The Most Promising Cancer Treatments In a Century Have ArrivedBut Not For Everyone

In 1891, a New York doctor named William B. Coley injected a mixture of beef broth and Streptococcus bacteria into the arm of a 40-year-old Italian man with an inoperable neck tumor. The patient got terribly sick—developing a fever, chills, and vomiting. But a month later, his cancer had shrunk drastically. Coley would go on to repeat the procedure in more than a thousand patients, with wildly varying degrees of success, before the US Food and Drug Administration shut him down.

Coley’s experiments were the first forays into a field of cancer research known today as immunotherapy. Since his first experiments, the oncology world has mostly moved on to radiation and chemo treatments. But for more than a century, immunotherapy—which encompasses a range of treatments designed to supercharge or reprogram a patient’s immune system to kill cancer cells—has persisted, mostly around the margins of medicine. In the last few years, though, an explosion of tantalizing clinical results have reinvigorated the field and plunged investors and pharma execs into a spending spree.

Though he didn’t have the molecular tools to understand why it worked, Coley’s forced infections put the body’s immune system into overdrive, allowing it to take out cancer cells along the way. While the FDA doesn’t have a formal definition for more modern immunotherapies, in the last few years it has approved at least eight drugs that fit the bill, unleashing a flood of money to finance new clinical trials. (Patients had better come with floods of money too—prices can now routinely top six figures.)

But while the drugs are dramatically improving the odds of survival for some patients, much of the basic science is still poorly understood. And a growing number of researchers worry that the sprint to the clinic offers cancer patients more hype than hope.

When immunotherapy works, it really works. But not for every kind of cancer, and not for every patient—not even, it turns out, for the majority of them. “The reality is immunotherapy is incredibly valuable for the people who can actually benefit from it, but there are far more people out there who don’t benefit at all,” says Vinay Prasad, an Oregon Health and Science University oncologist.

Prasad has come to be regarded as a professional cancer care critic, thanks to his bellicose Twitter style and John Arnold Foundation-backed crusade against medical practices he says are based on belief, not scientific evidence. Using national cancer statistics and FDA approval records, Prasad recently estimated the portion of all patients dying from all types of cancer in America this year who might actually benefit from immunotherapy. The results were disappointing: not even 10 percent.

Now, that’s probably a bit of an understatement. Prasad was only looking at the most widely used class of immunotherapy drugs in a field that is rapidly expanding. Called checkpoint inhibitors, they work by disrupting the immune system’s natural mechanism for reining in T cells, blood-borne sentinels that bind and kill diseased cells throughout the body. The immune cells are turned off most of the time, thanks to proteins that latch on to a handful of receptors on their surface. But scientists designed antibodies to bind to those same receptors, knocking out the regulatory protein and keeping the cells permanently switched to attack mode.

The first checkpoint inhibitors just turned T cells on. But some of the newer ones can work more selectively, using the same principle to jam a signal that tumors use to evade T cells. So far, checkpoint inhibitors have shown near-miraculous results for a few rare, previously incurable cancers like Hodgkin’s lymphoma, renal cell carcinoma, and non-small cell lung cancer. The drugs are only approved to treat those conditions, leaving about two-thirds of terminal cancer patients without an approved immunotherapy option.

But Prasad says that isn’t stopping physicians from prescribing the drugs anyway.

“Hype has encouraged rampant off-label use of checkpoint inhibitors as a last-ditch effort,” he says—even for patients with tumors that show no evidence they’ll respond to the drugs. The antibodies are available off the shelf, but at a list price near $150,000 per year, it’s an investment Prasad says doctors shouldn’t encourage lightly. Especially when there’s no reliable way of predicting who will respond and who won’t. “This thwarts one of the goals of cancer care," says Prasad. "When you run out of helpful responses, how do you help a patient navigate what it means to die well?”

Merck and Bristol-Myers Squibb have dominated this first wave of immunotherapy, selling almost $9 billion worth of checkpoint inhibitors since they went on sale in 2015. Roche, AstraZeneca, Novartis, Eli Lilly, Abbvie, and Regeneron have all since jumped in the game, spending billions on acquiring biotech startups and beefing up in-house pipelines. And 800 clinical trials involving a checkpoint inhibitor are currently underway in the US, compared with about 200 in 2015. “This is not sustainable,” Genentech VP of cancer immunology Ira Mellman told the audience at last year’s annual meeting of the Society for Immunotherapy of Cancer. With so many trials, he said, the industry was throwing every checkpoint inhibitor combination at the wall just to see what would stick.

