Doctors successfully treat two babies with leukemia using gene-edited immune cells

am Ward

Scientists are using gene-editing techniques to fight cancer.

IT’S A PROMISING APPROACH, BUT STILL NEEDS A LOT MORE RESEARCH

By Claire Maldarelli

In a study out this week in the journal Science Translational Medicine, a group of British doctors reported that they had successfully “cured” two infants of the blood cancer leukemia using a treatment that involves genetically modified immune cells from a donor.

The study was incredibly small—just two babies—and the infants have only been free of leukemia for 16 and 18 months. Technically, that’s not long enough to say they are cured. Declaring someone who previously had cancer as “cured” usually doesn’t happen until that person has been free of the disease for a few years, at least. But what’s significant about this study is that it combines a promising, novel approach—CAR T cell therapy—with a relatively new gene-editing technique called TALENS, which enables the direct manipulation of genes within a person’s DNA.

In the cancer community, CAR T cell therapy is already touted as a promising immunotherapy treatment (which involves harnessing a person’s immune system to fight cancer on its own), but in preliminary trials, it’s had its limitations. Before it can become a universal cancer treatment, these kinks and logistics need to be worked out. And researchers in the field think that many of them can be solved using gene-editing techniques such as TALENS, the one used in this study, as well as CRISPR, supposedly the easiest such technique to date.

First, what is CAR T-cell treatment?

CAR T, which stands for chimeric antigen receptor T cell, is a new type of cancer treatment which is not yet publicly available, but is in active clinical trials in the United States as well as many other countries such as the United Kingdom and China. The therapy involves removing some T cells (specialized immune cells) from a patient's blood. Then those cells are genetically altered in a lab, giving them special receptors on their surface called CARs. Once the cells are ready, they are infused back into the patient’s blood, where the new (CAR) receptors seek out tumor cells, attach to them, and kill them.

CAR T-cell trials are currently in phase II clinical trials in the United States. A few drug companies, including Novartis, have plans to make the therapy available as early as this year.

How does gene-editing help?

This new treatment has worked really well for blood cancers like leukemia, especially in young children. The problem, as the researchers point out in their study, is that each set of T cells have to be custom made for each patient. That takes a lot of time, and a lot of money. Further, it’s not always feasible, or even possible, to harvest T cells from leukemia patients who simply don’t have enough healthy ones to begin with.

And that’s where gene-editing comes in. The researchers took T cells from donor recipients and made a total of four genetic changes. The two they made with TALENS enabled the T cells to become universal—allowing them to be used in any person without the risk of rejection (a phenomenon called graft-versus-host disease, where the recipient’s immune system creates such an overwhelming response to the foreign cells that the patient can die as a result). The other genetic alterations added that signature receptor to seek out and attack cancer.

What are the limitations of this study?

The two infants in the study—aged 11 and 18 months—both had an aggressive form of leukemia, and had already been subjected to other treatments like chemotherapy and stem cell transplants. And the fact that they have remained cancer free is extremely promising. But again, the study was small. Further, according to a report in MIT Technology Review, many CAR T experts argue that because the children also received other treatments simultaneously (one had a stem cell transplant soon after receiving the CAR T cells) it’s impossible to know for sure whether the CAR T cells were the sole reason the cancer cells stayed away. “There is a hint of efficacy but no proof,” Stephan Grupp, director of cancer immunotherapy at the Children’s Hospital of Philadelphia, told MIT Tech Review. “It would be great if it works, but that just hasn’t been shown yet.

What’s next?

The combination of CAR T cell immunotherapy with gene-editing remains an incredibly promising area of research. Not only to create a “universal donor” CAR T cell, but also to make the treatment more effective. Researchers at the University of Pennsylvania are currently researching using the the gene-editing technique CRISPR to edit out two genes—called checkpoint inhibitors—that prevent CAR T from working as well as it should. The trial, which could take place this year, would be the first case of a CRISPR-altered cell being used in a human patient in the United States. In November, a Chinese group tested their first CRISPR gene-edited T cells in a patient with lung cancer.

However, it’s important to remember that CAR T cell therapy is in its early stages, and CRISPR/TALEN gene edited CAR T is even newer. There’s still a lot more work to be done, including many, many more studies like this one, with a lot more patients, before it’s available for everyone.

Jimmy Carter is no longer being treated for cancer

Former President Jimmy Carter isno longer being treated for cancer.

In December 2015, Carterrevealed he had tested cancer freeonly a few months after initially sharing that he'd been diagnosed with metastatic (meaning it's spread from its primary spot) melanoma that had spread to his brain. Just a few months later, his doctors have let him know he no longer needs to be treated.

