There have been many advances made towards the treatment of various cancers, such as deadly forms of leukemia and lymphoma, that were once considered a death sentence and thought to be incurable. Unfortunately, there are still people who do not respond to treatment or eventually relapse and see the cancer return. However, researchers at UCLA are attempting to fine-tune some of these approaches to help people with these recurring and non-treatment responding cancers.
Dr. Sarah Larson and Dr. Yvonne Chen at UCLA are conducting a clinical trial that involves genetically-modifying a patient’s own T cells, which are an immune system cell that can destroy foreign or abnormal cells. The T-cells are modified with a protein called a chimeric antigen receptor (CAR), which identifies and destroys the cancer by detecting a specific protein, referred to as an antigen, on the cancer cells. These genetically modified T-cells are referred to as CAR-T cells and are re-introduced back into the patient as part of the therapy.
Previous CAR-T cells developed can only recognize one specific protein. For example, one FDA-approved CAR-T cell therapy is able to recognize a protein called CD19, which is found in B-cell lymphoma and leukemia. However, over time, the cancer cells can lose the CD19 antigen, making the CAR-T cell ineffective and can result in a reoccurrence of the cancer.
In a news release by UCLA, Dr. Larson describes the limitations of this design:
“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.”
But Dr. Larson and Dr. Chen are using a CAR-T cell that is able to recognize not one by two proteins simultaneously. In addition to recognizing CD19, their CAR-T cell is also able to recognize a protein called CD20, which is also found in B-cell lymphoma and leukemia. This is called a bispecific CAR-T cell because of it’s ability to identify two protein targets simultaneously.
In the same UCLA news release, Dr. Larson hopes that this approach will be more effective:
“One way to keep the CAR T cells working is to have more than one antigen to target. So 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.”
Before the clinical trial, Dr. Chen and her team at UCLA conducted preclinical studies that showed how using bispecific CAR-T cells provided a much better defense compared to single target CAR-T cells against tumors in mice.
In the same UCLA news release, Dr. Chen elaborate on the results of her preclinical studies:
“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.”
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.