Chasing Checkpoints: James Allison in Time Magazine Top 100

Kate Johnson

May 16, 2017

If you listen to James Allison, PhD, talk about the discoveries that put him on the list of Time magazine's 100 most influential people in 2017, his career sounds like a fascinating series of serendipitous adventures.

Dr James Allison

Yet, the soft-spoken Texan has had his focus keenly trained on the mysteries of the T cell for his entire career. 

Dr Allison's discovery of the T-cell receptor catapulted cancer therapy into the new era of immunotherapy, in which the word "cure" is no longer considered hyperbole.

He went on to develop the field of checkpoint blockade, leading to the breakthrough drug ipilimumab (Yervoy, Bristol-Myers Squibb), the first of the checkpoint inhibitors, which is approved for use in melanoma. But this led to an avalanche of other drugs, including programmed cell death inhibitors, such as nivolumab (Opdivo, Bristol-Myers Squibb) and pembrolizumab (Keytruda, Merck & Co). These checkpoint inhibitors are now approved for six late-stage cancers — melanoma, lung cancer, renal cell carcinoma, head and neck cancer, urothelial cancer, and Hodgkin's lymphoma — with many other tumor types being investigated in clinical trials.

This new approach to cancer treatment — interfering with the immune system and its response to cancer, rather than attacking the cancer directly — has been hailed as a clinical cancer research advance for 2 years running by the American Society of Clinical Oncology (ASCO).

However, Dr Allison, currently professor and executive director of immunotherapy at Houston's MD Anderson Cancer Center in Texas, was not trained as an immunologist.

"I was trained in biochemistry, but I took a course in immunology as an undergraduate," he said in an interview with Medscape Medical News. "T cells had just been discovered, but my professor was an antibody guy and he told me he didn't even necessarily believe that T cells existed."

It was the mid-1960s, a tumultuous time in the field of immunotherapy when Bede Morris, FAA, a colorful Australian veterinarian and professor of immunology at Canberra's John Curtin School of Medical Research, is rumored to have likened B and T cells to "the first and last letters of the word 'bullshit.' "

But Dr Allison was not deterred.

In fact, he became obsessed with the T cell.

"T cells are the soldiers of the immune system, but no one knew how they were turned on," he recalled, when he wrote about his research in Cell's Lasker Award Stories, after receiving the prestigious award in 2015 (Cell. 2015;162:1203-1205).  

"In 1982, I published a paper reporting what seemed to be the T cell antigen receptor protein [J Immunol. 1982;129:2293-300]. All of a sudden, I was totally hooked on understanding T cell activation."

Until that point, Dr Allison describes his T-cell work as almost an aside, experiments undertaken with a colleague in the lab "unbeknownst to my mentor" to relieve the boredom of "just another biochemistry project." But he describes that first paper as "pretty high profile" — and then things began in earnest.

Over the next decade, after zeroing in on the T cell's antigen receptor, which is essentially its ignition switch, Dr Allison and his colleagues showed that a molecule called CD28 acts as the accelerator and CTLA-4 as the brake.

This T-cell activation and inhibition are the key to cancer immunotherapy. Cancer cells do not express CD28 and therefore do not trigger the body's protective T-cell response, he explains. "The tumor gets a head start and it grows without the immune system even being aware of it, until it gets big enough to cause damage, for example if it's too big to get enough oxygen, or nutrients, then some of the tumor cells start dying and that causes inflammation and the immune system starts."

Once triggered, T cells go about their job of attacking the tumor. But the body's built-in brakes — CTLA-4 — are designed to stop the T-cell response before it gets out of control.

"The idea is that if the T cells kill all the cancer before CTLA-4 kicks in, then the immune system wins, but if CTLA-4 turns off the T cells before they've eliminated all the tumor, then the tumor wins," he explained.

So the key was to turn off the brakes. Dr Allison, who today is almost 70, and has personally battled melanoma, prostate cancer, and bladder cancer, could not ignore the calling.

"I did not think of myself as a cancer researcher," he insisted, adding that saving lives was "the farthest thing from my mind."

However, having lost his mother to lymphoma when he was only 11 years old  ("I actually held her hand as she was dying," he commented), as well as two uncles and a brother to cancer, he did "what any basic scientist should do: occasionally stop and think about the implications of your fundamental findings for application to human disease," he wrote in his Lasker Award article.  

