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6

January/February 2018^ DISCOVER^17

JAY SMITH

❯

IMMUNOTHERAPY,

THE HOTTEST FIELD IN

CANCER RESEARCH, seeks

to supercharge the body’s natural

defenses against deadly tumors. Two

different approaches are driving the

buzz, and one of them got a big boost

in August when the Food and Drug

Administration approved a “living

drug” to treat acute lymphoblastic

leukemia (ALL) in children and young

adults who’ve stopped responding to

chemotherapy. The product, dubbed

tisagenlecleucel (pronounced tis-a-

gen-LEK-loo-sell), is the first gene

therapy of any kind to be approved in

the United States.

More specifically, tisagenlecleucel

is a type of chimeric antigen receptor

T cell (CAR-T) therapy, a technique

pioneered by immunologist Carl June

and colleagues at the University of

Pennsylvania. First, an inactivated

form of HIV, the virus that causes

AIDS, is packed with snippets of

custom-designed DNA. Next, T cells

— the immune system’s foot soldiers

— are harvested from the patient’s

blood and infected with the virus,

which rewrites their genetic code to

recognize and destroy cancer cells.

Once the engineered T cells have

multiplied, they’re infused into the

patient, where they go to war.

Like the other leading-edge

immunotherapy technique — a

class of drugs known as checkpoint

inhibitors — CAR-T has shown

unparalleled potency against cancers

that once meant almost certain

death. In clinical trials that June’s

team initially launched in 2010,

over 80 percent of children with

recalcitrant ALL went into remission.

The therapy was also effective for

several other types of blood cancer. “It

was really extraordinary,” says David

Porter, director of Penn’s blood and

bone marrow transplant program.

“These were patients for whom

nothing else had worked.”

The pharma giant Novartis, which

agreed to fund further research in

exchange for ownership of the results,

will bring tisagenlecleucel to market

under the trade name Kymriah. In

October, the FDA approved a second

CAR-T therapy, axicabtagene ciloleucel

(developed by Kite Pharma and

dubbed Yescarta), for patients with

relapsed or refractory non-Hodgkin

lymphoma. Rival companies are racing

to develop similar products.

CAR-T has its hazards. Many

patients develop severe whole-body

inflammation that can last for days.

(Trials of another CAR-T therapy,

by Juno Therapeutics, were halted

in 2016 after five patients died

from brain swelling.) But if the

one-time procedure is successful,

they’re spared the months or years

of side effects that often accompany

chemotherapy. The treatment can

also eliminate the need for a bone

marrow transplant, which carries a

far greater risk of death.

Researchers are now testing CAR-T

therapies against other cancers,

including pancreatic and the deadly

brain cancer glioblastoma. They’re

trying combinations of CAR-T with

other treatments, and working to

make the technique safe enough

to use as an early stage therapy

rather than a last resort. “We’re at a

tipping point,” says June. “Someday,

our current ways of treating cancer

will be looked on as barbaric.”

 KENNETH MILLER

ESSAY

‘LIVING DRUG’ GETS

GREEN LIGHT

HOW TO BUILD BETTER T CELLS

Source: Novartis

➊ White

blood cells

called T cells

are collected

from the

patient's

blood.

➋ Researchers insert genes that

recognize specific cancer cells into the

T cells, through an inactive virus.

➌ The genes

reprogram the

T cells to produce

specific receptors

that will target

proteins on the

surface of a

cancer cell.

➍ The modified

T cells are grown

in a lab for

about 10 days.

➎ The engineered

T cells are infused

back into the

patient.

➏ Once inside

the patient, the

T cells multiply.

They hunt cancer

cells displaying

the target

protein and kill

them.