboratory of Ralph Weichselbaum, the Daniel K. Ludwig Distinguished Service Professor of Radiation and Cellular Oncology.
In animal studies, GA1CAR-T cells performed as well or better than conventional engineered cells. Both reduced tumor growth, but the GA1CAR-T cells showed greater activation and produced more inflammatory cytokines in response to the same target.
Importantly, GA1CAR-T cells maintained their function over extended periods and could be reactivated weeks later with a fresh dose of Fab. This capability opens the door for repeatable therapy where the dose can be adjusted as needed, without having to create new cells each time.
Further developing the new cancer immunotherapy system
The research team is now exploring ways to integrate radiation therapy with the GA1CAR platform and to develop next-generation Fab fragments that stay in the body longer and reach tumors more effectively.
This study was a collaboration between the Department of Radiation and Cellular Oncology and the Department of Biochemistry and Molecular Biology at UChicago. Kossiakoff, an expert in protein engineering, developed the GA1 and Fab variants using phage display technology.
“Our lab handled the biochemical design and validation of the modular system,” Kossiakoff said. “Then we conducted in vivo testing in cancer models to prove that this strategy works beyond the test tube.”
With further refinements, the GA1CAR system could serve as a universal platform for precision cancer immunotherapy—suitable for a wide range of cancers and potentially other diseases.
The study, “A universal chimeric-antigen receptor (CAR)- fragment antibody binder (FAB) split system for cancer immunotherapy,” was supported by Searle Foundation under the auspices of the Chicago Biomedical Consortium, the Ludwig Foundation for Cancer Research and the National Cancer Institute.
Additional authors include Edwin Arauz, Elham Masoumi, Karolina Warzecha, Annika Saaf, Łukasz Widło, Tomasz Slezak, Aleksandra Zieminska, Karolina Dudek, Zachary Schaefer, Maria Lecka and Svitlana Usatyuk from UChicago.
This article was originally published on the UChicago Medicine website.
