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Turmoil in Immuno-oncology

Immuno-oncology! It’s such a big deal, let’s just do what everyone in the field is doing and call it “IO”. The recent successes in this area have rearranged every company’s oncology strategy, in some cases rearranging its entire oncology portfolio right out the door. There are several possibilities open to you now, if you’re working in the anti-cancer area, but these have closed off a lot of others. You can (1) be an IO player yourself, competing directly in the immuno-focused targets, or (2) not have any of those yourself, but align your efforts to complement those that are already on the market or are heading there, or (3) deliberately aim for those oncology indications that look like they’re going to be difficult to target via immunotherapy at all. What you can’t do, most likely, is carry on as if IO hasn’t reshaped everything, because it has.

And that reshaping is a pretty lively process. Witness the news that Roche has had a major unexpected clinical failure with their antibody therapy Tencentriq (atezolizumab) in bladder cancer. This is another antibody targeting the PD-1/PD-L1 system, like Keytrude, Opdivo, etc. (in this case, it’s going after PD-L1 itself), and it was the first one approved against any form of bladder cancer. It’s also been approved for metastatic non-small cell lung cancer, which is a more traditional indication in this area, if by “tradition” we mean the last couple of years. The bladder cancer approval, though, was an accelerated one after just Phase II data, with re-evaluation to come after the Phase III numbers came in.

Well, now they’re in, and the drug missed its primary endpoint. This not only puts Tencentriq’s continued approval for this indication in doubt, but it cannot be good news for the other companies in this space who are targeting it as well. Opdivo (nivolumab) from Bristol-Myers Squibb got approval in February, Pfizer and Merck KGaA’s Bavencio (avelumab) got a similar accelerated approval just a couple of days ago. Merck’s Keytruda (pembrolizumab), meanwhile, showed a good response Phase III (so much so that the trial was cut short), and is under review at the FDA, and there’s AstraZeneca’s entry in this area Imfinzi (durvalumab), too.

Roche is saying that one problem was an unexpectedly robust response in the chemotherapy standard-of-care group, but there are other things to worry about. PD-L1 status in bladder cancer seems to be correlated with disease progression, but perhaps not as tightly as in some other areas. In lung cancer, Merck was able to succeed by rigorously screening its clinical trial populations for PD-L1 expression (and BMS famously has fallen behind by trying to expand their own patient populations, although the situation is murky). The bright spot is that Keytruda now has some improved survival numbers to back up its durable-response data, but this Roche news makes you wonder if everyone else is going to see that or not, or if the FDA is going to back off some of these accelerated approval requests in light of it. No one knows yet if there’s a difference in this indication between targeting PD-1 (Opdivo and Keytruda) or PD-L1 (the others), or if there are differences between the drugs in each class.

I do have to note, though, that this is different from the Alzheimer’s issue that I was writing about the other day, and from most right-to-try ideas. In the case of these approvals for bladder cancer, the drugs have indeed shown efficacy, up to a point – the tumors are responding to the therapy. That’s a lot more than just saying “OK, this drug passed an initial safety screen, so why don’t you people all have at it”. The question here is the long-running one in oncology, that is, the relationship between a response (tumor shrinkage or the like) and overall survival and/or quality of life. It does a patient little good to die at exactly the same time they would have died without treatment, but just with a smaller tumor load. Survival data are, and always have been, the real currency.

It’s worth remembering that this whole area is still very new, and that there’s a lot that we don’t know about it. To that point, here’s a new paper in Science Translational Medicine from a Mass General/Harvard Medical School team that has some insights into just what happens to these antibodies in vivo. They’re using fluorescently tagged versions and tracking them intracellularly, and it turns out that although these mAbs have long circulating half-lives, their target engagement time may be a lot shorter than anyone realized. :

Here, by using time-lapse intravital microscopy, we uncovered in real time how the immune checkpoint blocker aPD-1 mAb distributes in tumors and physically interacts with tumor microenvironment components. This approach enabled us to detect aPD-1 mAb association with cytotoxic T cells infiltrating tumors in vivo. Furthermore, by following the drug’s pharmacokinetics over time, we found the drug to be rapidly removed from PD-1+ CD8+ T cells and transferred to neighboring PD-1−TAMs. The transfer of aPD-1 mAbs from T cells to macrophages was unexpected because macrophages do not directly take up aPD-1 mAbs in culture. We further identified that aPD-1 uptake by macrophages depends both on the Fc domain of the antibody and on FcgRs expressed by macrophages. Interactions between the drugs and macrophages are likely important because blocking Fc/FcgR binding inhibited aPD-1 transfer from CD8+ T cells to macrophages in vivo and enhanced aPD-1 therapeutic efficacy.

