instagram pinterest linkedin facebook twitter goodreads facebook circle twitter circle linkedin circle instagram circle goodreads circle pinterest circle

Genetic Linkage

Will Layla Save Gene Editing?

(Great Ormond Street Hospital)
I had planned to blast last Thursday’s news of the use of gene-editing to save a British baby from aggressive leukemia. “Two months later, Layla was cancer-free,” proclaimed one of many enthusiastic reports.

I’m always skeptical when I hear the words “cancer” and “cure” in the same sentence, let alone uttered so soon after treatment and without an accompanying technical paper so I can see the data. But when I considered the timing of unfolding events, I realized that the seemingly premature reporting of Layla’s rapidly restored health just might add an important point to the heated discussion over gene and genome editing. That is, can we keep the promising clinical applications on somatic cells, while forbidding the Frankenstein scenarios of germline manipulation?

DÉJÀ VU
Fear of novel biotechnologies is nothing new. Louise Joy Brown, the first “test-tube” baby, made headlines in 1980, regarded as somewhat of a freak until it became clear she was a normal little girl. A decade later, the first couples to select disease-free embryos after in vitro fertilization (IVF) were vilified on morning talk shows. The procedures are commonly teamed today. The closest precedent to the controversy over gene editing is the famous conference to discuss recombinant DNA technology held in Asilomar, California in 1975. I remember my mentor in grad school a few years later calling the objections to recombinant DNA research the "triple-headed purple monster" mindset.

I was on vacation last week when several friends emailed me the first newspaper accounts of Layla’s treatment. They were fairly uniform, as happens in this age of echo journalism, based on news releases from Great Ormond Street Hospital (GOSH) and University College London (UCL), and Cellectis, the biotech company that produced the treatment.

In the rush to publish, some reporters muddled gene editing and gene therapy. William French Anderson, MD, who led the first gene therapy clinical trial, in 1990, actually first uttered the idea at a journal club meeting back in 1958: “What if we found out what is wrong in sickle cell anemia? We could put in a normal globin gene and cure it!” he told me for my gene therapy book. As originally envisioned and carried out in a few thousand clinical trials, gene therapy adds a gene to compensate for a mutant one. The newer gene editing, which uses different tools, replaces or removes a gene.

I noticed right away that the first sentence of the Wall Street Journal article that several friends sent me last Thursday linked “gene-editing technique” to an article about the very gene therapy that I wrote my book about, for a form of hereditary blindness. It adds a gene that doesn’t integrate into a chromosome. Other gene therapies stick the healing genes into chromosomes somewhat randomly. Gene editing, in contrast, switches out or replaces a gene at its precise site in a chromosome. The distinction isn't just genetic jargon -- it could mean the difference between a sustained effect and one that fades as modified cells divide.

Gene editing, so far, uses DNA cutting enzymes – nucleases -- to remove or swap in a very specific DNA sequence at its chromosomal home. The headline-maker is CRISPR (I will post an interview with its inventors soon). Layla’s treatment is the first to use TALENs. And gene editing of HIV using a third tool, zinc finger nucleases, has been in clinical trials since 2009. The HIV trials use the patients' own cells, but Layla was too sick to provide enough.

Instead, Layla received “off-the-shelf” healthy T cells from a donor, altered to attack her cancerous B cells, using CAR (“chimeric antigen receptor) technology. (T and B cells are major immune system white blood cells.) At the same time, TALEN enzymes snipped out the genes in the donor cells whose activity would have alerted Layla's immune system and also rendered the incoming cells resistant to a powerful chemotherapy, which could then be used to mop up any lurking cancer cells. CAR isn’t new, but using TALENs and donor cells is.

That’s huge! Layla’s treatment is PRECISION medicine because it attacks the cancer cells only, but not PERSONALIZED medicine because donor cells can help. It's a powerful partnership that could drastically lower costs.

OUT OF OPTIONS
Layla Richards was born in June 2014 and diagnosed with very aggressive acute lymphoblastic leukemia at 14 weeks. Chemo and a bone marrow stem cell transplant hadn’t completely wiped out her cancer cells. Just before the little girl’s first birthday, Waseem Qasim, MD, Consultant Immunologist at GOSH and Professor of Cell and Gene Therapy at UCL, asked Cellectis for a special license to try its experimental product on his very sick patient. The hospital only had one vial, but the desperate request went through. The infusion took just minutes to administer, which the child didn’t even notice, said her dad.

