Celling out cancer

As immunotherapies start to change clinical practice, we hope for more.


For a blockbuster drug, pembrolizumab comes with a strange history, nicely told here by David Shaywitz.

Pembro is a “checkpoint inhibitor”, a biologic designed to take the brakes off T cells so that they can wipe out tumors. Back in 2014, it was the first drug that targets the PD-1 protein on the surface of T cells to get FDA approval. Also now known as Keytruda, pembro has received FDA green lights for many kinds of cancers. It accounts for billions of dollars each year and is in more than 500 clinical studies.

But it was born in a small Israeli biotech trying to develop treatments for autoimmune diseases by putting brakes on T cells (yes, the reverse of checkpoint inhibition).  The small biotech that created pembro and realized it was a promising cancer drug candidate was soon bought by a larger pharma firm, which was then acquired by Merck & Co. As Shaywitz notes, the giant pharma shut down development not once but twice, before successful trials of other checkpoint inhibitors changed its mind.

Today pembro comes as a colorless liquid in a small IV pouch, looking very much like saline solution. It lists at around $50 a milligram, one case in point for the extremely real concern about how any country can pay for such drugs as they start to become standard of care.

You don’t think about costs, however, if you’re in a clinic as I was earlier this month, watching a friend with metastatic melanoma joke with the nurse hooking up his IV. You just hope the treatment works.

It’s been a pleasure to edit this month’s Nature Outlook on cancer immunotherapy. Many thanks to the outstanding authors, editors and designers who put it together! And to Elin Svensson, who created the great cover art above.

Blossoms in biomedicine

The remarkable global push for cancer immunotherapies.
El_Talayón.byJose Ignacio Martinez Navarro
Editing a Nature special report on cancer immunotherapies, I’m struck most by the sheer scale of the development effort. Something like 3,000 clinical trials are underway, 800 of them combining treatments. The FDA has approved five checkpoint inhibitors, designed to unleash T cells against tumors. The agency seems close to approving the first CAR-T cell treatment, in which a patient’s T cells are removed, reengineered to attack cancer cells, regrown in volume and returned to the patient. Old dogs of immunotherapies are learning new tricks. Some newer approaches are getting much attention—notably personalized neoantigen vaccines, in which individual tumors are sequenced to give clues on how to best target their unique sets of immune-system-alarming antigens. Some clinical trials fail, some do surprisingly well.  The competition is more than intense and trials are not always carefully planned or analyzed. But the landscape is changing.

Mooning cancer

Buzzing aroundBuzzing around Tranquility Base.

We can only applaud a big push to add resources for attacking cancer, but it’s a mistake to call this newly announced federal initiative a moonshot. We won’t land on the cancer cure moon in a decade.

Never mind what it says about our society that our only common metaphor for a large successful national effort is more than a half-century old. The metaphor doesn’t work here.

The actual moon shot built on existing engineering. And the National Aeronautics and Space Administration created its infrastructure from scratch. That’s not possible in our health system, and its irrationalities are increasingly slowing down the grand march toward more personalized medicine.

If the space program had been run like our current health system, computers at Mission Control in Houston and the launch site at Cape Canaveral would not have talked to each other.

Promising efforts like the American Society of Clinical Oncology’s CancerLinQ program are threatened by our inability and unwillingness to share clinical data. As Otis Brawley, chief medical and scientific officer for the American Cancer Society, wrote this week in STAT, “real or perceived privacy issues, along with difficulties connecting disparate electronic health records, may scuttle it.”

As cancer research rockets ahead in the lab, clinical studies may lag years or decades behind. We can take steps to speed them up, but there’s no quick fix.

If NASA had worked like our medical system, the rocket engine makers would have charged whatever they liked. Contrast that with the famous quote from astronaut John Glenn about how he felt before liftoff: “you were sitting on top of two million parts — all built by the lowest bidder on a government contract.”

And if we had run space like medicine, all engineering decisions would have been second-guessed by non-engineers.

