The Nobel committee’s account of discoveries critical to harnessing the immune system to treat cancer lists just under 100 papers authored by hundreds of scientists. But the message that “it takes a village” to move a discovery in basic science out of the lab and into the lives of patients — as 2018 medicine laureates James Allison of MD Anderson Cancer Center and Tasuku Honjo of Kyoto University did in work that led to drugs that sic the body’s immune cells on cancer — is outweighed by one simple number: three.

That’s the maximum number of laureates that, the Nobel foundation decreed in 1968, can win any Nobel prize. Because of that limit, it’s rare that Nobel announcements don’t produce grumblings about who was left out, and this year was no exception. At least three other scientists were major contributors to the basic research that led to cancer immunotherapy.

Allison won for discovering that a molecule on the surface of the immune system’s T cells, called CTLA-4, acts as a “checkpoint inhibitor” (a term he coined), a biological brake on the T cells, and that jamming the brake (including with an antibody that he developed) can unleash those T cells to fight cancer. Honjo discovered another such checkpoint, called PD-1, that also keeps T cells from attacking cancer cells.

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“I think they got the right two people,” immunologist Fred Ramsdell, vice president of research at the Parker Institute for Cancer Immunotherapy and a colleague of Allison’s for decades, said about the Nobel committee’s choice.

That was not a universal opinion. At an immuno-oncology meeting in New York — where on Monday afternoon Allison was greeted like a rock star, with scientists asking for his autograph and requesting selfies — three experts in cancer immunotherapy said they were “shocked” that three scientists who were key to the development of checkpoint inhibitors that exploit the PD-1 pathway were overlooked, rule of three or not.

Checkpoint blockade as an anti-tumor strategy had many midwives. A year before Allison, then at the University of California, Berkeley, concluded that CTLA-4 is a “negative regulator” of T cell activation, meaning it acts as a brake, Jeffrey Bluestone of the University of California, San Francisco, and colleagues published the same finding. It was Allison’s lab alone, however, that found, in late 1994, that cancer-ridden mice treated with monoclonal antibodies against CTLA-4 showed a “spectacular” response, as the Nobel committee put it, their tumors vanishing.

“After that it was somebody else’s work,” Allison said at a news conference Monday, referring to efforts to develop the antibody into a drug. Those were led by Jedd Wolchok, now at Memorial Sloan-Kettering Cancer Center, and F. Stephen Hodi of Dana-Farber Cancer Institute, who ran the first clinical trial of what would become Bristol-Myers Squibb’s Yervoy, the first checkpoint inhibitor approved for cancer. The Nobel committees, however, rarely honor this kind of move-it-along research.

The PD-1 story is more complicated. Honjo discovered and named it: “PD” stands for programmed cell death, reflecting his belief that the molecule had something to do with cells’ committing suicide under dire circumstances. Over the next 10 years, he figured out that, like CTLA-4, PD-1 acts as a brake on T cells.

It does so, though, only when a mirror-image molecule wedges itself into PD-1. The search was on for that molecule. Collaborating with immunologist Gordon Freeman at Dana-Farber, Honjo’s team found it in 2000, at least in mice. The year before, however, scientists led by Dr. Lieping Chen at the Mayo Clinic discovered the human version, now called PD-L1.

Chen then found that the PD-1/PD-L1 combo affects whether, and how, T cells attack tumors, a mere month before Honjo, Freeman, and their collaborators showed much the same thing: When tumor cells have PD-L1 on their surface, and it docks with the PD-1 on a T cell, that disables the T cell and protects the tumor cell from being attacked.

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Asked at the Monday announcement of the medicine Nobel whether Chen, now at Yale University, was unfairly overlooked, members of the Nobel committee said they were happy to speak about the laureates but not about scientists who had not been chosen.

“I agree that the rule of 3 is not a wise one,” Chen told STAT. “Because of this rule, many scientists spend a lot of time promoting themselves, rather than doing discovery to solve the problem.”

Last year, the prestigious Warren Alpert Foundation Prize was awarded to Allison, Honjo, and Chen — but also Freeman and Arlene Sharpe of Harvard Medical School.