The paper demonstrates transfer of the antibodies to macrophages taking place within a half hour, which is rather alarming. That’s the bad news. But the good news is that these antibodies are still showing efficacy anyway, and that this response might be greatly enhanced by blocking this macrophage transfer pathway. FcgR binding has already been shown to be very important for the action of other monoclonal antibodies, and this paper suggests that the PD-1 and PD-L1 antibodies are going to be in the same category. These results also have implications for the antibodies used as diagnostic tools to select patients, both for clinical trials and in clinical practice itself. We’re going to have to better understand the role of Fc receptors in all this before we can get a handle on things.

27 comments on “Turmoil in Immuno-oncology”

  1. Mo Shoreibah says:

    Reducing Fc receptor mediated uptake is actually a lot simpler than many other manipulations to biotherapeutics. There is a detailed understanding of that process documented in the literature. With proper glycan engineering of the Fc region (http://www.pnas.org/content/114/13/3485.full.pdf) which can be readily accomplished by using the right CHO strain cell. To be precise, by expressing the mAb in a host that adds a core fucose to the glycan on Asn 238 in the Fc region one can dramatically limit Fc receptor binding.

    1. Dionysius Rex says:

      Fucosylation strategies have been around a lot lot longer than this PNAS 2017 paper – perhaps over a decade with BioWa Potelligent platform. Back in the day Medarex amongst other had licenses to this, but i havent kept up with the field.

  2. bhip says:

    A couple of points that may be pertinent. PD-L1 is only one of two ligands for PD-1, the other being (big surprise), PD-L2. Reagents/methods for reliable detection of PD-L2 is farther behind re: that for PD-L1 . This may explain a couple of things, namely efficacy of PD-1 blockers in the absence of appreciable PD-L1 expression & efficacy of ab directed to PD-1 (i.e. Merck, BMS) vs. that seen with anti-PD-L1 drugs (i.e. Roche). Interestingly, the anti-PD-1 ab from Medimmune blocks interaction with PD-L1 but not PD-L2 (it will be interesting to see what happens with that profile).
    Re: transfer of blocking ab to TAM (not my area of expertise) but I suspect that this could vary with the affinity of the ab to PD-1 (pM affinity anything generally dissociate very slowly) and the makeup of the antibody itself as human Fc receptors and their polymorphic variants have different affinities for human IgG subclasses (described here; http://www.bloodjournal.org/content/bloodjournal/113/16/3716.full.pdf?sso-checked=true). Just a thought.

    1. Ronan says:

      Moreover, PD-1 is not the only thing PD-L1 binds to. It has considerable affinity for CD80, and it’s unclear from my reading of the literature whether that interaction is pro- or anti-immune. Does Tencentriq block PD-L1/CD80 as well? What effect does that have? What if it doesn’t block PD-L1/CD80? Now you have a larger pool of free PD-L1 that isn’t tied up with PD-1… lots going on here beyond “just block this interaction and cure cancer”.

  3. Chris says:

    I’d argue that a significant increase in quality of life, even if there was no extension of lifespan, could be clinically important to cancer patients. Conversely, a drug that extends life but in a miserable state is questionable in my mind. Quality of life is more subjective, though, and harder to measure reliably than survival.

  4. Yvar says:

    In my experience, there is also a significant motivation among some cancer patients to have their death mean something to others. If they can join clinical trials, even if it makes them miserable and doesn’t improve their quality of life, they find some benefit in the concept that it may help others be treated better. Naturally, this impulse can and has been abused which is loathsome, but without this impulse I worry that a lot of medical advances would not be possible.

  5. Kelvin says:

    I wrote an article just a few days ago that attempts to answer whether it is wise for so many companies to be targeting the same approach. The analysis and conclusions might surprise you:

    https://www.linkedin.com/pulse/easiest-most-effective-way-improve-return-investment-rd-kelvin-stott

  6. MoMo says:

    Ye Gods!- its all Doom and Gloom here on this site! Turmoil here, PR Stunts there, drugs are failing everywhere. The Government Teats for hungry scientists are drying up, Alzheimers is a rat hole for investor money and we are all going to die of incurable diseases!

    But its not all bad-yet. The Tech and Pharma giants haven’t started designing suicide nets to adorn American buildings, like they have in other countries, but when they do lets hope they match the architecture. And above all banners like this aren’t being put up yet in the rotaries in Cambridge and billboards of South SF- yet.

    ” Work hard on the job today or work hard to find a job tomorrow”
    – Banner on Chengdu office building.

  7. ScientistSailor says:

    Derek, It’s TECENTRIQ, because it costs a lot more than $0.10

  8. steve says:

    Agree with MoMo. To paraphrase Trump, who knew that cancer was complicated? Immunotherapy is a new field (OK, a new reincarnation of an old field) and of course there is still a lot to learn. We can throw our hands up and say it’s impossible or roll our sleeves up and get at it. The exciting part is that it’s now proven that the immune system can destroy tumors that have resisted all conventional chemotherapy. It’s also been shown that conventional chemo often works because it invokes immunogenic cell death and activation of the immune response. There’s still lots of work to do, much more to understand, so don’t despair, just get to work.

    1. Little buddy says:

      Preach Brother!