The world’s largest cancer center, MD Anderson in Houston, launched its own Moon Shots cancer program three years ago. The initiative helped MDA raise about $300 million, sharpen its priorities and add a few important efforts. And it seems to have achieved progress in a few fairly narrow treatment areas. That’s good news and about what we should expect so far.

There’s nothing theoretical to me about the suffering that cancer inflicts on human lives. I’m happy to see our vice president bringing in the best and brightest to plan an initiative, and especially to figure how to connect the data silos.

But we need another metaphor to help us conceptualize the effort. (And no, not the War on Cancer.) Maybe we can try a title based more closely on another major healthcare initiative (Obamacan? Bidencare?). Grand national projects can live or die by their metaphors.

Man petabytes dog


One of the earliest stories I wrote about genomics past the gee-whiz aspects of the Human Genome Project covered the first whole-genome sequencing of a dog. Kerstin Lindblad-Toh of the Broad Institute patiently explained the project to me, and scientists who used dog models to study inherited blindness told me why they were more than excited about the prospects.

More than a decade later as I’m putting together a special report on big data for Nature, the genomic revolution has marched ahead, well, much as predicted.

The cost of genomic sequencing has dropped arguably faster than any other technology in human history. Research initiatives that most of us haven’t heard about are gathering genomic data on hundreds of thousands of people. This flood of data is multiplied with data from proteomics and other omics now scaling up to the genomic scale. We talk casually about petabytes (millions of gigabytes). Data scientists, many of them coming in from fields outside biology, are integrating these data and making some astonishingly good predictions about what drugs might work for a given condition, without needing any new wet-lab work. We’ve seen wonderful progress in stem cells and cellular models and genetic engineering tools. And this revolution is on television, also websites, social media and an entirely sufficient plenitude of TED talks.

Not so much in the clinic, though.

Of course omic research on many diseases is starting to pay off for actual patients—for example, The Cancer Genome Atlas has spun off clues for real advances in many cancers—and its grand march points straight ahead through enormous but movable objects.

But clinical steps are slow. Part of the reason is the sheer complexity of disease, for instance the ways cancers duck and weave to dodge treatments. And, of course, clinical trials can’t be rushed.

Last week I asked one neuroscientist why we still lack drugs that treat the causes of neurodegenerative diseases, as opposed to their symptoms. She responded, reasonably enough, that it takes years to build better lab models of the disease and push findings from those models into the long tunnel of pre-clinical work toward trials. She expected that some of the compounds coming from her work will help. She didn’t predict home runs.

But we haven’t lost the gee-whiz discoveries and our faith that they’ll end up in the clinic in our lifetimes. My favorite: Scientists can take a human skin cell, bombard it with select small molecules until it morphs into a reasonable facsimile of an insulin–producing cell (a notoriously fickle beast) and produce such cells in the millions. Maybe those cells will arrive in the next decade, bringing actual cures. And although I don’t follow discoveries in dog proteomics, I see that University of California/Berkeley researchers have restored vision to blind dogs via genetic therapy. Progress, yes. Dogged research!


Fitting tumors to a T

Registration statements for initial public offerings are the Eeyores of public documents, and the prospectus Juno Therapeutics released on Monday is no exception. It drones on for page after page about the very real and highly numerous risks in launching up a business to treat cancer by re-engineering T cells.

But I like the ambition of the opening statement: “We are building a fully-integrated biopharmaceutical company focused on revolutionizing medicine by re-engaging the body’s immune system to treat cancer.”

Most of Juno’s research and almost all of its early trials are centered on chimeric antigen receptor (CAR) T cells designed to treat B cell leukemias and lymphomas. This technique plucks out some of a patient’s own T cells and genetically modifies them to glom onto a certain receptor on the cancer cell and start a snowballing immune attack. The reengineered cells are replicated in large volume and put back into the patient, where the immune attack often can effectively wipe out the disease.

