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A Nobel for Immuno-Oncology

As many had expected, the Nobel prize in medicine/physiology this year recognizes advances in immuno-oncology: James Allison (for CTLA4) and Tasuku Honjo (PD-1). For some years now, that has been a huge, massive, unstoppable wave in cancer research, and I would not want to try to estimate how much time, effort, and money has gone into it. But it’s been worthwhile, very worthwhile, and the good part is that the story is still going on. Here’s the Nobel scientific summary, which as always is very well put together.

People have been trying to get the immune system enlisted into cancer treatment for at least a hundred years. That involves both figuring out ways to activate an immune response, and understanding how tumors largely manage to evade such a response in the first place. But as anyone who has looked into the field for fifteen seconds can tell you, immunology is one of the most fiendishly complex areas of medicine. It would have to be: left unchecked, a full-blown immune crisis can kill you where you stand, within minutes. That’s one reason why I roll my eyes when I hear ads for “dietary supplements” and the like promising to “activate my immune system”. You want to be really sure about what you’re asking for, because an activated immune system is capable of fearsome amounts of damage if it gets even slightly mis-aimed.

But that’s all the more reason to try to aim it at tumor cells. This gets to the intricate question of “self and non-self” recognition in immunology, which has been the subject of research for many decades now. The medical implications for better control of this process are immediately clear – to start with, organ transplants (keeping your immune system from attacking foreign tissue) and cancer therapy (making your immune system recognize some defined tissue as foreign) and treatment for autoimmune diseases (persuading your immune system to realize that your own tissues are not, in fact, foreign after all). It’s an intricate process, though – it would have to be. There are multiple, overlapping checks and balances, switches and regulators everywhere you look. We are clearly the descendants of creatures who found it beneficial to have a complex, decentralized immune response. Our ancestors are the ones who managed to balance things better than the ones who were killed off more easily (or made less likely to reproduce) either by insufficient responses to infection or by too-vigorous immune responses when they weren’t needed.

Today’s Nobel recognizes the discovery of some of these regulatory systems. Allison’s work involved CTLA-4, a protein found on the surface of T-cells. It was discovered in 1987, and by 1995 it had been worked out that it was a negative regulator of T-cell function. Many labs were working in this area, with the more clinically-oriented ones going after just those sorts of applications mentioned in the previous paragraph. Mutations in CTLA-4 are very strongly associated with autoimmune diseases (a whole list of them), so a lot of work was directed at this area (trying to make the inhibitory pathway more active). But Allison’s lab concentrated on the possibility of cancer therapy – which frankly, was considered by some to be less likely to work. Immune approaches in this area had a history of failure, or at the very least underperforming greatly, along with a sprinkling of interesting, hard-to-replicate individual responses.

In this application, you’d want T-cells that were more active. Allison and co-workers developed an antibody to CTLA-4, blocking the blocker in a very direct approach. Interestingly, the detailed mechanism by which CTLA-4 inhibits T-cell activity remains a matter for debate (the standard immunology response of sighing deeply and saying “Well, it’s complicated. . .” works just fine here as well). But absolutely jamming it up on the cell surface with an antibody, you’d figure that would certainly do something. The first crucial experiments were done with mouse xenografts (transplanted tumors) in 1994, and they were dramatic indeed. See the data at right – now, xenografts are not endogenous tumors, and mice sure aren’t humans. But still. That’s the sort of thing you want to see!

It was still not easy to get this idea into humans. Kicking out the jams on CTLA-4 was a scary prospect, and there were not-unreasonable worries that you might shrink a patient’s tumors while killing them in an entirely new way via an autoimmune response. Medarex (then a small company that few knew much about) was interested, though, and development of a humanized antibody began. It was not a smooth and uneventful path to approval. There were indeed autoimmune side effects in human patients, and  there was the usual problem that a broad-spectrum oncology program has: where to start? It can be quite difficult to figure out which tumor types (and which patients) will benefit the most, and really useful therapies can be obscured if you go down the wrong path. I wrote here about ipilimumab, which is the antibody that came out of this work, which it produced hard-to-interpret results in prostate cancer patients (an area where it still has had difficulty showing a survival benefit). But that blog post mentions that results were already better in melanoma trials, and that’s where the drug has been approved (as Yervoy). Bristol-Myers Squibb bought Medarex for Yervoy and for the company’s antibody platform, in what has been called “one of the best biotech acquisitions of all time”.