Carter, 91, had used a combination of radiation therapy and Keytruda, a relatively new kind of cancer drug, which was delivered intravenously once every three weeks.

For decades, doctors have treated patients using a combination of chemotherapy, radiation, and surgery to try to stifle the disease.

But in the past few years, doctors have started researching and using a promising tool: immunotherapy.

Unlike chemotherapy, which involves administering powerful drugs that kill both cancerous and healthy cells (most healthy cells can repair themselves), immunotherapies harness the power of the immune system to help it identify and knock out just the cancerous cells.

In cancer patients, a type of protein called PD-1 stops the immune system from doing its job and fighting the cancerous cells. Keytruda — the drug Carter used — gets in the way of those dysfunctional proteins, allowing the immune system to access the cancer cells. Then, with the help of the radiation therapy to shrink tumors, it can help knock out the cancer in some people.

The incredible success of the drug in Carter's case brought the treatment into the spotlight, but the therapy has been a long time coming.

More than a century in the works

Recent immunotherapy successes are far from the first time researchers have explored using the immune system to fight cancer.

As NPR noted, in the 1890s a doctor named William Coley treated his cancer patients by infecting them with bacteria. The treatment worked for some of them — with the immune system at full force to knock out the invading bacteria, the immune system could also take on the cancerous cells and kill them on the way, which wouldn't necessarily happen if the immune system wasn't stimulated.

At the time, very little was understood about the immune system, and after Coley died, his methods stopped being used in favor of radiation therapy. But in 1953, Coley's daughter, Helen Coley Nauts, founded the Cancer Research Institute, which works to understand the relationship between cancer and the immune system.

Streptococcus bacteria.

In the 1970s, scientists pursued an immunotherapy using a protein called tumor necrosis factor, or TNF, which the body makes in response to foreign organisms in the body, including bacteria and tumor cells.

Jan Vilcek, a microbiology professor at New York University and one of the scientists who worked on developing a TNF treatment at the time, told Business Insider that in animal testing, TNF was able to block the growth of tumors. But when put into humans, the added TNF was so toxic that it made people sick, even at doses that wouldn't kill tumors.

That was the end of immuno-oncology research for a while (though not the end of the story for TNF-related therapies).

Even so, the Cancer Research Institute stuck with it, and eventually in 2011, the first immunotherapy was approved in the US to treat melanoma. The drug, called Yervoy or ipilimumab, helps the immune system respond to cancerous cells by keeping it from pushing on the brakes before it has a chance to kill the cells. Since then, a number of other cancer treatments using the immune system have been approved, with more still in development.

"For us, the excitement that we're now seeing in the clinic is phenomenal," Cancer Research Institute CEO Jill O’Donnell-Tormey told Business Insider. "It's very validating for us."

Vilcek, too, is optimistic about the state of immunotherapies to treat cancer.

"I think it's really very very encouraging and in certain types of cancer, it's making a huge difference," Vilcek said.

In the middle of a cancer-treatment revolution

A woman is screened for skin cancer.

Immunotherapies are working incredibly well for some cancers, such as melanoma, lung cancer, head and neck cancer, and multiple myeloma.

Yet for others, there's still a lot to learn.

"We're a long way from knowing the full story," said O'Donnell-Tormey. For example, while Keytruda, the drug Carter used, has worked "dramatically well," it still doesn't have a success rate on its own that's anywhere close to 100% for the type of cancer it targets. "We need to understand why someone like Jimmy Carter is responding."

In fact, roughly 30% of metastatic melanoma patients using Keytruda alone respond completely. That's still better than the average response rate of chemotherapy treatments on their own in cases of metastatic melanoma. When the drug is combined with others, that success rate goes up, which also holds true for other medications like chemotherapy. But for those who still don't respond at all, that's the challenge. And combining different medications and therapies might be the answer.

This year was a good one for immunotherapies: In October 2015, Keytruda was also approvedto treat a form of lung cancer. It moved forward in getting developed to treat a wide variety of other cancer types as well.

In the last year, Opdivo, another drug that targets the PD-1 protein like Keytruda and was originally approved to treat patients with certain types of melanoma, was also approved to treat forms of lung cancer and kidney cancer.

In blood-cancer treatment, 2015 saw the approvals of more than one multiple-myeloma immunotherapy. Others went so far as to get approval for a genetically modified herpes virus that's programmed to kill tumor cells in patients with melanoma that recurs after surgery (making history as the first cancer viral therapy).

And investors expect new cancer immunotherapies to make billions of dollars in sales in the next couple of years.

• Lydia Ramsey