Fine-Tuning Cells to Tune Out Disease: Immune System Discoveries Spur Hope

To understand what causes type 1 diabetes (T1D), imagine a spy novel. It starts with a hero, the T-cell, that roams your body like James Bond. The T-cell hunts down enemies — bacteria and viruses — and snuffs them out. Then something goes terribly wrong: The hero becomes a villain.

Like a double agent, T-cells can turn against your body and attack your pancreas, triggering T1D. It keeps attacking for years, methodically destroying your ability to produce insulin and control blood sugar. Your T1D becomes ever more debilitating.

Fortunately, there’s hope: One of Benaroya Research Institute’s real-life heroes, Alice Long, PhD, is moving closer to a therapy that makes the enemy T-cells so exhausted they surrender.

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BRI researcher Alice Long, PhD

“We think it could be possible to make the T-cells say ‘we give up, we’re too tired to keep attacking the pancreas,’” Dr. Long says. “That could slow down T1D or maybe even stop it.”

This approach of manipulating T-cells to stop disease could extend far beyond T1D. That’s why Dr. Long is teaming up with other BRI researchers, including BRI President Jane Buckner, MD, to study the machinery inside these cells more closely than ever before.

“This could reveal ways to dial T-cells down to stop autoimmune disease, or dial them up so they attack cancer,” Dr. Buckner says. “It’s a new frontier of immune research and BRI is excited to be at the forefront.” 

T-cell Discoveries

Dr. Long has dedicated her career to finding better therapies for the millions of people with T1D. The best available treatment is to inject insulin. Even then, T1D increases the risk of serious health issues like heart disease and stroke.

“There’s a desperate need for therapies that protect the pancreas so it can keep producing natural insulin, because that helps people with T1D stay healthier and have fewer complications,” Dr. Long says.

Dr. Long believes that understanding a phenomenon called “T-cell exhaustion” could unlock these therapies. Several years ago, researchers discovered the body is home to exhausted T-cells, which are alive but have stopped attacking. Everyone has these exhausted cells. But subsequent research showed that people with autoimmune disease who have higher numbers of these cells also have less severe disease and fewer complications. Then Dr. Long and Peter Linsley, PhD, made a key discovery of their own.

They showed that T1D progresses more slowly in people who have higher numbers of exhausted CD8 T-cells. They also found that a drug called teplizumab increased exhausted CD8 T-cells in most individuals. Even better, BRI researchers led a study that showed treatment with this drug delayed the onset of T1D by approximately three years in people who were susceptible to the disease.

“Those were ‘a-ha moments’ — we started to think, maybe it’s possible to create a therapy that exhausts these cells and stops T1D,” Dr. Long says. “But first we needed to understand these cells in much greater detail.”

Fine-Tuning the Immune System

Dr. Long recently received a $2.6 million National Institutes of Health grant to investigate why CD8 T-cells become exhausted and how this influences T1D. She’s also collaborating with Dr. Buckner and Erik Wambre, PhD, on an NIH-funded project that looks at T-cells in cancer patients.

People with cancer have the opposite problem as people with T1D and other autoimmune diseases. In cancer, T-cells should attack cancer cells, but something about cancer leaves them too exhausted to attack. Drugs called checkpoint inhibitors can nudge those cells back into attack mode. But those drugs can push T-cells into overdrive, until patients end up with symptoms similar to autoimmunity.

“If we can understand the process that leads to autoimmunity in these patients, it could help us understand the biological dial that controls how much T-cells attack,” Dr. Buckner says.

The BRI team’s vision is to be able to control both sides of the T-cell equation. This means they could adjust cancer therapies to prevent autoimmune attacks, or create therapies that exhaust attacker cells and stop autoimmune disease.

“We’re getting closer to being able to turn the immune system up or down depending on a patient’s needs,” Dr. Buckner says, “And that means we’re getting significantly closer to improving the lives of people with everything from T1D to cancer, and maybe even to stopping those diseases altogether.”


A version of this story originally appeared in the Benaroya Research Institute Autoimmune Life Blog

Surviving Lymphoma: Matthew’s Story

Matthew-webMy name is Matthew. I’m a city manager and I live in Ellensburg, Wash., with my wife and two children. We love doing outdoor things like camping and bike riding and treasure our annual trip to Disneyland. We are all proper Disney nerds!

Two years ago, I found out I had cancer the day before leaving on our annual Disney trip. While lathering my neck for an old-fashioned razor shave, my barber noticed a big rock-hard lump. While she froze in terror, I immediately realized it was probably cancer and would explain the mysterious symptoms I’d been experiencing.

On Valentine’s Day, 2013, a diagnosis of Hodgkins lymphoma was confirmed. I was confused, but not scared at first. I remember thinking that getting treatment as soon as possible would be beneficial.

The first oncologist we visited was not at Virginia Mason and it was an awful experience. His office was dark and bleak. He sat me down and, without talking to me at all, began detailing a litany of procedures, exams and the like that I would need. When my wife and I left, we were scared and felt very alone.

I went to work the next day in a daze. A friend came by who had heard about my diagnosis and recommended I go to Virginia Mason for treatment. I called right away and found out I could be seen that weekend. It was an answer to my prayers.

