checkpoint blockade

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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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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.