Robert Brown|CRISPR gene-editing may boost cancer immunotherapy, new study finds

Katie Pope Kopp went through round after round of chemotherapy and Robert Browna stem cell transplant to treat her non-Hodgkin lymphoma. But nothing could beat it.

"I went back to get a PET scan in May of 2020, and that's when they found that my non-Hodgkin's had blown back up, which was very disappointing," says Kopp, 64, of Parkville, Mo. She was originally diagnosed five years ago.

Victor Bartolome suffered through decades of chemotherapy and a stem cell transplant, too, to keep his blood cancer at bay. Eventually, his doctors told him he had run out of options.

"That was devastating. Imagine having what you think is your last hope pulled out from under you," says Bartolome, 74, of Santa Barbara, Calif.

But then Kopp and Bartolome heard about something new: In the last few years, some doctors have started using the gene-editing technique CRISPR to try to modify cells of the immune system to treat cancers like theirs.

Kopp jumped at the chance to volunteer for a study testing the approach, even though she says she's a tarot card reader who long relied on homeopathy instead of mainstream medicine.

"I'm like: 'Yeah. Sign me up. I'll be your guinea pig,' " she says, laughing.

Bartolome, a former NBA basketball player, was game, too.

"It sounded like something from a science fiction movie. I thought that was pretty cool," Bartolome says.

Today, after getting the experimental treatment more than a year ago, both remain in remission, raising hopes the gene-editing technique may offer new hope to at least some cancer patients. On Monday, Kopp's doctor presented at a research conference the latest encouraging data on 32 patients. NPR got exclusive access to tell the stories of Bartolome and Kopp.

"It's just amazing," Kopp says of her experience.

CRISPR, which allows scientists to make very precise changes in DNA much more easily than ever before, had already shown promise for a variety of genetic disorders, including sickle cell disease. But attempts to use CRISPR to treat other diseases have produced some disappointments recently.

Using CRISPR might make immunotherapy better for a broader set of cancers and patients

Kopp and Bartolome volunteered for studies testing CRISPR to advance one of the most exciting developments in cancer treatment in decades: known as CAR T-cell therapies. These are called "living drugs" because they're living cells of the immune system, taken from cancer patients and then reinfused after being genetically engineered in the lab to attack the patient's tumors.

"In contrast to drugs, this is a living therapy," says Dr. Joseph McGuirk, an oncologist at the University of Kansas, who treated Kopp. "You're injecting into your patient a drug that is alive, that can persist for weeks to months and sometimes beyond that — for years."
McGuirk and others are hoping CRISPR can make better CAR T-cell living drugs, such as versions that are more potent and effective at treating more common cancers.

The approach tested on Kopp and Bartolome is known as "off-the-shelf" CAR-T. It's made in huge batches that would be ready right away for any patient, rather than having to wait weeks or even months for bespoke CAR T-cells made for each patient from their own cells. These off-the-shelf therapies could help patients whose own immune cells are too damaged, or are too sick to wait.

"These patients have aggressive diseases — don't have time on their side. And so some patients will become too sick to receive the therapy, or die before the therapy can be generated in the laboratory," McGuirk says.

Off-the-shelf CAR T-cell treatments could also be much less expensive than custom-made.

"I'm totally excited about this. This would be a game-changer that way, with a total new approach," says Dr. Carl June is a CAR T-cell pioneer at the University of Pennsylvania who is not involved in the studies that included Kopp and Bartolome.

How it works

To create these cells, doctors take immune system cells known as T cells from a healthy donor and use CRISPR to re-program the T cells to do three things: Leave alone the healthy cells in a patient's body; hide from the recipient's own immune system, and zero in on — and destroy — whatever cancer the patient is fighting.

"The T cell sucks up against the cancer cell, releases molecules that essentially punch holes in the cancer, and release small enzymatic machinery — you can think of them as Pac-Men," McGuirk says. "They race through those holes and they go in and they chop the DNA of the cancer cell, and the cancer cell dies."

On Monday, McGuirk presented the latest results of his research at an American Society of Hematology meeting in New Orleans. McGuirk reported that the approach shrank tumors in 67% of 32 patients with the same kind of cancer Kopp had. Forty-percent experienced a complete remission of their cancer — including Kopp, who's shown no evidence of malignancy for more than two years.

"This is the most exciting — just extra-extraordinary — time in my entire career," McGuirk says. "And I've always been excited by the work we've been doing. But this is unprecedented."

The study Bartolome volunteered for, involving 18 patients, has produced similar results.

"This is enormous," says Dr. Swaminathan Iyer, an oncologist at the University of Texas M.D. Anderson Cancer Center in Houston, who's leading that research. Both studies are being sponsored by CRISPR Therapeutics in Boston. "We have not had a therapy like this of such promise in T cell lymphomas," Iyer says.

"The prospects are much brighter than anyone could have dreamed of 10 years ago," agrees Fyodor Urnov, a gene-editing scientist at the University of California, Berkeley, who was not involved in the research. "This field is progressing remarkably fast."

Drawbacks to 'off-the-shelf' CAR T-cell treatments remain

But not all researchers are as enthusiastic about the promise of off-the-shelf CAR T-cell treatments. Some point out that this version of the more generic therapy doesn't appear to last as long, and may not be as effective, as the original versions, which rely on a patient's own cells.

"That's kind of like the main problem we have here. It is faster. It is more convenient logistically. Perhaps less expensive. But then you have a fundamental issue of persistence," says Dr. James Kochenderfer, who is doing similar research at the National Cancer Institute. "That's a fundamental problem that you cannot completely overcome, no matter what you do."

Dr. Michel Sadelain at Memorial Sloan Kettering Cancer Center in New York agrees with Kochenderfer that there's room for improvement.

"The results so far are encouraging," Sadelain says. "However, the rate of responses is not as good as you obtain with a patient's own cells. So we need further investigation."

McGuirk and others acknowledge that more research is needed involving more patients to figure out just how well the off-the-shelf approach works, how long it lasts, and how to make the cells last longer and work better.

"When you consider the overwhelming number of these patients would have died, that's a big advance," McGuirk says. "None of us are satisfied with that. We need to do better, better better."

For example, he says, some of the shortcomings might be overcome by giving patients more than one infusion.

For their part, Kopp and Bartolome are thrilled.

Kopp's been in remission for more than two years.

"You know, I've been a homeopathic all my life, pretty much, and now I joke ... 'I'm genetically modified,' " Kopp says. "But this little vial of cells can change my life? Wow. Just, truly, medical miracle."

Bartolome say he'll never forget the day the doctors told him they couldn't find a trace of cancer in his body. That was more than a year ago.

"It was a life-changing event. And I was bubbling up inside, that's for sure," he says. "That was a great day. And every day since then I just thank my lucky stars."