August 05, 2025
Researchers at The University of Kansas Cancer Center are investigating a new treatment they designed and are manufacturing in-house to outsmart cancers that are resistant to a game-changing form of immunotherapy for various blood cancers.
Since the U.S. Food and Drug Administration (FDA) approved the first chimeric antigen receptor T-cell therapy in 2017, this form of treatment has been revolutionary for certain blood cancers such as leukemia, lymphoma and myeloma. CAR T-cell therapy, as it’s commonly known, uses immune cells in a patient’s own body, known as T cells, to identify cancer cells and destroy them. There are now seven FDA-approved CAR T-cell treatments, and they have produced dramatic results, even eliminating cancer in some people with advanced disease.
But CAR T-cell therapy does not work for everyone. “Not everybody responds to the commercially available CAR T cells, and not everybody who responds stays in remission,” said Joseph McGuirk, DO, director of the Hematologic Malignancies and Cellular Therapeutics program at KU Cancer Center. “And so understanding why that's the case has allowed us to leverage that knowledge and try to come at it from a different angle.”
The angle? A new type of CAR T-cell therapy dubbed Triple Threat, currently under evaluation via a Phase 1, first-in-human clinical trial initiated by McGuirk and other investigators at KU Cancer Center. The trial tests a CAR T-cell therapy created by these scientists that triples the number of molecular targets.
For all CAR T-cell therapies, T cells are removed from a patient’s blood, genetically modified and grown in large numbers in a laboratory, then infused back into the patient’s bloodstream. These modified CAR T cells express a protein on their surface that enables them to recognize and attach to a specific antigen (type of protein molecule) on the surface of cancer cells. The CAR T cells then punch holes in the cancer cells and release granzymes — proteins that McGuirk likens to “PacMen” — that race through those holes and destroy the cancer.
But cancer cells are smart, McGuirk noted. Sometimes they develop a resistance to the CAR T cells, by ceasing to express the antigen the CAR T cells are designed to target so that the cancer cells no longer can be found.
“The seven FDA-approved CAR T-cell therapies each target a single surface marker,” noted Scott Weir, PharmD, PhD, director of the Institute for Advancing Medical Innovation at KU Medical Center and an investigator on the trial. “There are no approved products that target multiple cell surface markers.”
The Triple Threat approach to CAR T-cell therapy is looking to change that. It aims to circumvent resistance to CAR T-cell therapy by simultaneously targeting three types of antigens on the surface of cancer cells, rather than just one. If the cancer stops expressing one of the three targeted molecules, then the cancer can still be killed via either or both of the others. Moreover, the CAR T cells produced for this trial are designed to multiply quicker and persist for a longer period of time. “They need to be around long enough to kill every last cancer cell,” said McGuirk.
The Phase 1 clinical trial, led by McGuirk, targets three different antigens (CD19, CD20 and CD22) that are overexpressed (increased) in B-cell malignancies. Participants in the trial are adults with B-cell non-Hodgkin lymphoma or B-cell acute lymphoblastic leukemia whose cancer has relapsed or did not respond to initial treatment.
For all currently available CAR T-cell therapies, the patients’ T cells must be sent away to a laboratory, where they are genetically modified to create the CAR T cells. But for this trial, that process happens in-house, at the Good Manufacturing Practices laboratory of KU Medical Center’s Midwest Stem Cell Therapy Center; this laboratory adheres to strict regulations set by the FDA to ensure human safety. The center is led by Sunil Abhyankar, MD, also an investigator on the trial.
“Creating CAR T-cells onsite requires a robust infrastructure and highly specialized experts. This type of manufacturing is found almost exclusively in National Cancer Institute-designated comprehensive cancer centers like ours,” McGuirk said.
In addition to assessing the feasibility and safety of the treatment, the trial is designed to identify the maximum tolerated dose, which will be used in a Phase 2 study. With assistance from KCAS Bio, a local bioanalytical research company, the researchers are also evaluating the initial efficacy of the treatment: what effect the CAR T-cell product has on killing malignant cells and stimulating the patient’s own immune system to fight the cancer.
The researchers also plan to open a trial for children and adolescents up to 21 years of age. “The goal is to study this therapy across the lifespan,” said Weir. “That's really important.”
This article originally appeared on the University of Kansas Medical Center's website.