by Laura López González, University of California, San Francisco

Killer T cells (green and red) surround a cancer cell (blue, center). Credit: NIH

UC San Francisco treated its first brain cancer patient with an experimental new CAR-T therapy discovered and manufactured at the university earlier this year. The treatment, known as E-SYNC, is a form of “switchable” CAR-T therapy that can be turned on and off to better target cancer and reduce side effects.

It was designed by UCSF Professor of Neurological Surgery, Surgery and Immunology Hideho Okada, MD, Ph.D., and Professor of Cellular and Molecular Pharmacology Wendell Lim, Ph.D. Lim is also the director of UCSF’s Cell Design Institute.

Although still in early clinical trials, if successful, E-SYNC could one day become the first CAR-T therapy to treat the aggressive brain cancer glioblastoma. About 12,000 Americans are diagnosed with the cancer annually, most of whom die within two years.

UCSF Neurology and Neurological Surgery Professor Jennifer Clarke, MD, MPH, at UCSF’s Weill Institute for Neurosciences, is leading the E-SYNC trial. She explains CAR-T therapy and why UCSF’s new gene therapy holds promise for not only treating glioblastoma but also HER2-positive breast cancer and maybe autoimmune diseases like HIV.

What is CAR-T therapy?

As part of CAR-T therapy, we take a kind of white blood cell from a patient called a T cell and engineer them to attack cancer almost like guided missiles. We do this by adding receptors, special molecules that allow a cell to communicate with its environment and react on the T-cells’ surfaces. The receptors are called chimeric antigen receptors (CAR), and are built to target molecules we know are on the patient’s cancer cells, much like a key fitting a lock, in order to kill them.

The supercharged T cells are then infused back into patients, where the newly added receptors allow the T cells to seek out, find and latch onto cancer cells, killing them.

What cancers can be treated with CAR-T therapy?

CAR-T therapy has been approved for use to treat several types of blood cancers in patients whose cancer has relapsed or is resistant to other standard treatments:

• Acute lymphoblastic leukemia
• Diffuse large B-cell lymphoma
• Multiple myeloma
• Chronic lymphocytic leukemia

More recently, physician-scientists have begun testing CAR-T on solid tumors.

“Supercharged” T-cells: See how T-cells are modified in CAR-T therapy to bind to the surface of cancer cells and launch an attack.

How well does treatment work?

It’s been pretty effective for blood cancers, but it hasn’t necessarily been a permanent cure for everyone. There are still cases in which tumors grow back and need follow-up treatment.

Why don’t we have an approved CAR-T therapy for solid tumors like brain cancer?

There are several reasons for this—for one, brain cancer cells have many different molecules on their surfaces, and not all cancer cells have the same molecules. If we think of our supercharged T cells as guided missiles, it is harder for them to select one right target that hits all the cancer cells.

Another challenge is that, over time, the T cells tire out, making treatment less effective.

How is UCSF’s switchable CAR-T therapy hope to get around this?

UCSF Professor Wendell Lim developed a technology called synNotch, which adds an “on” switch to CAR-T cells. With synNotch, the CAR-T cells are not automatically on, as in the past, but enter the body in a resting state.

The neat thing about synNotch is that it allows UCSF to be very specific about when cells switch on. CAR-T therapy is designed to target molecules we know are present on a patient’s cancer cells but sometimes these molecules can also be present on healthy cells. E-SYNC introduces a molecule on the T cell that allows it to sense that it’s near the tumor, signaling it to turn on and launch its attack, potentially making the treatment even more effective and reducing side effects.

Once the T cells kill the cancer, they automatically turn off, further reducing the risk that they’ll attack healthy cells. All of this, we hope, will make E-SYNC more effective than traditional CAR-T therapy and with fewer side effects. If it does, I think there’s a reasonable chance we can apply similar approaches to other cancers, like HER2-positive breast cancer.

Could CAR-T therapy, one day, be used to treat diseases other than cancer?

Potentially. UCSF researchers are already testing CAR-T therapy for autoimmune conditions like multiple sclerosis and HIV.

Provided by University of California, San Francisco

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