Two Infants Treated with Universal Immune Cells Have Their Cancer Vanish

In a medical first, the children were treated with genetically engineered T-cells from another person.

by Antonio Regalado January 25, 2017

Doctors in London say they have cured two babies of leukemia in the world’s first attempt to treat cancer with genetically engineered immune cells from a donor. The experiments, which took place at London’s Great Ormond Street Hospital, raise the possibility of off-the-shelf cellular therapy using inexpensive supplies of universal cells that could be dripped into patients’ veins on a moment’s notice.

The ready-made approach could pose a challenge to companies including Juno Therapeutics and Novartis, each of which has spent tens of millions of dollars pioneering treatments that require collecting a patient’s own blood cells, engineering them, and then re-infusing them.

Both methods rely on engineering T cells—the hungry predator cells of the immune system—so they attack leukemic cells.

The British infants, ages 11 and 16 months, each had leukemia and had undergone previous treatments that failed, according to a description of their cases published Wednesday in Science Translational Medicine. Waseem Qasim, a physician and gene-therapy expert who led the tests, reported that both children remain in remission.

Although the cases drew wide media attention in Britain, some researchers said that because the London team also gave the children standard chemotherapy, they failed to show the cell treatment actually cured the kids. “There is a hint of efficacy but no proof,” says Stephan Grupp, director of cancer immunotherapy at the Children’s Hospital of Philadelphia, who collaborates with Novartis. “It would be great if it works, but that just hasn’t been shown yet.”

Rights to the London treatment were sold to the biotech company Cellectis, and the treatment is now being further developed by the drug companies Servier and Pfizer.

Treatments using engineered T-cells, commonly known as CAR-T, are new and not yet sold commercially. But they have shown stunning success against blood cancers. In studies so far by Novartis and Juno, about half of patients are permanently cured after receiving altered versions of their own blood cells.

But commercializing such personalized treatments raises unprecedented logistical headaches. Grupp says Novartis has outfitted a manufacturing center in New Jersey and that patient cells have been flown in from 25 hospitals in 11 countries, modified, then quickly shipped back. Novartis has said it will seek U.S. approval to sell its T-cell treatment for children this year.

The promise of immunotherapy has drawn huge investments, yet many newer entrants are betting instead on the off-the-shelf approach. Among them are biotech giant Regeneron, Kite Therapeutics, Fate Therapeutics, and Cell Medica.

“The patient could be treated immediately, as opposed to taking cells from a patient and manufacturing them,” says Julianne Smith, vice president of CAR-T development for Cellectis, which specializes in supplying universal cells.

In the off-the-shelf approach, blood is collected from a donor and then turned into “hundreds” of doses that can then be stored frozen, says Smith. “We estimate the cost to manufacture a dose would be about $4,000,” she says. That’s compared to a cost of around $50,000 to alter a patient’s cells and return them.

Either type of treatment is likely to cost insurers half a million dollars or more if they reach the market.

Robert Nelsen, a venture capitalist and a founder of Juno Therapeutics, which raised hundreds of millions for the custom approach, says he’s not worried about companies developing universal alternatives. “What they can do in the future is what we can do today,” Nelsen said in an interview last year. “And I guarantee you even if things were equal, which they are not, you would want your own stuff, not someone else’s cells.”

The London treatment is notable for involving the most extensively engineered cells ever given to a patient, with a total of four genetic changes, two of them introduced by gene editing using a method called TALENs. One alteration was to strip the donor cells of their propensity to attack the body of another person. Another directs them to attack cancer cells.

In the U.S. and China, scientists are also racing to apply gene editing to make improved treatments for cancer and other diseases.

What ’60 Minutes’ Got Right And Wrong On Duke’s Polio Virus Trial Against Glioblastoma

by David Kroll on Forbes.com

An engineered version of the poliovirus has been in development for more than 20 years as a treatment for one of the most difficult-to-treat cancers, a brain tumor called glioblastoma multiforme, abbreviated GBM. A human safety trial of the virus, called a Phase I study, is ongoing at Duke University’s Brain Tumor Center in Durham, North Carolina. The patients who’ve been enrolled have the toughest form of this disease: GBM that has returned after previous surgery and treatment.