After more than a decade stretching out the promise of checkpoint inhibitors, patients—and businesses—were ready for something new. And this year, they got it: CAR T cell therapy. The immunotherapy involves extracting a patient’s T cells and genetically rewiring them so they can more efficiently home in on tumors in the body—training a foot soldier as an assassin that can slip behind enemy lines.

In September, the FDA cleared the first CAR-T therapy—a treatment for children with advanced leukemia, developed by Novartis—which made history as the first-ever gene therapy approved for market. A month later the agency approved another live cell treatment, developed by Kite Pharma, for a form of adult lymphoma. In trials for the lymphoma drug, 50 percent of patients saw their cancer disappear completely, and stay gone.

Kite’s ascendance in particular is a stunning indicator of how much money CAR-T therapy has attracted, and how fast. The company staged a $128 million IPO in 2014—when it had only a single late-phase clinical trial to its name—and sold to Gilead Science in August for $11.9 billion. For some context, consider that when Pfizer bought cancer drugmaker Medivation for $14 billion last year—one of the biggest pharma deals of 2016—the company already had an FDA-approved blockbuster tumor-fighter on the market with $2 billion in annual sales, plus two late-stage candidates in the pipeline.

While Kite and Novartis were the only companies to actually launch products in 2017, more than 40 other pharma firms and startups are currently building pipelines. Chief rival Juno Therapeutics went public with a massive $265 million initial offering—the largest biotech IPO of 2014—before forming a $1 billion partnership with Celgene in 2015. In the last few years, at least half a dozen other companies have made similar up-front deals worth hundreds of millions.

These treatments will make up just a tiny slice of the $107 billion cancer drug market. Only about 600 people a year, for example, could benefit from Novartis’ flagship CAR-T therapy. But the company set the price for a full course of treatment at a whopping $475,000. So despite the small clientele, the potential payoff is huge—and the technology is attracting a lot of investor interest. “CAR-T venture financing is still a small piece of total venture funding in oncology, but given that these therapies are curative for a majority of patients that have received them in clinical trials, the investment would appear to be justified,” says Mandy Jackson, a managing editor for research firm Informa Pharma Intelligence.

CAR-T, with its combination of gene and cell therapies, may be the most radical anticancer treatment ever to arrive in clinics. But the bleeding edge of biology can be a dangerous place for patients.

Sometimes, the modified T cells go overboard, excreting huge quantities of molecules called cytokines that lead to severe fevers, low blood pressure, and difficulty breathing. In some patients it gets even worse. Sometimes the blood-brain barrier inexplicably breaks down—and the T cells and their cytokines get inside patients’ skulls. Last year, Juno pulled the plug on its lead clinical trial after five leukemia patients died from massive brain swelling. Other patients have died in CAR-T trials at the National Cancer Institute and the University of Pennsylvania.

Scientists don’t fully understand why some CAR-T patients experience cytokine storms and neurotoxicity and others come out cured. “It’s kind of like the equivalent of getting on a Wright Brother’s airplane as opposed to walking on a 747 today,” says Wendell Lim, a biophysical chemist and director of the UC San Francisco Center for Systems and Synthetic Biology. To go from bumping along at a few hundred feet to cruise control at Mach 0.85 will mean equipping T cells with cancer-sensing receptors that are more specific than the current offerings.

Take the two FDA-approved CAR-T cell therapies, he says. They both treat blood cancers in which immune responders called B cells become malignant and spread throughout the body. Doctors reprogram patients’ T cells to seek out a B cell receptor called CD-19. When they find it, they latch on and shoot it full of toxins. Thing is, the reprogrammed T cells can’t really tell the difference between cancerous B cells and normal ones. The therapy just takes them all out. Now, you can live without B cells if you receive antibody injections to compensate—so the treatment works out fine most of the time.

But solid tumors are trickier—they’re made up of a mix of cells with different genetic profiles. Scientists have to figure out which tumor cells matter to the growth of the cancer and which ones don’t. Then they have to design T cells with antigens that can target just those ones and nothing else. An ideal signature would involve two to three antigens that your assassin T cells can use to pinpoint the target with a bullet instead of a grenade.