  9. Little buddy says:

    The whole immunooncolgy was dumb to start with. You can’t simply coopt the immune system, very well established to primarily to rid the body of exogenous pathogens, to attack cancer cells. The whole theory is dead on arrival.

  10. Little buddy says:

    It’s going to be absolutely hilarious when the early students of today’s big dogs can’t find students themselves to sustain their careers becuase their advisers spent the last part of their career treating those would be students like garbage. Enjoy it.

  11. James C. says:

    It’s the sugars stupid. Glycobiology was long ignored until about the 80s. Even today, many, many scientists who are classically trained have 0 knowledge of the importance of glycobiology in biomedical applications, especially with regards to immune system modulation.

    PD-L1 itself is glycosylated, and its type of glycosylation regulates how much of it appears on the surface of a tumor. Hell, there is a very interesting class of molecules known as Sialic Acid Immunoglobulin Like Lectin (SIGLECs) that are found on immune cells and can bind to Sialic acids which are often over abundant on the surfaces of cancer. Upon binding, SIGLECs essentially put the brakes on the immune response.

    Tons of secreted proteins and biologics that are drugs are glycosylated or need glycosylation. The half life of EPO, for example, can be changed by nearly an entire day simply by adding or removing a Sialic Acid.

    Glycoengineering the Fc region is absolutely important as the previous posted said. And don’t forget, nearly every molecule involved in immune response and regulation is either secreted or on the cell surface, meaning they’re not just proteins, they’re GLYCO proteins.

    There’s a reason why glycans and sugar biology have been called the third language of life after proteins and DNA. Unfortunately, however, is the fact that glycosylation in biology behaves more like quantum mechanics that classical physics, which would be akin to DNA and protein biology. That’s because the glyco realm has no code to control and it makes our work as drug developers of biologics that much harder.

    Glycobiology is literally the next great frontier in biology and is going to produce hordes of Nobel prizes in the future for discovering how it regulates biology, figuring out the chemistry, and simply making the tools that will create breakthroughs in the field. Fields like IO would absolutely benefit tremendously by studying up and becoming familiar with the glyco realm in immune response as well as becoming familiar with some of the uncommon techniques it takes to work with sugar biology.

    1. John Trant says:

      Preach Brother!

  12. James C. says:

    Also to add one more thing–what really needs to be done with antibody engineering is creating more types of MAbs that not just recognize a protein, but also an aberrant form of glycosylation. Such a duel acting ab could radically increase specificity/safety and efficacy, as many glycoproteins have altered forms of glycosylation in cancer or have very specific cell/tissue changes in glycosylation.

  13. steve says:

    It’s amazing how stupid immunologists are and how incredibly smart you guys are! The immune system can only fight infections, not cancer! I’m sure no one ever thought of that. It’s ask sugars! Can’t believe they waste their time in those silly proteins. Of course, the patients cured with PD-1 inhibitors, etc. would beg to differ but I’m sure they’re so glad you’re able to just dismiss the whole effort with a wave of your hand. You’ve sure saved taxpayers a lot of wasted money!

    1. Derek Lowe says:

      Considering that we’re all impressed with what’s been accomplished so far in the field, these are rather odd things to say. . .

      1. steve says:

        I was referring to Little Buddy and James C. comments.

    2. Little buddy says:

      My guess is the researcher proposed research that would have saved more lives, and it was dismissed at once becuase it didn’t catch the funder or superior’s fancy. This is just the way scientists work. Rejection of ideas is the default, unless you are a master showman. To be consistent, unfounded and uninformed rejection of established principles should be practiced as widely, which is what the researcher is doing.

      1. Little buddy says:

        As an example, witness the “preach brother ! ” jab right in the middle of his post. Scientists are cruel, myopic,and manipulative.

    3. James C. says:

      Or maybe it was just sarcasm and you need to calm down.

      Seriously though, attend a glycobiology conference or one that focuses on glycoimmuno oncology. The data coming out of the glyco realm for major diseases like AZ, diabetes, and cancer is amazing.

      1. Little buddy says:

        OK– Whatever. I stand by my ideas. You can capitulate to steve’s arrogance and hatred for humanity if you want.

        1. Some idiot says:

          Just curious: are you on this blog page in order to contribute constructively? I (and I think the most of the people here too) are really fine about people who disagree with them, as long as it good, constructive arguementation. Just something to think about…

          1. Little buddy says:

            Definitely trying to be productive, always. As far the sardonic criticism and sarcasm contained in some posts, as I explained above, that is just the culture of science, at least where I did my PhD ( La Jolla, California).

  14. ImmuNOoncology says:

    More to the puzzle on PD-1. These authors reported human and mouse TAMs express PD-1 directly and contribute to phagocytosis (https://www.nature.com/nature/journal/vaop/ncurrent/full/nature22396.html). It won’t be long before a retrospective correlative study on TAM, PD-1 expression, and CPI performance.

  15. Liu Bing says:

    How about small molecular inhibitors of PD-1/PD-L1?

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