Two weeks later, Layla developed a mild rash that reflected her body noticing the introduced cells. Over the next two weeks, fixed T cells showed up in her circulation, and their numbers climbed, there and in her bone marrow too. At the two month mark, deemed the GOSH news release, Layla was “cancer free.” She then received another bone marrow transplant to replace her immune system. She did so well that a mere month later, she went home.

A CLOSER LOOK
Layla’s treatment is a mouthful: “Cellectis’ TALEN® gene edited allogeneic UCART19 product candidate,” or just UCART19; “U” stands for “universal.” The “CAR” -- chimeric antigen receptor -- is a hybrid cell-surface protein that doesn’t form naturally in the body. It’s part T cell receptor, part antibody. Like a drone and a missile, the CAR directs the T cell to a specific target, such as cancerous B cells or HIV-infected cells. (See here for background.)

I spoke with Bruce Levine, PhD, the Barbara and Edward Netter Professor in Cancer Gene Therapy at the Perelman School of Medicine and a pioneer of CAR technology, at a conference in January 2013. The New York Times had just published a piece about one of his patients, another little girl who had an astonishing recovery from the same type of leukemia, 6-year-old Emma Whitehead. The Times article appeared the day before co-inventor Carl June presented the data at a major conference, and he was a little surprised to be in the position where his audience already knew about the case, Dr. Levine recalled. But that data presentation and media coverage was 9 months after the treatment.

The CAR effect lasts. Emma, more than 3 years later, “is doing fantastic,” Dr. Levine recently told me. “This year so far she has met President Obama, Tom Brokaw, and Heidi Klum!” Unlike Layla, Emma’s own cells were used.

The idea to arm T cells to attack cancerous B cells wasn’t new, even when Emma made headlines. “Zelig Eshhar at the Weitzmann Institute in Israel published a paper in 1989 that you can combine an antibody with a signal,” Dr. Levine said. The Penn group has deployed CARs in clinical trials against HIV, and more recently a case of multiple myeloma.

Despite the frequent use of “cancer-free” and “breakthrough” in the news coverage of Layla and her vanishing leukemia, the quotes were appropriately qualified. "We have only used this treatment on one very strong little girl, and we have to be cautious about claiming that this will be a suitable treatment option for all children. But, this is a landmark in the use of new gene engineering technology and the effects for this child have been staggering,” said Dr. Qasim in the news release. Clinical trials needed to add evidence that it was the gene editing and not the chemo or the stem cell transplant that led to remission likely will begin in 2016.

TIMING

Two months may seem way too soon to report even startling results on a single cancer patient. “Cancer-free” is usually evoked only 5 years after treatment, and I wouldn’t even use it then.

Of course I hope Layla stays well, but I can't help but recall the little girl treated for HIV infection with antiretrovirals shortly after birth and widely declared HIV-free when the researchers published 2 years later. By age 4, the virus had re-emerged, leading to such headlines as "Girl who was declared 'functionally cured' of HIV now has active virus."

So why issue the news release so soon? It’s not as if there aren’t already treatments for leukemia. And a patient can't just go and order her complex treatment at the local clinic.

The timing of the announcement may be important when we look back on the birth of gene and genome editing, just as we did 40 years ago for the recombinant DNA technology that has given us many useful drugs.

The news releases came out Thursday, November 5, as Layla and her family appeared on television throughout Britain. That was also the day that abstracts were published online for the American Society of Hematology annual meeting, to be held December 5-8 in Orlando. Cellectis’s stock rose, 11% after the news broke and another 3% the next day.

But between November 5 and December 5 will be another meeting, the International Summit on Human Gene Editing to be held in Washington, D.C. December 1-3. And that may be where Layla’s story has its greatest impact.

The international summit, called for in September with a stellar planning committee, will focus on scientific as well as ethical and societal issues that might arise if gene editing is used to alter the human germline, which would transmit a change to the next generation. That’s something that most nations have banned, but researchers in China have already done, albeit on doomed human embryos. That work was published last April 1, but was most definitely not a joke.

I hope that Layla’s remission is forever, and that her story can help to preserve a technology that has such enormous potential for treating or even preventing cancer, infectious disease, and genetic disease. Let's not throw the baby out with the bathwater.
Be the first to comment