The other half of today’s award is PD-1. Honjo’s group discovered this cell-surface protein in the early 1990s while working on dying mouse cells. It was thought to have a role in such cell death pathways (thus the name, from Programmed cell Death), but knocking it out in mice led only to an apparently mild phenotype that seemed to have something to do with the immune system. The animals had enlarged spleens, and developed lupus-like symptoms late in life. Further work (by groups all around the world) helped establish that PD-1 was in the same general family as CTLA-4, and was part of yet another regulatory pathway to keep T cells from going wild. Honjo’s group and collaborators discovered twos endogenous ligand for the receptor, the PD-L1 and PD-L2 proteins, and also found clues that this pathway might be important to tumor cells.

The first report of the use of a PD-1 antibody against tumors came in 2005 from Honjo’s group and from the group of Lieping Chen, who had also made fundamental discoveries in this area (and who is a plausible candidate, one of several, for the “How come there aren’t three people on this prize” question). At right is the effect of that antibody on mice who had had susceptible tumor cells introduced, and this is another one of these no-contest graphs that tells you that a hypothesis has been nailed. These papers went into the details of what’s been driving the field ever since: whether or not a given tumor expresses PD-1, and to what degree, and the idea of using antibodies against either the receptor or the ligand protein. Ono Pharmaceuticals in Japan got into the field and partnered with Bristol-Myers Squibb (again!) to advance nivolumab (known as Opdivo) into the clinic. It has performed very well, at times spectacularly, and there are plenty of other PD-1 based therapies out there with it by now (Merck’s Keytruda/pembrolizumab being the most famous).

The whole PD-1 field is too large and too fast-moving to be capable of easy review. It seems that every couple of months there’s another study in another tumor type, or another combination. But I do want to mention the intersection of PD-1 and CTLA-4, because there’s no obvious reason why they might not work at the same time. That is beginning to be decided right now in the clinic, but it’s too early to say what’s going to happen overall. I have little doubt that there will be a number of situations where that combination will be better than either agent alone, though. Frankly, one of the biggest problems of the whole immuno-oncology area is that there are just too many things to try, which is quite a situation to be in. The number of I/O clinical trials is arguably already into hold-on-a-minute-here-dudes territory, and there’s an immense amount of dust in the air.

But what’s clear is that this has been a revolution in oncology. For all the false starts, missed endpoints, fights over credit and struggles for market share, let there be no doubt: immuno-oncology has been pulling people out of their graves. Cancer cells being what they are, tumors can eventually turn around and mutate their way past the existing therapies in many cases. But there are people with advanced cancers who had been told to get their affairs in order who are still walking around, watching their children grow up. Many of these combinations of drugs and specific tumor types are too new to even be sure what the overall survival benefits are, other than being (in many cases) very substantial compared to the options that anyone had before. Those curves are still being drawn. One other point: I’ve mentioned some of the companies involved along the way in this post, and it should be emphasized that industrial development of these discoveries has been absolutely crucial in getting them available to the world.

And the good part, as I said at the beginning, is that the story is still going on. Today’s prize was widely anticipated, and that’s because it’s so well-deserved. The only regret I have about it – and it’s a regret that shows up every year during Nobel season – is that the prize tends to make discoveries like these seem like the work of far fewer people than they really are. This one has absolutely taken a scientific army, and the campaign continues.

35 comments on “A Nobel for Immuno-Oncology”

  1. Emjeff says:

    Want to know why today’s drugs are so expensive? Because they’re worth it…

    1. Anon says:

      Only in the US. Nice try.

      1. metaphysician says:

        Why is it always “drugs are too expensive in the US”, and never “drugs are too cheap in the rest of the world”? Because, bluntly, there’s a strong case for the latter, given how many national healthcare systems basically go “Take whatever pennies we offer, or else we’ll void your patent and just make it anyway”.