If the attack is too strong, though, it can kill the patient, which apparently happened several times in recent trials. Juno and its clinical partners took steps this spring to minimize that danger, mostly by selecting patients more rigorously. And they’re pursuing a technique to make the engineered T cells susceptible to certain chemotherapies, so that the reintroduced cells can be killed off if their onslaught threatens to overwhelm the recipient.

Juno also is investigating another adoptive T cell approach called high-affinity T cell receptor (TCR). These T cells are modified to better seek out fragments of protein brought to the surface of tumor cells by major histocompatibility complex (MHC) cell-surface molecules.

“TCRs recognize proteins that are presented to the immune system as a peptide bound to an MHC, and are therefore restricted to a certain MHC type,” the prospectus notes. “Approximately 80% of the U.S. population has one of the four most common MHC types. Due to this variability, multiple different TCR product candidates will be needed to address any given target protein for a broad population.”

That requirement further complicates drug development. But unlike CAR T cells, TCR T cells can go after cancer cells that are flagged by peptides presented from inside the cell, which might make them useful against a much broader group of cancers.

Juno is pursuing both technologies to treat not just blood cancers but difficult-to-treat solid tumors, with at least four product candidates scheduled for clinical testing by 2016. Among them is a TCR T cell agent that targets WT-1, an intracellular protein overexpressed in adult myeloid leukemia (AML) and breast, colorectal, non-small cell lung and pancreatic cancers. The company expects to give first results of an AML trial this year, and to begin another trial both for AML and solid tumors next year.


Nanostepping up against cancer

Most ovarian cancer is discovered at an advanced stage, responds to standard treatments of surgery and chemotherapy, and then relapses. Unsurprisingly, the better the job of surgically removing tumors, the better the patient’s prospects.

This month in PNAS, MIT’s Angela Belcher and colleagues described a near-infrared imaging system based on an injected nanodevice combining carbon nanotubes with peptides that latch onto ovarian cancer cells, assembled neatly via synthesized bacteriophage virus. In an early surgical test on mice, the technique proved very effective at detecting tiny clumps of cancer cells.

Presenting her work last week at an ovarian cancer event at the Koch Institute for Integrative Cancer Research, Belcher noted that this imaging technique currently works through about 10 cm of tissue, which covers a lot of territory in the human body. She hopes that the method can be extended to gather molecular information about tumor cells that could aid in treatment.

Also at the Koch event, which drew a mix of survivors and researchers, Belcher’s MIT colleagues Sangeeta Bhatia and Paula Hammond presented their ongoing work on cancer nanotherapies.

Bhatia and co-workers are developing nanodevices in which various types of short interfering RNAs (siRNAs) designed to attack cancer tumors can be wrapped inside peptides configured to penetrate tumors and pass through cell membranes. Years of painstaking work are paying off in dramatic results in mice models.

Hammond and her research partners take another approach to cluster-bombing cancer (see cartoon below). They assemble nanoparticles layer by layer, starting with a core of doxorubicin or another chemotherapy agent, adding layers of siRNAs and topping off with a “stealth” outer wrapping meant to let the nanoparticles glide through the body until they can glom onto cancer cells.

All very promising, all in early animal research, and the survivors at the Koch event kept politely asking when each advance might reach humans. “We’re still vertical,” one survivor pointed out.


Running interference into the clinic

Writing a story on therapeutics based on RNA interference, so far I’ve interviewed half a dozen experts, most of them research executives at biotechs leading that charge. There’s a steady stream of early clinical trials with RNAi drugs, almost all targeting liver-expressed genes. In the last week of May, for example, Tekmira launched a phase 1/2 trial for liver cancer and Benitec dosed the first patient in a phase 1 hepatitis B trial. The experts emphasize that animal models have proved highly predictive in studying the effects of RNAi and claim that the delivery obstacles that plagued the first wave of RNAi drugs have been overcome, at least for the liver. They also suggest that regulatory authorities, so far, have been pleased by the clear biomarkers and consistent data available for RNAi agents. Of course, everyone is also properly guarded at this stage of clinical research. I’m looking forward to getting more perspectives on June 13 at the Koch Institute’s symposium on RNA biology, cancer and therapeutics.

