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Where Cancer Immunotherapy Works (and Doesn’t)

The immunological approaches to cancer therapy that have come on in the last few years are some of the best news that field has had in a long time, and with any luck the revolution is just beginning. There’s a huge amount of research going on to profile various sorts of tumors for specific antigens, both to target therapies to them and to understand what these things mean clinically. The mutations that are constantly being generated in cancer cells should produce altered proteins on the cell surface, and these “neoantigens” would be natural candidates for  immune targeting, since they shouldn’t exist in the normal cell population. But it’s tricky: that same mutation rate may also produce such a variety of neotantigens (in such a variety of cells) that specific targeting stops becoming feasible. (Even if it works, this is probably going to be personalized medicine for sure, with every patient having their own set of mutant proteins). As pointed out here, there are also two broad possibilities for such therapies – that once you start an immune response to the tumor cells that it picks up momentum on its own as they get destroyed, or that you’re going to have to be specific all the way, because otherwise the immune response is going to end up chasing after various proteins in a way that’s at the least ineffective and at worst harmful.

There’s a new paper out in Science that should advance the field. A large (and high-powered) team spanning the UK and US (and funded by Cancer Research UK and the Rosetrees Trust) has been profiling antigens in developing tumors (two varieties of lung cancer) and correlating that to clinical outcome. The quick answer is that in adenocarcinoma, when there’s been a broad clonal similarity in the antigens, the patients treated with the PD-1 antibody Keytruda (pembrolizumab) have had much better responses than when there’s a lot of subclonal variety. The same relationship is seen in melanoma samples and responses to the CTLA-4 antibody Yervoy (ipilimumab).

The paper notes that such tumors are under immune attack already in patients, but not to a useful degree. Thus the immunoenhancing antibody therapies – one of the problems is that these tumors secrete various immune-suppressing proteins, and taking out those signaling pathways allows an effective immune response to develop. It appears now that such an effective response is strongly correlated with the clonal neoantigen state.

That also helps to confirm that (as had been suspected) that if you’re raising responses to tumor cell antigens that you should go down as close to the main branch as possible, and pick antigens that are shared widely. Once you start sequencing for potential neoantigens, you could have a choice of hundreds (or thousands) of them, and it appears that you’d better choose wisely. But this paper also shows another area that needs some work, because the authors also looked at squamous cell carcinoma samples, and found that these cells tended not to display many neoantigens at all, which is the opposite problem. A target-poor environment is even worse than a target-rich one.

And this brings up something for us small-molecule people to think about: as the march of the immunotherapies continues, it’s possible that we’re going to have to modify our own targets. It could well be that the unmet medical need is going to concentrate more in the tumor types that are not good candidates for immune approaches (such as the squamous cell example above), and that for maximum clinical impact we should be deliberately looking for these areas. Thoughts?

19 comments on “Where Cancer Immunotherapy Works (and Doesn’t)”

  1. pipelineGSK says:

    One of the attribute of wishful thinking is a PATHETIC. The moment you realize that no one is your enemy, except yourself.
    For my personal view the PD1 is only an attribute. A Red Lamp is an attribute to indicate to customers the nature of the business. Cells used PD1 for signaling and delivering, and most cancer cells carried one with them as they got “in house” problems which can not be resolved on their own.

  2. bhip says:

    The suggestion of targeting tumor types which are less likely to respond to immune checkpoint therapies with small molecules is certainly reasonable. That said, the overall response rate to current immunotherapies is 15-30%. Targeting the tumor defense mechanisms which suppress these immune response is still very attractive prospect.

  3. miles says:

    Thank you Derek, something to get the mind working, and thankyou pipelineGSK for showing us that minds are not always rational or coherent.

  4. pipelineGSK says:

    Get your facts first, then you can distort them as you please but not opposite way.

  5. PruritusAni says:

    God piece!
    Is that comment from “pipelinGSK” meant to be comprehensible or have GSK R&D writing skills sunk as low as this?