        1. Some idiot says:

          Interesting… do you have an example of a European country voiding the validity of a drug patent because the product was too expensive? I am not aware of one…

          I am aware of companies withdrawing products from the market because they did not believe that the price was reasonable, but that is another matter…

        2. Jan says:

          That is stupid. No one ever voids any patent because the drug is too expensive.
          Socialized healthcare systems just have a much bigger bargaining power to keep the prizes lower.

      2. MrRogers says:

        European lives are worth less?

        1. a-non says:

          In many countries, drugs are cheaper because the government subsidizes them, meaning companies make more per sale than the cost to patient.

  2. Isidore says:

    I would quibble slightly with the characterization of the Nobel scientific summary as “very well put together”:
    “In 1996, James P. Allison and coworkers used this accumulated knowledge to demonstrate that antibodies directed against a cell surface molecule on T-cells, CTLA-4, is (sic) capable of unleashing an immune response, which cured mice from tumors.”

  3. CA says:

    Congratulate to Clarivate Analytics on who will not get Nobel this year!

  4. Imaging guy says:

    When you read the original article from which the first graph is obtained (Derek has provided the pdf link), you will notice that this graph is for mice injected with 4 x 10^6 (V51BLim10) tumor cells then left untreated, treated with anti CTLA4 or anti CD28. When injected with 1 x 10^6 (V51BLim10) tumor cells, anti CTLA4 therapy was not effective. Here is what they say, “anti-CTLA-4 appeared to be less effective at a tumor dose of 1 x 10^6 cells, where treatment resulted in significantly reduced tumor growth rates, but four of five mice developed progressively growing tumors (25)”. When you check reference (25), it says “data not shown”. What I find surprising is that they honestly admitted that their therapy did not work at lower tumor dose. I don’t think they can get published this kind of result in Science now because they expect you to get perfect result for everything.

  5. Chemistry World says:

    “Today’s medicine #Nobelprize went to two men.” Oh no! Insufficient diversity detected, sorry Dr Honjo.

    Soon, the Nobel list can look like the Hugo Awards.

    1. RD says:

      What is the gender to do with the discovery?!
      Why don’t people call for diversity representation in NBA and NFL?

  6. PeripheralTolerance says:

    I see Roche has bought a small British I-O biotech for, so far as I can tell, a CD25 T cell depleting antibody. Does anyone here have an opinion on where this fits in in the whole I-O are? I’m just curious to learn more, link to story:

    1. johnnyboy says:

      CD25 is a marker for regulatory T-cells (Tregs), which have a role in inhibiting T-cell responses. Depleting Tregs is done in the hope that this will stimulate the anti-tumour T-cell response.

    2. KeithD says:

      Though CD25 is used as a marker for Tregs (along with CD4 & FoxP3), alone it is also an activation marker of T cells so at 1st glance it doesn’t seem to have the specific function you would expect for a targeted IO approach

  7. Anonymous says:

    (The Chem Prize is to be announced on Oct 3. I would like put down a bet on Fujishima of the Fujishima – Honda Effect, re: photocatalyzed decomp of H20 on TiO2, without which there would be no Graetzel cells, etc.. Also, it is a tribute to Honda (d. 2011), a PI who allowed grad student Fujishima to pursue and publish the accidental – and world changing – discovery. Sorry. Back to IO …)

  8. An Old Chemist says:

    Derek, I want to put a number on your comment, “The number of I/O clinical trials is arguably already into hold-on-a-minute-here-dudes territory, and there’s an immense amount of dust in the air.” Merck’s Keytruda is currently in about 800 clinical trials either as a monotherapy or in combination with other cancer drugs, for 30 different types of cancers. And, Keytruda has already been approved for 13 cancer types!!!

  9. Nick K says:

    It’s great to have some good news for once!

  10. ScientistSailor says:

    Are we ever going to see one for angiogenesis?

    1. MrRogers says:

      No. Folkman’s untimely passing ten years ago made it difficult. The additional passage of time makes it (sadly for those of us in the field) nearly impossible.

  11. Ru bippie says:

    Ugh! Another bio one! NOT REAL CHEMISTRY!!

    1. M says:

      This wasn’t the chemistry prize tho.

