CAR T-cell therapy and how it’s used at CIRM 

/ California Institute for Regenerative Medicine (CIRM)

By Holly Alyssa MacCormick 

The human body is very good at defending itself from harmful cells and foreign substances, but sometimes it needs help. CAR T‑cell therapy may offer a way forward. Scientists boost the immune system through a form of genetic engineering called chimeric antigen receptor, or CAR T‑cell therapy. This therapy is used today to treat certain cancers, and it may soon treat other diseases as well.

The biology behind CAR T-cell therapy 

T-cells are a special type of immune cell that works as a sentinel in the body, constantly scanning for threats. CAR T-cell therapy helps the body’s own immune system work more effectively by genetically modifying T-cells so they can scan neighboring cells with greater accuracy.   

Simplified explanation of how CAR T-cell therapies work. (Memorial Sloan Kettering).

T-cells are formed in bone marrow and travel through the bloodstream and lymph system, scouring the surface of every cell they encounter.  They come in various shapes with different cell coatings made of bits of protein (called antigens) that dot the surface like toppings packed on the outside of an iced donut hole. The different shapes of those antigens help T-cells identify harmful cells through a kind of “lock and key” recognition system. 

T-cells have receptor “keyholes” that lock in with antigen “keys” on harmful cells. Cells studded with “familiar” antigens are considered friendly by T-cell receptors and are allowed to go on their way. But cells with antigens that T-cell receptors are programmed to read as harmful are actively bound by the T-cell and killed with chemicals released by the modified T-cell.  

How CAR T-cell therapy works 

CAR T‑cell therapy works like a “living drug,” reprogramming key immune cells to target disease with a one‑time treatment. To create a personalized therapy, clinicians draw a small blood sample from the patient to collect T cells. After separating the T cells from other blood cells, they mix them with an inactivated virus designed to deliver genetic instructions for the engineered receptor, or CAR.

This genetic modification allows the CAR T cells to recognize and lock onto a specific harmful cell type, such as a patient’s cancer cells.

To make the therapy effective, millions of these engineered T cells are grown in a laboratory. The expanded cells are then given back to the patient through an intravenous infusion.

Inside the body, the modified cells scan nearby cells in the bloodstream. When a CAR T cell identifies a harmful target, it directs the patient’s immune system to destroy it. After killing the targeted cell, the CAR T cell remains intact and continues searching until no harmful cells remain.

CAR T-cell therapy at CIRM 

CAR T‑cell therapy was developed in the 1980s to treat HIV. Those early efforts did not succeed, but the approach showed promise against cancer. In 2017, the FDA approved the first CAR T‑cell therapy to treat a form of childhood leukemia. Scientists are now exploring how this therapy could treat other cancers and diseases.

Current CAR T‑cell therapies focus on blood cancers, including multiple myeloma, leukemia, and non‑Hodgkin lymphomas. This focus exists partly because T cells circulate in the blood. They also travel easily through the blood and lymph systems to reach these cancers. T cells work in other parts of the body too. However, solid tumors are harder to target. Dense tissue creates a barrier, tumors often display multiple proteins instead of one, and they can release signals that weaken nearby immune cells.

The California Institute for Regenerative Medicine (CIRM) has funded CAR T‑cell research for leukemia. CIRM has also supported studies using CAR T cells to treat other blood cancers, autoimmune diseases, HIV, and aggressive brain cancers that affect children.

There are currently 14 CIRM‑funded clinical trials using CAR T‑cell therapy. The agency supports, or has supported, dozens of research grants to expand and improve this approach. These studies include a small early‑stage clinical trial led by Steven G. Deeks, MD, that could help pave the way for a potential one‑shot cure for HIV. They also include a study investigating a CAR T‑cell therapy for the most common type of kidney cancer, and another exploring CAR T‑cell therapy for Systemic Lupus Erythematosus, a debilitating autoimmune disease.