Still, other groups that pride themselves on honoring scientific breakthroughs before the Nobel committees get around to them have struggled with how to deal with the four key contributors to the PD-1/PD-L1 story. A close look at the winners of the Lloyd J. Old Award in Cancer Immunology, given by the Cancer Research Institute and the American Association for Cancer Research, shows that the PD-1/PD-L1 discoveries have never been honored. The reason for the glaring omission, said one scientist involved in the selection, is that it has been impossible for the award committee to pick out just one scientist for PD-1 work. The Nobel committee apparently felt no such qualms, selecting Honjo alone.

Sharpe, Freeman, and their colleagues showed that PD-1 is overly abundant and active on dysfunctional T cells and that PD-L1 is overexpressed on tumor cells that manage to fend off T cell attack. They also discovered that using antibodies to block either PD-1 or PD-L1 revived T cells and made tumor cells vulnerable to them.

Freeman told Nature on Monday that he was “disappointed not to be recognized for his contributions,” since his and Sharpe’s “discoveries were foundational” in the development of such PD-1 inhibitors as Keytruda and Opdivo. Other organizations, such as the Cancer Research Institute and the Alpert Foundation, “have chosen Honjo, Freeman, Sharpe, and Lieping Chen for PD-1/PD-L1,” Freeman told STAT. “I feel this is accurate.”

A colleague of Sharpe’s noted that it was she who found that the PD-1 receptor was functioning on T regulatory cells and was “ultimately responsible for the T cell death observed in how cancer cells evade the immune system.” The colleague asked not to be named to preserve professional relationships.

The 2018 medicine Nobel is only the latest where the rule of three gives a misleading impression of how science is done. Because it perpetuates the lone genius myth, said Venkatraman Ramakrishnan of Britain’s Medical Research Council, a winner of the 2009 Nobel Prize in chemistry and president of the Royal Society, “the rule of three is inappropriate to 21st-century science.”

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  • I disagree about Wolchok and Hodi. You could have chosen nearly any competent clinician and they could have performed those trials. The barrier was broken by Allison [and other colleagues] upstream of the trials.

  • for any major discoveries there are many who lay claim. For the discovery of TCR there are indeed too many to pick one or three (including Allison). Hence, no Nobel for that. For ctla4 and pd1 Nobel got it right. Allison and Honjo made seminal first discoveries; the rest did follow up, derivative and/or obvious studies. Most T cell immunologists who do not have axe to grind or skin in the game see the rest found wanting. Not in the same league.

  • there is more than snub involved, the best example is Dr.Rosalinda Franklin and how Watson and Crick used her research to win the prize for the double helix. regarding M.D.Anderson Cancer Center I was involved in the University of Waterloo committing NIH fraud and they had to suppress my research to do the felony . I contacted Dr.G.L.Nicolson a Chair at M.D.Anderson circa 1988 and explained the Cell Death Signal Gene Theory and how luteal cells were a model to tell tumours to die and restart the immune system as a natural cycle already existed. Tho Dr.Nicolson supported me, the University of Waterloo used political connections and had the RICO investigation stopped and blacklisted me. To help save lives I sent out DOZENS and DOZENS of research proposals in the US and UK .It is more likely than not that Dr.Allison was aware of the theory and may have spurred his research . on http://www.cancerfraudbadbiotech.com you can see the letter of apology from, Dr.Jocelyn Elders, the US Surgeon General to me. And the email from Noam Chomsky who states the NEW research which branched from this maybe “of phenomenal importance to mankind’s survival !!” Drs. Alison and Honjo could help research if they care to answer questions of ethics and integrity : 1. is research listed in official documents/Ministry of Health Canada as so bad they used the street term for feces , is excellent ? Y?N ? FOI requests have been refused by Canada. and 2. Is lying for NIH money fraud ? Y?N ? I can not continue the research until this is exposed and cleared up. Allison and Honjo had opportunities denied to me because of criminal acts.Will they stand up for scientific integrity and demand answers as the NEW research which has gone beyond what they are dong “may be of phenomenal importance to mankind .” Thank you .E.A.Greenhalgh

  • Correction to paragraph 3:
    CTLA-4 is not, itself, a “checkpoint inhibitor”, it is a checkpoint molecule. A checkpoint inhibitor is a drug which inhibits(blocks) the activity of CTLA-4 (or other checkpoint molecules).

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