As the field of immunotherapy continues to revolutionize the way people with incurable cancers are treated, there still are many people who do not benefit from treatment or who have a relapse of their cancer. In an effort to further improve therapy to help more people, UCLA Health researchers have begun a pioneering chimeric antigen receptor (CAR) T cell immunotherapy trial that will attack cancer cells on two fronts. By launching a simultaneous bilateral assault against two targets — CD19 and CD20 — that are expressed on B-cell lymphoma and leukemia instead of using the conventional single-target approach, researchers are hoping to minimize resistance and increase the life expectancy for people diagnosed with these cancers.
“One of the reasons CAR T-cell therapy can stop working in patients is because the cancer cells escape from therapy by losing the antigen CD19, which is what the CAR T cells are engineered to target,” says Sarah Larson, MD, a UCLA hematologist-oncologist and the principle investigator on the trial, which is being offered exclusively at UCLA. In fact, up to two-thirds of the patients who experience relapse after being treated with the FDA-approved CD19 CAR T-cell therapy develop tumors that have lost CD19 expression.
“One way to keep the CAR T cells working is to have more than one antigen to target,” says Dr. Larson, a member of UCLA’s Jonsson Comprehensive Cancer Center. “By using both CD19 and CD20, the thought is that it will be more effective and prevent the loss of the antigen, which is known as antigen escape, one of the common mechanisms of resistance.”
In preclinical studies led by Yvonne Chen, PhD, associate professor of microbiology, immunology and molecular genetics and codirector of the UCLA Jonsson Comprehensive Cancer Center Tumor Immunology Program, the team was able to show that by simultaneously attacking two targets, the engineered T cells developed in her lab could achieve a much more robust defense compared to conventional, single-target CAR T cells against tumors in mice.
Dr. Chen’s team designed the CARs based on the molecular understanding of the CAR’s architecture, the antigen structure and the CAR/antigen binding interaction to achieve optimal T-cell function. This design helps the T cells have dual-antigen recognition to help prevent antigen escape. “Based on these results, we’re quite optimistic that the bispecific CAR can achieve therapeutic improvement over the single-input CD19 CAR that’s currently available,” Dr. Chen says.
This first-in-humans study will evaluate the therapy in patients with non-Hodgkin’s B-cell lymphoma or chronic lymphocytic leukemia that has come back or has not responded to treatment. The goal is to determine a safe therapeutic dose.
Patients enrolled in the trial will have their white blood cells (T cells) collected intravenously then reengineered in the laboratory so the T cells can produce tumor-specific receptors, which allow the T cells to recognize and attack the CD19 and CD20 proteins on the surface of tumor cells. The new “smarter and stronger” T cells are then infused back into the patient and primed to recognize and kill cancer cells.
For more information about this clinical trial, visit: tinyurl.com/car-t-clinical-trial
To refer a patient for possible enrollment in the clinical trial, email: [email protected]
For more information about CAR T-cell therapy at UCLA, visit: uclahealth.org/car-t-cell-therapy