Last year Lim launched a startup called Cell Design Labs to try to do just that, as well as creating a molecular on-off-switch to make treatments more controlled. Only if researchers can gain this type of precise command, says Lim, will CAR-T treatments become as safe and predictable as commercial airline flight.

The field has matured considerably since Coley first shot his dying patient full of a dangerous bacteria, crossed his fingers, and hoped for the best. Sure, the guy lived, even making a miraculous full recovery. But many after him didn’t. And that “fingers crossed” approach still lingers over immunotherapy today.

All these years later, the immune system remains a fickle ally in the war on cancer. Keeping the good guys from going double-agent is going to take a lot more science. But at least the revolution will be well-financed.

Read more: https://www.wired.com/story/cancer-immunotherapy-has-arrived-but-not-for-everyone/

Jennifer Doudna: I have to be true to who I am as a scientist

Crispr inventor Jennifer Doudna talks about discovering the gene-editing tool, the split with her collaborator and the complex ethics of genetic manipulation

Jennifer Doudna, 53, is an American biochemist based at the University of California, Berkeley. Together with the French microbiologist Emmanuelle Charpentier, she led the discovery of the revolutionary gene-editing tool, Crispr. The technology has the potential to eradicate previously incurable diseases, but also poses ethical questions about the possible unintended consequences of overwriting the human genome.

Were you nerdy as a child? What got youhooked on science?
Yes, I was nerdy. My father was a professor of American literature in Hawaii and he loved books. One day I came home from school and he haddropped a copy of The Double Helixon the bed, by Jim Watson. Onerainy afternoon I read it and Iwasjust stunned. I was blown awaythat you could do experiments about what a molecule looks like. I was probably 12 or 13. I think that wasthebeginning ofstarting to think,Wow, that could be an amazingthing to work on.

Youve spent most of your career uncovering the structure of RNA and never set out to create a tool to copy andpaste human genes. How did you endup working on Crispr?
I think you can put scientists into two buckets. One is the type who dives very deeply into one topic for their whole career and they know it better than anybody else in the world. Then theresthe other bucket, where I wouldput myself, where its like youre at a buffet table and you see an interesting thing here and do it for a while, and that connects you to another interesting thing and you take a bit of that. Thats how I came to be working on Crispr it was a total side-project.

But when you first started your collaboration with Emmanuelle Charpentier, did you have a hunch youwere on to something special?
We met at a conference in San Juan, Puerto Rico, and took a walk around the old town together. She was so passionate, her excitement was very infectious. I still remember walking down this street with her and she said: Well Im really glad you want to work with us on the mysterious [Cas9 the enzyme that snips DNA at the chosen location in the editing process]. It was this kind of electrifying moment. Even then I just had this gut feeling that this was something really interesting.

How important is personal chemistry inscience collaborations?
Its essential. Working in a lab is analogous to being in a high-school play: youre rehearsing long hours, itscrowded, there are stressful things that come up. Its the same thing in science. Things never work as you think they will, experiments fail and so to have people around that really get along with each other is super important. Many collaborations dont work out, usually just because peoples interests arent aligned or people dont really like working together.

The real frenzy around your work started in 2012, when you showed that Crispr-Cas9 could be used to slice up DNA at any site [of the DNA molecule] you wanted. Did you realise this was abig deal gradually orimmediately?
It wasnt a gradual realisation, it was one of those OMG moments where you look at each other and say holy moly. This was something we hadnt thought about before, but now we could see how it worked, we could see it would be such a fantastic way to do gene editing.

After you demonstrated Crispr could edit bacterial DNA, two rival labs (Harvard and the Broad Institute) got there first in human cells. How come they beat you to it?
They were absolutely set up to do that kind of experiment. They had all the tools, the cells growing, everything was there. For us, they were hard experiments to do because its not thekind of science we do. What speaksto the ease of the system was that a lab like mine could even do it.

The Broad Institute won the latest round of an ongoing legal battle over patent rights they claim that it wasnt obvious that Crispr could be used to edit human cells too. Where do you stand?
People have asked me over and over again: Did you know it was going to work? But until you do an experiment you dont know thats science. Ive been lambasted for this in the media, but I have to be true to who I am as a scientist. We certainly had a hypothesisand it certainly seemed likea very good guess that it would.

Theres the patent dispute and you and Emmanuelle Charpentier also ended up pursuing rival projects to commercialise the technology. Are you all still friends?
If theres a sadness to me about all of this and a lot of its been wonderful and really exciting its that I wouldve loved to continue working with Emmanuelle, scientifically. For multiple reasons that wasnt desirable to her. Im not blaming her at all she had her reasons and I respect her a lot.