Last night, the CBS News program 60 Minutes devoted two segments of the broadcast to correspondent Scott Pelley’s 10-month-long glimpse into this clinical trial. (Disclosure: I have held an unpaid adjunct faculty appointment in Duke University’s Department of Medicine since 2002, was a paid faculty member there in 2001, and did a year-long research sabbatical there in 2000 while I was a pharmacy professor at the University of Colorado.)

The segment, called “Killing Cancer,” was produced by Michael Radutzky and Denise Schrier Cetta and did a responsible job of illustrating the potential power of this new treatment with the sober realities of the challenges presented by a cancer whose prognosis is measured in months. The program, the entire transcript, and supplementary materials are available at the 60 Minuteswebsite.

Using the virus that causes the childhood paralytic disease called poliomyelitis to treat cancer seems outrageous. We’ve been trying to eradicate the virus from the planet since the 1950s, when two types of vaccines were developed by Drs. Jonas Salk and Albert Sabin. The Americas were declared polio-free in 1994 and the disease only remains in three countries: Nigeria, Pakistan, and Afghanistan.

But the way that the polio virus infects cells and what it does afterwards are the precise actions that Matthias Gromeier, MD, thought could be harnessed to treat cancer. Gromeier has been at Duke for the last 15 years painstakingly shepherding his studies from lab to clinic. But the German-trained molecular biologist began this work in earnest 25 years ago when he came to the States to work with the renowned virologist, Eckard Wimmer, at the State University of New York at Stony Brook.

Some technical background

Detailed in this seminal 1996 paper in the Proceedings of the National Academy of Sciences, Gromeier and colleagues in Wimmer’s lab replaced a segment of the poliovirus’s RNA genome with a corresponding piece from a human rhinovirus, a type that causes the common cold. (The virus is still known in the literature and on Duke’s webpage by the cumbersome name, PVS-RIPO.)They found that this recombinant (or chimeric) virus could still infect cells that had the poliovirus receptor, but that the virus didn’t replicate. Many cancer cells, including glioblastoma, overproduce the poliovirus receptor (known as CD155 or Necl-5). So, by using the right amount of this designer virus, the researchers could selectively kill glioblastoma cells in culture without affecting normal neuronal cells. For this reason, this virus is called an oncolytic virotherapy, meaning that it causes lysis or bursting open of cancer cells.

But that’s not all. The way that cancer cells make proteins is different from that of normal cells. So even when the virus gets into some normal cells that have the receptor, it’s not as damaging. This two-part difference between cancer cells and normal cells is the basis for trying to treat human glioblastomas by directly infusing very small amounts into the tumor through a one millimeter diameter catheter that’s inserted into the tumor through the skull, guided by 3-D imaging. That part of the work is done by Duke neurosurgeon, John Sampson, MD.

But once in the brain, the virus triggers the body’s immune response against the tumor cells. In fact, the patient’s own immune response is probably more important than the initial bursting of the cancer cells.

As Gromeier explained on 60 Minutes, “So cancers, all human cancers, they develop a shield or shroud of protective measures that make them invisible to the immune system. And this is precisely what we try to reverse with our virus. So by infecting the tumor, we are actually removing this protective shield. And telling the– enabling the immune system to come in and attack.”

But the immune response must be carefully manipulated because too much virus can cause a massive swelling of the brain. So that’s why the goal of this first Duke trial isn’t to determine the virus’s effectiveness. The purpose is to get to the right dose, as explained by the Brain Tumor Center’s deputy director, Henry Friedman, MD.

A personal aside

While I was on sabbatical at Duke in 2000, Gromeier had joined the faculty in microbiology and immunology in the same building where my mentor, Ken Kreuzer was located. I remember when Gromeier’s first independent grant was funded through the National Cancer Institute’s RAID program, a mechanism that allowed unique cancer treatments discovered in academia to be cultivated for clinical trials using the preclinical toxicology, medicinal chemistry, and biologics expertise of the NCI Developmental Therapeutics Program to produce the clinical trial-quality viral study agent.