From the start, I knew I was in the right place. I had done research before my appointment and found out how good the program was and that I would be seeing one of the top oncologists in the Pacific Northwest. He walked in and his first words were that while I had cancer, and we would treat that, he wanted to know about me as a person and human being. He asked about my hopes, my fears, whether I planned to have more kids and how chemotherapy might impact that.

He also went over a much smaller list of tests, letting me know that in his opinion the tests the other oncologist wanted (such as a bone marrow biopsy) were most likely not needed. He explained the benefits of a ‘port’ over other infusion methods and I left hopeful and confident we would beat Hodgkin’s!

My cancer treatment was “surreal” in a good way. Virginia Mason has gone to great lengths to make the experience as comfortable and stress-free as possible. I had several chemotherapy regimens and a stem cell transplant. It was a huge and unique benefit that all my care was provided in the same facility and test results were always returned the same day. I never had to ‘go home and wait.’ As anyone who has faced cancer knows, a long wait for test results is just dreadful!

Everyone we met — from the janitors, to the volunteer concierge cart folks, to people in radiology, general surgery and all throughout the organization — they all had passionately embraced a culture of service, positivity, safety and professionalism. We had a seemingly tireless team of health care professionals who fought the good fight with us, comforted us and helped us heal both emotionally and physically.

My daughter has severe anxiety disorder, so you might imagine what my diagnosis and treatment did to her. Virginia Mason staff went out of their way to include her where appropriate, empower her to help, and to understand the process. I could go on for quite some time bragging about so many amazing people at Virginia Mason!

All that said, it wasn’t an easy road. I remember just after one of my chemotherapy treatments that my kids woke me up one day and said, “Dad, we are so sorry to bother you, we know you’re sick, but can you please make us some breakfast? We don’t know how.” That broke my heart. My sweet kids, so compassionate and needing something so simple that was almost impossible for me to do.

This experience has taught me so much about the journey of life we are all on. I find myself wanting to give back, to comfort and help others as they face a cancer diagnosis. People tell me I am way more relaxed and ‘laid back.’ Having faced the shadow of death helps you figure out what’s truly important.

I think I am in a “new normal.” I am considered cancer free but I don’t want to forget the experience that has gotten me to this point. Today, I am grateful for everything and take nothing for granted, not one single moment…

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This story originally appeared on VirginiaMason.org. Meet other patients who bravely shared their stories of fighting cancer, and get the latest information on cancer treatment outcomes and wellness and support at Virginia Mason.

Did You Miss Melanoma Monday?

Downtown Seattle in a Rain Storm and FogWhen the first few days of May bring about torrential downpours in the Seattle area, the thought of slathering on sunscreen to protect against skin cancer is likely far from one’s mind. And Melanoma Monday – a day set aside to bring awareness to this serious form of skin cancer – was probably a little outshined by Cinco de Mayo. Who wants to think about melanoma when there are margaritas and Mexican food to enjoy?

Luckily, May is Skin Cancer Detection and Prevention Month so you still have time to turn your attention from festive beverages and buying flowers for Mother’s Day to your skin.

It is estimated that one in five Americans will be diagnosed with skin cancer in the course of their lifetime, and one person dies from melanoma – the deadliest form of skin cancer – every hour. Melanoma is the result of an abnormal growth of melanocytes, the cells that produce melanin, the pigment that gives color to the skin. Unlike more common skin cancers, such as basal cell and squamous cell carcinoma, melanoma can spread to other organs, making treatment more challenging.

Like many other cancers, melanoma is potentially curable when caught at an early stage. This is why you should learn what to look for on your skin and when to see a doctor. To increase the chances of spotting skin cancer early, the American Academy of Dermatology recommends everyone learn the ABCDE rule, which outlines the warning signs of melanoma:

  • A is for Asymmetry: One half of the mole does not match the other half.
  • B is for Border irregularity: The edges are ragged, notched or blurred.
  • C is for Color that varies from one area to another.
  • D is for Diameter: Melanomas are usually greater than the size of a pencil eraser (5 to 6 mm) when diagnosed, but they can be smaller.
  • E is for Evolving: A mole or skin lesion that looks different from the rest or is changing in size, shape or color.

Anything suspicious should be looked at by your doctor. Some people have a genetic mutation and family history that makes them highly susceptible to developing melanoma, and it requires lifelong surveillance.

For the rest of us, it’s all about prevention. And you probably already know the best way to prevent it. Yes, it’s wearing sunscreen. Yes, even when the only sun you’ve seen for a while was painted on the wall of your favorite Mexican restaurant. Yes, even when it is dark and rainy out. Your skin is exposed to the sun’s harmful UV rays every time you go outside, even on cloudy days and in the winter. Sunscreen is the most important tool in protecting against these rays that cause skin cancer, including melanoma.

 

Intraoperative Radiation Therapy (IORT)

Here’s something we think you will be hearing a lot more about very soon. Virginia Mason is the first medical center in Washington state to offer intraoperative radiation therapy (IORT) to treat women with early stage breast cancer. Watch this 4-minute video to learn more.