The media loves to drive wedges, but we are very cordial. I was just with her in Spain and she was telling me about the challenges [of building her new lab in Berlin]. I hope on her side, certainly on my side, we respect each others work and in the end were all init together.

In your book you describe a nightmare youhad involving Hitler wearing a pig mask, asking to learn more about your amazing technology. Do you still have anxiety dreams about where Crispr mightleave the human race?
I had the Hitler dream and Ive had a couple of other very scary dreams, almost like nightmares, which is quite unusual for an adult. Not so much lately, but in the first couple of years after I published my work, the field was moving so fast. I had this incredible feeling that the science was getting out way ahead of any considerations about ethics, societal implications and whether we should be worrying about random people in various parts of the world using this for nefarious purposes.

In 2015, you called for a moratorium on the clinical use of gene editing. Where do you stand on using Crispr to edit embryos these days?
It shouldnt be used clinically today, but in the future possibly. Thats a big change for me. At first, I just thought why would you ever do it? Then I started to hear from people with genetic diseases in their family this is now happening every day for me. Alot of them send me pictures of their children. There was one that Icant stop thinking about, just sent to me in the last 10 days or so. A mother who told me that her infant son was diagnosed with a neurodegenerative disease, caused by a sporadic rare mutation. She sent me a picture of thislittle boy. He was this adorable little baby, he was bald, in his little carrier and so cute. I have a son and myheart just broke.

What would you do as a mother? You see your child and hes beautiful, hes perfect and you know hes going to suffer from this horrible disease and theres nothing you can do about it. Its horrible. Getting exposed to that, getting to know some of these people, its not abstract any more, its very personal. And you think, if there were away to help these people, we should do it. It would be wrong not to.

What about the spectre of designerbabies?
A lot of it will come down to whether the technology is safe and effective, are there alternatives that would be equally effective that we should consider, and what are the broader societal implications of allowing gene editing? Are people going to start saying I want a child thats 6ft 5in and has blue eyes and so on? Do we really want to go there? Would you do things that are not medically necessary but are just nice-to-haves, for some people?Its a hard question. There area lot of grey areas.

Are you worried about cuts to science funding, including to the National Institutes of Health (NIH) budget?
I am very concerned. Science funding is not a political football but in fact a down payment on discovery, the seed money to fund a critical step toward ending Alzheimers or curing cancer.

Researchers currently working on projects aimed at improving numerous aspects of our agriculture, environment and health may be forced to abandon their work. The outcome is that people will not receive the medical treatments they need, our struggle to feed our exploding population will deepen, and our efforts to manage climate change will collapse.

Over the long term, the very role of fundamental science as a means to better our society may come into question. History and all evidence points to the fact that when we inspire and support our scientific community we advance our way of life and thrive.

Were you disturbed when Trump tweeted, If U.C. Berkeley does not allow free speech and practices violence on innocent people with a different point of view NO FEDERAL FUNDS? in response to a planned alt-right speaker being cancelled due to violent protests on campus?
Yes. It was a confusing tweet since the university was clearly committed to ensuring that the event would proceed safely and first amendment rights were supported. Few expected the awful actions of a few to be met with a willingness from the highest office to deprive more than 38,000 students access to an education.

Youve spoken at Davos, shared the $3m2015 Breakthrough prize, been listedamong the 100 most influential people in the world by Time magazine. Areyou still motivated about heading intothe lab these days?
Yesterday I was getting ready to go to a fancy dinner. I was in a cocktail gown and had my makeup on and my hair done, but I wanted to talk to a postdoc in my lab about an experiment he was doing, so I texted him saying can we Skype? It was 8am in California, I was over here [in the UK] in my full evening gown, talking abouttheexperiment.Thats how nerdy I am.

A Crack in Creation: The New Power to Control Evolution by Jennifer Doudna and Sam Sternberg is published by The Bodley Head (20). To order a copy for 17 go to bookshop.theguardian.com or call 0330 333 6846. Free UK p&p over 10, online orders only. Phone orders min p&p of 1.99

Read more: https://www.theguardian.com/science/2017/jul/02/jennifer-doudna-crispr-i-have-to-be-true-to-who-i-am-as-a-scientist-interview-crack-in-creation