When I ran into Gromeier again a few years into the process, he said that the level of detail required to get the product even made was tortuous. When they were using cholesterol in the mix to originally help the virus into the cells, he said that NCI and FDA were concerned about the source of the cholesterol being cattle and that they had to be sure that the preparation didn’t have any miniscule amount of the virus that causes mad cow disease. Every step of the process had to overcome this degree of scrutiny. And even when the clinically-qualified batches of virus were made, the FDA required seven more years of safety testing, up to and including administration to three dozen monkeys, before the first human subject was permitted in 2011.

My near-teenage daughter just walked past the computer as I’m writing this and I was struck by the fact that Gromeier has been working on this at Duke a couple of years longer than she has been alive. The rigor with which the safety of this approach is being evaluated is remarkable.

I encourage you to watch both parts of the 60 Minutesstory. Knowing some of the folks involved but also putting on my critical hat as a scientist and writer, I have a few thoughts on how the story was presented.

What I liked:

1. The program was careful to note that the effectiveness of the virus in three of the study volunteers interviewed was offset by an equal number of patients who are no longer alive. Eleven of the 22 volunteers have succumbed to their disease.

2. The program gave time for Henry Friedman to say that a clinical effect of the study agent is not the goal of a Phase I study.

3. Annick Desjardins, MD, the neurooncologist who followed the patients and evaluated their post-surgical functioning, showed the true level of compassion and teamwork that forms the nucleus of the Brain Tumor Center’s reputation.

4. Even when Scott Pelley pushed Friedman and center director, Darell Bigner, MD, PhD, to use the word “cure” or “miracle,” both were very measured and guarded but still conveyed a sense of optimism. In Friedman’s 34 years at Duke and Bigner’s 49 years, they’ve seen a lot of death. But they’ve also made significant contributions globally in the treatment of brain cancers. So for them to both say that the recombinant poliovirus approach was the most promising agent they’ve seen for glioblastoma in their careers, it’s hard not to be excited.

5. Both the program and Duke made it very easy for prospective patients to have their questions answered about potential eligibility for the trials: Editor’s Note: For more information on the Duke University polio trial or other brain cancer trials, click here or call 919-684-5301. The Duke page is very easy for interested subjects to navigate for referrals and information on this and other clinical trials at the Brain Tumor Center. The site was clobbered last night and was unreachable for the first two hours after the program aired, but it has been available every time I’ve clicked this morning.

What I liked less:

1. At the outset, Pelley made it sound like very few advances have been made in cancer treatment over the last 100 years: “The long war on cancer has left us well short of victory. Radiation flashed on in the 19th century, chemotherapy began to drip in the 20th but, for so many, 100 years of research adds up to just a few more months of life.” That’s partly true, but partly nonsense. Tremendous strides have been made within many cancers, from childhood leukemia cures to cancer survivors who are counting decades since their treatment. The program needn’t have denigrated how far we’ve come to show the promise of the viral therapy. It’s impressive enough on its own.

2. Pelley: “Duke went to the FDA for approval of this new Frankenstein virus.” Frankenstein? No, no, no, no. Moreover, the virus wasn’t approved. It was granted Investigational New Drug status to begin clinical trials.

3. The emotional power of the two people who are in remission, particularly the first recipient, Stephanie Lipscomb, was so positively overwhelming that I don’t think the risks were fully balanced by the story of another patient who did not do well and withdrew from the study. The positive anecdotes were very compelling and a viewer hoping to get into subsequent trials might be overly optimistic. While I mentioned above that I liked the fact the the 11 of 22 response statistics were a valuable inclusion, the amount of time given to that point led to its underrepresentation.

4. For Forbes readers, there was a paucity of information on the intellectual property considerations of the polio virus therapy and detail on how the drug will ultimately be commercialized. The program mentioned briefly that the investigators have a financial stake in the drug’s success, as with many clinical trials. But there was no discussion of the fact that the first patents on the therapy were granted to Gromier with Wimmer and the Research Foundation of SUNY-Stony Brook. Issued in 2003 and 2006, we don’t know if any hurdles exist for Duke’s commercialization of the technology (I have no inside information on this; I’m just raising it as a viewer who expected the issue to be addressed.).

5. While interviewing Gromeier, Pelley led him to speak about the use of the virus against other cancers. I don’t think the program made clear that the work in prostate, breast, and pancreatic cancer, among others, was still in the experimental phase.

