The “next frontier” for pioneering cancer therapies

Cancer treatments that modify a patient's immune cells to attack cancer cells are being re-engineered to try to treat more cancers in more people.

Why it matters: CAR-T immunotherapies have been successful in treating certain types of blood cancers in some people. But they struggle against solid tumors, which make up about 90% of cancers in adults.

• "Solid tumors are the next frontier," says J. Joseph Melenhorst, an immunologist at the University of Pennsylvania who develops CAR-T therapies.

How it works: CAR-T cells are made by collecting a patient's T cells — one actor in the immune system — and reprogramming a receptor on the T cell surface to bind an antigen found on the surface of cancer cells.

• Those reprogrammed cells are then put back into the patient, where they can attack the cancer cell.
• CAR-T therapies are approved by the FDA to treat some blood cancers and multiple myeloma.
• They've been successful in treating those cancers in some people, even those with advanced disease, but not all, and they are expensive and can have side effects, including releasing cytokines in the blood and affecting the nervous system.

The challenges: Solid tumors — including breast, prostate or lung cancers — are "almost impenetrable" for immune cells, Melenhorst says.

• The T cells used in therapies need to enter the tumor's microenvironment — a hostile arrangement of blood vessels, proteins, and immune and other cells that surround a tumor, interact with it and influence its fate — to access the cancer cells.
• Another challenge: solid tumor cancers can spread in the body and be difficult for T cells to find.
• And T cells can also become exhausted if they are exposed to the antigen they are targeting for prolonged times.

Both solid tumor and blood cancers can reemerge if cancer cells stop making the antigens on their surface that CAR-T cells target, allowing them to evade the attacking immune cells.

What's new: Scientists are experimenting with designing new CAR-T cells and therapies to find, attack and continuously surveil solid tumor cancers.

• T cells are being engineered to target multiple antigens on a cancer in an effort to make it more difficult for cancer cells to escape and for cancers to return. In one study of a small group of patients with B-cell lymphoma, a blood cancer, the approach has shown early promising results.
• But most of the antigen targets on solid tumors are also on types of healthy cells people can't live without, which poses safety concerns for patients.

A key aim for new CAR-T therapies is to be able to tailor their specificity.

• "How to find an antigen that you can both safely target and use to effectively eliminate the tumor is a very challenging question," says Yvonne Chen, a scientist at UCLA who designs CAR-T cells.
• She and other researchers are exploring designing T cells that target cancer cells using an approach similar to logic gates in computing.

• CAR-T cells can be engineered to only attack a cell if it has one antigen but not another, making it more specific. But if it is too specific, cells of some types of cancer can slip by, prompting researchers to try to also program T cells to attack a cell that has one antigen or another one.
• The best strategy then depends on the cancer in question, Chen says.

Between the lines: Finding and entering cancer cells that may have spread to different corners of the body can also be a problem for CAR-T cells, in part because tumors have their own defenses.

• It's especially challenging to access "cold" tumors that box out immune actors like T cells that CAR-T therapies use.
• Researchers at City of Hope used a virus that infects cancer cells to enter the cells in mice and get them to make an antigen recognized by CAR-T cells. Other strategies suppress, redirect, or otherwise modify the cells and cues of a tumor's defense system so the T cells can attack.
• As CAR-T cells are being developed and tested, there's a need to monitor where they go in patients. Researchers this week described a technique that uses nanoparticles to track the engineered cells and whether they can find tumors.

The bottom line: "Immunotherapy has promise for solid tumors, but there is a need for a lot more research to make solid cancers respond like blood cancers do," Carl June, an immunologist and oncologist at the University of Pennsylvania who led the early development of CAR-T therapy, said at a press conference this week.

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Editor's note: This story originally published on Feb. 3.