  12. No Cure says:

    The entire cancer therapeutics field is largely a steaming pile of bullshit. THERE IS NO CURE FOR CANCER MORONS! Sooner you realize that, the better off your life will be, until then all you’re doing is support the jobs of several useless “scientists” who only get to dick around with their lame ideas to come up with a cure.

    1. Derek Freyberg says:

      There may not be a CURE (since you insist on capitalization), but there are certainly effective treatments. Come to think of it, there are cures for few diseases, but there are effective treatments for a lot of them. As someone who is alive today because of effective cancer treatment, I’ll happily settle for that and not demand a CURE.
      I don’t know about cures for MORONS.

      1. Some idiot says:


        Yes, the latter is difficult to treat…

      2. Nick K says:

        There is no known treatment for stupidity, let alone cure.

    2. Jim Hartley says:

      Russian troll, paid in rubles to spout bs whenever the news is good.

      1. No Cure (Derek Lowe is a zionist pig) says:

        No its actually Chinese getting paid in renminbi, muthafooka! Muahahahaha!

    3. eyesoars says:

      That is true: I am not aware of any medically approved treatment for CANCER MORONS.

      Maybe someday there will be hope for you, too.

    4. Silverlakebodhisatva says:

      Well, my father got the “put your affairs in order” speech after interferon didn’t touch his HCL, and he got into one of the first pentostatin trials. 25 years later, at age 85, he passed away, outliving at least one of his oncologists. It may have not been a “cure” (they don’t yet ever say you’re in “permanent remission” from leukemia) but it was close enough…..

      1. Nick K says:

        Well said. There is no cure for cancer, but there are many highly effective treatments. My father was diagnosed with advanced prostate cancer 24 years ago. Thanks to Zoladex and radiotherapy, he is still alive today at the age of 87.

      2. RTW says:

        Pentostatin came from Parke Davis Research in the late 1980s and was a product of fermentation of bacteria from soil samples I believe. My supervisor when I first started in the PD Research Oncology Group was instrumental in getting that to market. It was a very interesting chemical structure as its had a non natural 7 membered ring as part of its structure instead of the normal Purine 6 member fused ring. Its considered an antimetabolite.

        BTW Small molecule anticancer drugs are still being approved Dacomitinib was recently approved as Vizimpro a irreversible EGFR Inhibitor I was involved in researching at PD in the late 90’s early 2K. It sat on the shelf for a long time after the Pfizer takeover of WL/PD.

  13. TMS says:

    When the inevitable CRISPR prize comes, there will a lot more howling about the rule of three. Especially since CRISPR may have gotten more press coverage than any other discovery in decades. In that case more than even this one, people outside the field know that there are more than 3 major contributors in play. I wonder if many Nobel Prizes have been delayed because of the committee not being able to split the thing into 3 winning camps.

    1. dearieme says:

      I don’t see the difficulty. If you have six leading candidates give the prize to the three oldest this year and to the other three next year.

    2. artkqtarks says:

      I think the discovery of tumor suppressor genes is a case where the committee has not been able to decide the three winners. There were enough people who contributed to the discovery of the retinoblastoma gene alone: Alfred Knudson (now deceased) proposed the two-hit hypothesis; Thaddeus Dryja was an independent PI who had done a lot of legwork before collaborating with Bob Weinberg’s lab to clone the gene; Bob Weinberg was the other PI of the collaboration, who acknowledged that the retinoblastoma work was “something of an unearned run” and placed himself as the fourth author of the seven authors for the key paper; Stephen Friend was a postdoc of Weinberg and did much of the work for cloning; and others. For p53, there are David Lane, Arnold Levine, Bert Vogelstein, and possibly others. Then there is Mary-Claire King for BRCA1.

      As for CRISPR, I feel like it is going to be Charpentier, Doudna, and possibly Siksnys, if it is going to be the Chemistry Prize. They discovered the enzymatic activity of Cas9 by reconstituting the reaction in test tubes. That seems more “chemical” than the work of Zhang, Church and others. If they really want to give a prize for gene editing, someone like Chandrasegaran or Carroll should also be considered for their work on ZFN.

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