Bridging Cancer and Immunology Worlds

Bridging the gap between the cancer and immunology worlds meant he felt the heat from both sides. "When I started out, the whole field of immunotherapy was held in disrepute by the rest of the cancer field," he said. And then, among immunologists, "because I worked out the structure of the T-cell receptor on T cells specific for lymphoma, my immunology colleagues who were more senior than me would snicker that I was 'a tumor immunologist.' "

Dr Allison is also a musician. He plays harmonica for the CheckPoints, a blues/rock band made up entirely of oncologists and immunologists. They do it for fun — and to raise money — and have become a regular feature at the annual Society for Immunotherapy of Cancer meetings. He's also a Willie Nelson fan, whom he once got to jam with on stage. "Without a doubt, it was one of the top five moments in my life," he is reported to have said afterward.

It's not often that you meet a basic scientist who seems to have as much fun as Dr Allison. He has the gift of seeing things through an alternate lens, which is how he came to recognize that the immune system could be more than just a shield against cancer — it could be a weapon.

Although cancer immunology researchers had been trying (and failing) to "harness" the immune system with vaccines, he sought instead to "unleash" it by using antibodies to block CTLA-4.

"People say, 'Oh, you're just arguing semantics,' but it does have an effect on the way you think about it," he said. "Checkpoint blockade is just taking the breaks off and letting the immune system do its job."

Today, dozens of T-cell activator and inhibitory molecules are under investigation, along with corresponding drugs to manipulate them. Hundreds  of patients are alive who wouldn't otherwise be after all other forms of treatment had failed. Although he is not a physician and does not treat many patients, they still recognize him in odd places, like airplanes, and he gets emails from them every few days. He spoke particularly fondly of one of the first patients whose spectacular recovery made him cry.

The Lasker Award article features a photograph of Sharon Belvin, shown almost 10 years after receiving anti–CTLA-4 therapy, with her two children. When she received the drug, as a last resort for stage IV metastatic melanoma, she had been given only a few months to live.  

"Until then it was all numbers to me, but when I met her I really did stop and think for the first time. We exchanged emails a few weeks ago, and I asked her to send me a photo of her family. She must have sent me about 30," he said, laughing.

Despite the advances, Dr Allison, who is also director of the Cancer Research Institute scientific advisory council, still has a hunger to go further.

Checkpoint inhibition still does not work for everyone, and he wants to understand why. Combining T-cell manipulation with chemotherapy is one new direction, as is combining the manipulation of different inhibitor molecules. In the field of melanoma, where the first stunning results began, he can envision doubling the long-term survival rate. In prostate cancer, he is working with his clinician-scientist wife, Padmanee Sharma, MD, PhD, a genitourinary oncologist, to boost response by using several inhibitor molecules.

The CheckPoints end every show by playing Journey's "Don't Stop Believin'." One might assume that's a message to patients who have exhausted all other treatment options. But another story is that the song pays tribute to the resistance that cancer immunotherapy has faced throughout the years.

Persistence has obviously paid off for Dr Allison (apparently even his wife denied his first marriage proposal), and there's no sign he'll be letting up any time soon.

 

Foundation for Immuno-oncology: Comments From ASCO

Dr Allison's transformative work serves as the foundation of much of the immuno-oncology research now being presented at ASCO meetings and published in our journals, commented Richard Schilsky, MD, chief medical officer at the society.  

"The successful development of drugs that effectively treat advanced cancer by unleashing the immune system to attack tumor cells has reinvigorated the entire field of cancer," Dr Schilsky  told Medscape Medical News.

"For many patients with cancer, immunotherapy is now a component of standard care," he said, noting that "immunotherapy agents are now [Food and Drug Administration]-approved for treatment of many cancer types either as first-line treatment or when standard first-line treatment is no longer helping."

"As researchers and clinicians, immunotherapy has given us more tools in our toolbox to help patients live longer and better," he added.

"It's also made us shift our focus from treating the disease site to treating the specific tumor characteristics," Dr Schilsky noted.

"An important paradigm shift is underway in the way we treat cancer," he said. "Immunotherapy, precision medicine, and cancer genomics are, in some cases, allowing physicians to treat an individual's tumor biology rather than the organ affected by cancer. The concept is still in its infancy, but in the future, we anticipate that cancer treatments will be far more "organ-agnostic" because what will matter most when it comes to treatment selection is the tumor biology."

Looking ahead, Dr Schilsky noted that  "a sizeable portion of the puzzle that remains to be solved" is, Why does immunotherapy treatments work so well in some cancers and not at all in others? And among patients with the same type of cancer, why do some respond to immunotherapy whereas others do not?

In addition, there is the issue of rare but occasionally life-threatening side effects due to immune cell attack on normal organs and tissues. "Better understanding of the mechanisms that underlie these toxicities will enable us to more effectively manage them," he said.

Also, research is already underway to test combinations of immunotherapy treatments, as well as various combinations of immunotherapy and chemotherapy, he added.  

 

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