Researchers at UCLA are fine-tuning approaches to help people with recurrent, non-treatment-responsive cancers.

CAR T-cells

Dr. Sarah Larson and Dr. Yvonne Chen at UCLA are conducting a clinical trial that involves genetically modifying a patient’s T cells, immune system cells that can destroy foreign or abnormal cells.

Researchers modify the T cells with a protein called a chimeric antigen receptor (CAR), which identifies and destroys cancer by detecting a specific protein, called an antigen, on cancer cells. These genetically modified T-cells are called CAR-T cells and are reintroduced into the patient as part of the therapy.

Previously developed CAR T-cells can recognize only one specific protein. For example, one FDA-approved CAR-T cell therapy recognizes a protein called CD19, which is found in B-cell lymphoma and leukemia. However, over time, cancer cells can lose the CD19 antigen, making the CAR T-cell ineffective and causing the cancer to recur.

CAR T-cell therapy

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 can recognize two proteins simultaneously. In addition to recognizing CD19, their CAR-T cell can also recognize a protein called CD20, which is also found in B-cell lymphoma and leukemia. This is called a bispecific CAR-T cell because it can identify two protein targets simultaneously.

Preclinical work

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 showing that bispecific CAR T-cells provided much better defense than single-target CAR-T cells against tumors in mice.

In the same UCLA news release, Dr. Chen elaborates 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.