cancer immunotherapy

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Crossing the Ts in diabetes

Advances in cancer immunotherapy may help autoimmune therapies defend themselves.

allogeneic label

Is human immunology basically too crazy complex for the human mind? Evidence to date suggests yes, at least for my mind.

In almost every story I write about cancer immunology or autoimmune disease, I learn about previously unknown (to me) functions within the three-ring circus of immune cells. Or I find out about yet more types of these cells, like double-negative T cells, which can defend against graft disease and maybe type 1 diabetes. Who knew?

Well, yeah, thousands of immunologists.

All of us who follow cancer research, though, do know a (simplified) version of one genuine breakthrough in immunology, checkpoint blockade inhibitors, which garnered Nobel Prizes last October.

These drugs take on one of deepest questions in cancer biology: why the immune system doesn’t snuff out cancer cells, which by definition are genetically abnormal, often wildly abnormal.

Checkpoint blockades can hold off the T cells on patrol for just such outsiders. It turns out that a protein on the surface of tumor cells called PD-L1 can grab onto a surface protein on the T cell called PD-1 and so disarm the T cell. (Nothing to look at here, officer! Ignore my multiple heads and antitank guns!)

Other headlines in cancer immunotherapy come from chimeric antigen receptor T (CAR-T) cell drugs, treating patients with certain blood cancers in which B cells go bad. The two such drugs with FDA approval work by taking T cells from the patients, reengineering the T cells to attack those cancerous B cells, and reinserting the T cells.

This method is often effective when nothing else works, but is always worryingly slow and extremely costly.

So there’s plenty of work in labs, and a few clinics, to take a logical but intimidating next step: Engineering off-the shelf T cells to do the job, hiding them from each patient’s immune system with tricks learned from checkpoint blockade research and similar  immunology findings.

Still with me?

Okay, if those cell-shielding techniques eventually work, can a similar attack be made in autoimmune diseases such as type 1 diabetes?

In type 1 diabetes, effective ways to stop the autoimmune attacks from trigger-happy T cells exist only in lab mice. And that’s a problem not just in slowing or stopping disease progression but in trying to treat it. The most promising current approach is to encapsulate insulin-producing beta cells. This has been pursued for many decades, with many barriers. Perhaps the highest (if least surprising) barrier is that the capsules always get clogged up.

The latest capsule approaches, starting with beta cells made by reprogramming cells, try sophisticated material-science strategies to blunt this attack and may do much better.

But as long as we’re already playing genetic games with those engineered beta cells, why not also try  immune-evading tricks similar to those being studied in CAR-T experiments?

That’s the basic idea behind efforts by Altheascience, a Viacyte/CRISPR Therapeutics collaboration, and others. Which just maybe will produce capsules that, replaced every year or so as necessary, are working cures for type 1 diabetes. Which we would all fully understand.

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Celling out cancer

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

CI_cover_crop

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.

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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.

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Unlocking the combinations

tsMouse regulatory T cell and human T cell, courtesy NIAID.

The autoimmune attack that triggers type 1 diabetes has been beaten in the non-obese diabetic mouse, the best animal model of the disease.

More than 500 times, in fact, notes Jay Skyler, professor of medicine at the University of Miami.

But in humans: never.

Researchers have painstakingly picked apart the genetics of the disease and many of the intricacies of the immune attack that wipes out insulin-creating cells in the pancreas. And recent studies suggest that we might, just might, have a smoking gun in the form of disease-triggering populations of gut microbes. But we don’t really know the trigger mechanisms and we really can’t stop the disease.

However, as Skyler reviewed the disappointing decades of type 1 trials in a lecture last week at Joslin Diabetes Center, he pointed out research approaches that might lead closer to a cure.

Among them: examining the effects of treatments by subgroups (such as age), coordinating dosing with the timing of immune events, and administering multiple doses or higher doses of a drug.

Given the unending complexity of the immune system, though, maybe the most promising strategy is to hit it at multiple points. That’s the thinking behind Skyler’s upcoming Diabetes Islet Preservation Immune Treatment (DIPIT) trial.

DIPIT will compare two groups of people recently diagnosed with type 1, one group given five drugs and the other a placebo. The drugs, all giving hints of helpfulness in earlier type 1 trials and approved by the Food and Drug Administration for other conditions, are

• anti-thymocyte globulin (an antibody used to prevent rejection in organ transplants)
• etanercept (which inhibits tumor necrosis factor, a master regulator of immune response)
• pegylated granulocyte colony stimulating factor (a growth factor that boosts production of certain white blood cells)
• Interleukin 2 (a cytokine whose effects include increasing growth of the regulatory T cells that can guard against autoimmune onslaughts), and
• exenatide (a synthetic hormone that boosts glucose-dependent insulin secretion).

As Skyler told the Miami Herald, “we have one drug to stop the cavalry; one drug to stop the artillery; two drugs that help bring in support systems that favor the immune response; and one drug that helps beta cell health so they can resist the attack better.”

When he first proposed this kitchen-sink idea, “everybody said I was crazy,” Skyler remarked to his Joslin audience. The trial did get FDA approval. He’s still looking for funding, though.

Okay, let’s contrast these combinations with those in another arena of biomedical research that’s almost the reverse of type 1: cancer immunotherapy.

This field tries to activate (rather than suppress) the immune system at multiple points. Also unlike the case with type 1 and other autoimmune diseases, it is awash in drug-discovery money.

In fact, we’re living in the breakthrough decade for cancer immunotherapy. The two clear winners so far are CAR-T cells (chimeric antigen receptor T cells, in which a patient’s own cells are re-engineered to seek and destroy blood cells gone bad) and checkpoint blockade drugs (which prevent tumors from presenting false IDs).

The first checkpoint blockade drug approved by the FDA targets CTLA-4, a surface receptor on T cells and B cells. About a fifth of advanced melanoma patients given the drug survive for ten years with no further treatment. And in clinical trials, combining a CTLA-4 inhibitor with a drug that clogs up another checkpoint receptor, PD-1, has significantly broadened the population of survivors.

Combination is a familiar theme in cancer treatment, since tumors are so adept at evolving to resist whatever you throw at them. There are very high hopes for adding immunotherapies to the mix.

And in that mix, proven treatments like checkpoint blockaders will be joined by other drugs that hit different points of immune activation. There’s much excitement, for instance, about agents that activate the STING (stimulator of interferon genes) pathway, which can kick off defenders in both the innate and the adaptive immune systems and maybe act as a kind of cancer vaccine.

In both cancer and diabetes, nothing will be easy in bringing combination therapies into clinical trials and then ideally into regular practice. Researchers must identify exactly which patients might benefit from which combos, juggle drug dosages and timing, watch for serious side effects and struggle to quantify any improvements in health. These will be long rough roads. But for some patients, we hope, combos will lead to cures.

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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.

TCR

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Flash mobbing adoptive T cell therapy

flashmob1

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.

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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.