6. The program only briefly touched on other therapies that exploit the immune system for cancer but didn’t mention that viral approaches are being taken by quite a few other research teams and companies. Forbescontributor, Arlene Weintraub, has a more comprehensive discussion this morning.

7. Without knowing Henry Friedman, one might think that CBS was being disrespectful to him because he chooses not to dress as a typical physician: He was wearing a Duke hoodie and jeans and Pelley said that’s how Friedman’s brain thinks about fashion. Indeed, his dress is most often casual but I know that it breaks down barriers with his patients, most who are coming from far away and freaked out about their disease. Friedman is a fierce advocate of every facet of Duke and has contributed immensely to the brain cancer treatment internationally. Moreover, I admire him most for his establishment of a program (with neurosurgery colleague, Allan Friedman, MD – not related) for Duke’s women athletes who wish to pursue medical school and his strong support of Duke women’s basketball. Perhaps that’s just me.

Why the absence of the Tisch name?

And my final observation was one that just struck me as odd. The Duke Brain Tumor Center, originally established in 1937, was renamed the Preston Robert Tisch Brain Tumor Center after the Tisch family donated $10 million for research at the Brain Tumor Center and the Duke Comprehensive Cancer Center. Yet the 60 Minutes program made no mention of this name.

The late Bob Tisch was treated at Duke for his brain cancer, living for 14 more months after he was given a two-month prognosis in New York. Bob Tisch was the brother of the late Larry Tisch, CEO of the CBS network from 1986 to 1995. During his tenure, Larry Tisch slashed jobs in the news division and one can’t help but think that the remaining old-timers at 60 Minutes might hold some grudge. Alternatively, they might not have wanted to cloud the story with this two-steps-removed association with the Duke Brain Tumor Center.

In any case and for whatever reason, the omission was glaring. CBS has not responded to a request for information.

From Sky News

Tests of a potentially revolutionary cancer therapy have had “extraordinary” results on terminally ill patients, scientists have revealed.

In one study, more than nine out of ten participants with a severe form of leukaemia saw their symptoms completely vanish.

Four out of five patients with some other blood cancers responded positively to the treatment and more than half ended up symptom free.

Lead scientist Professor Stanley Riddell, from the Fred Hutchinson Cancer Research Center in Seattle, US, said the results were among patients who were projected to have two to five months to live.

He said: “This is extraordinary. This is unprecedented in medicine to be honest, to get response rates in this range in these very advanced patients.”

The technique involves removing immune cells called T-cells from patients, tagging them with “receptor” molecules that target cancer, and putting them back into the body in an infusion.

The targeting molecules, known as chimeric antigen receptors or Cars, came from specially bred genetically engineered mice.

Once attached to the T-cells, they reduce the ability of the cancer to shield itself from the body’s natural immune system.

Speaking at the American Association for the Advancement of Science (AAAS) annual meeting in Washington DC, Prof Riddell described the results as a “potential paradigm shift” in cancer treatment.

Much more work was required, he said, adding that it was not clear how long the symptom-free patients would remain in remission.

Prof Riddell hopes to try the therapy on patients suffering from cancers with solid tumours, but said they would present challenges.

Although the body’s natural immune system is geared to tackle cancer, it is often unable to. Sometimes, the body’s defences cannot recognise cancer cells or they find ingenious ways to mask their identity.

In the most promising of Prof Riddell’s studies, around 35 patients with acute lymphoblastic leukaemia (ALL) were treated with the modified cells.

Almost all – 94% – went into complete remission. Being in remission is not the same as saying they are cured, because the symptoms can return.

Here, medics are urging caution. Dr Yvonne Doyle, from Public Health England, said: “It’s an important breakthrough, in that it’s a new technology that seems to have developed something innovative.

“However, it is on 30 patients who are at a very advanced stage of a particular cancer. So what we need to know is does this work in a wider situation?”

The treatment is similar to a technique used with success last year on Layla Richards, a one-year-old girl with ALL, by doctors at Great Ormond Street Hospital, who described the results as “staggering”.

A consultant immunologist who treated Layla, Professor Waseem Qasim, told Sky News it was still early days: “We will have to wait and see how these type of treatments play out for solid cancers such as cancers of the lung or the bowel or the breast and so on…

“The first tranche of investigations and successes I think will be in the blood-type cancers.”