Flash mobbing adoptive T cell therapy


Here’s the basic idea behind adoptive T cell therapy: Patients whose cancers don’t respond to conventional treatments can have some of their own immune cells known as T cells plucked, genetically re-engineered to better target their cancer cells, and reinserted. In recent years these treatments have achieved dramatic early clinical successes, and there’s a lot of excitement about them.

This excitement made adoptive T cell therapy a prime candidate for the third annual Biology Flash Mob at the Koch Institute for Integrative Cancer Research at MIT, which drew about 180 volunteers on Friday morning.

We volunteers were a diverse group—by a show of hands, one third of us worked at Koch and one third had never heard of the institute—and several of us were only two years old.

Our Koch hosts divided us into groups of healthy cells (green shirts), cancer cells (red shirts), T cells (blue shirts) and scientists (purple shirts and white lab coats). After a quick rehearsal, the healthy cells marched out and arranged themselves in the center of the quad behind the Koch. They cheered as the T cells filed through them and kept them in line. When one healthy cell popped a red umbrella to show that it had turned cancerous, the T cells took their pom-poms and pummeled it into submission.

But then several healthy cells not only broke bad but hid themselves from the T cells (as real cancer cells do all too often), the T cells wandered around in helpless zombie fashion and dozens of other cancer cells poured in.

Virtue triumphed, however, after the T cells hurried out to be genetically re-engineered (fortified for battle with big foam hands). They charged back into the mass of cancer cells, and swiftly demolished all the bad guys.

The flash mob ended with loud cheers, even from the cancer cells. And we hoped that the cheers will keep echoing in the real world of cancer medicine.

A video of the flash mob will be posted in coming weeks. Meanwhile, you can view the 2012 Koch flash mob, which acted out a targeted cancer therapy technique based on nanoparticles, here.

Photo courtesy Koch Institute for Integrative Research on Cancer at MIT.

Paying the price (or not)

As PD-1 inhibitors march toward FDA approval, the excitement is warranted–at last, cancer immunotherapies that seem to work for more than a few percent of patients, and maybe even arrive with biomarkers that can identify those patients who can benefit. But the stories about these new drugs, like this one a week ago in the Wall Street Journal, often carry an uneasy undertone about pricing. While the drug makers very understandably don’t want to talk about pricing, Citigroup suggests that this new crop might come in at around $240,000 a year, according to the WSJ story. Moreover, these drugs are likely to be combined with other therapies for best results. Paul Workman of the UK Institute of Cancer Research commented that “with combinations, pricing could quickly become completely unsustainable.” That could be true not just in the UK but in the US, where patients are often bankrupted by their cancer care. The deep concern among oncologists about this issue is becoming more and more public, one sign being the American Society of Clinical Oncology’s plans to assess drug value on cost as well as benefits and toxicity.

When centers cannot hold

A million people get cancer each year in India and 980,000 die. “The system is overwhelmed,” as one epidemiologist told me. The government is strengthening and expanding national and state cancer institutes, and some cancer treatment is covered by new national insurance programs. However, there’s concern that boosted spending on treating patients with advanced cancer in both public and (essentially unregulated) private cancer centers will quickly soak up most funding for cancer care, at the expense of more cost-effective prevention and early detection programs. Such issues in cost-effectiveness may be clear–but they wouldn’t be clear to you or me if we were among the million.

Cancer stigma, cancer pain

Writing a story on the tidal wave of cancer in low- and middle-income countries, I expect to hear heartbreaking anecdotes about the lack of funding and other resources. But I also keep hearing about two problems that have relatively little to do with money. One is the combination of fear and social stigma that keeps so many women around the world from fully participating in screening and diagnostic programs. The other is the lack of opiates for palliative care, leaving so many patients in the poorest countries to die in extreme pain. Even in these countries morphine is fairly cheap, but the regulations meant to prevent its illicit use also can keep it from its proper clinical role.