  6. Anon says:

    Are you sure pipeline GSK is a person – the comments seem more like a bot.

  7. PruritusAni says:

    GSK person or bot? Hard to tell the difference sometimes!

    1. Anon says:

      A bot with such bad English? Nah, even bots can spell.

    2. Ken says:

      Also, no payload. Bots usually try to get you to click on a link, most commonly to adware, malware, or viruses.

      1. banzaipipelineAZ says:

        I’m inclined to thing pipelineGSK is your basic self-starting crank, who decided he’d tee off on Derek because… he’s a self-starting crank.

  8. A BOT says:

    Happy to loose my dignity and to hear more comments. Why it did not work in mostly patients treated with the PD-1 antibody/ Keytruda?

  9. See Minerva Technologies for the fast track

  10. See Minerva Technologies for the key to cancer

  11. Anon says:

    Just like tumours, it seems that lack of scientific progress always has the same single root mutation: Let’s call it the “Hubris1” mutation.

  12. steve says:

    This column needs a few more immunologists posting 😉 PD-1 is a marker of an exhausted T cell response. Tumors have a host of ways of avoiding immune responses – they can up-regulate PDL-1 (the ligand for PD-1), they can down-regulate HLA (which presents the antigens to T cells), they can secrete immune-suppressing cytokines such as TGFb, IL-10, etc. or immune-suppressing enzymes like IDO, they can nitrosylate T cell receptors by secreting NO, they can recruit immune-suppressing myeloid suppressor cells, etc., etc., etc. The list just goes on and on. PD-1 seems to be a major pathway in many tumors but it’s not a panacea. As we get more sophisticated in knocking out these various defenses (or avoiding them by replacing the T cell receptor with an antibody fragment, making a CAR-T cell) the field will advance and more and more cancers will be curable. IMO this is the only way to cure cancer since only the immune system can adapt to the changing environment present by clonal tumor cells that present differently and get selected by various chemotherapies. Chemo will be used to debulk the tumor and to kill tumor cells in an immunogenic manner (much of the effective chemo regimens are now thought to be due to a type of cell death that activates the immune system) but it will be finding ways to trigger the immune system that is the answer to cancer.

  13. steve says:

    By the way, to Derek’s point about concentrating on non-immunogenic cancers, the authors were looking at T cell responses, there are other potential antigens on tumors that can be addressed with specific antibodies. I wouldn’t say that chemists should take refuge in confining themselves to those cancers. I would say that they should join the effort in finding drugs that activate the appropriate immune responses. Inhibitors of IDO were a low-hanging fruit. But how about oral drugs that block the PD-1 or PDL-1 pathway? How about drugs that inhibit Tregs or MDSC? How about drugs that block inhibition of T cells by TGFb or IL-10? There is a wealth of opportunities for the imaginative chemist.

  14. robot says:

    Adding a new dimension always imply that the situation has become more complex or you may give the situation another perspective.
    Performance of Pixel from French choreographer Mourad Merzouki
    The phenomena of preconditioning always work in young and healthy and never for somebody with compromised susceptibility. Steve, It seems you have 30 more years to be sophisticated.

  15. SM says:

    Derek your comment section needs an upvote and downvote mechanism, it would make productive conversations easier to follow and readily discovered

  16. nicolae says:

    There is the chance that the individual may control efficiently the occurrence and development activity of malign cells.

    The tumor cells and the disturbances caused by them represent a very complex problem with various unknown elements which make difficult the doctors’ efforts and the patients’ expectancies.
    All information held by the human being until now about the tumor cells are insufficient in order to sole efficiently the malign affections. To this effect, we have to enlarge the knowledge horizon by new „key” information and I have not renounced and I have made this with all my passion and power – in the research study named „All about the malign cells and their fighting”. Now, the importance of the new discoveries may have a significant impact on our anti-tumor defense.
    I have not created this work in order to impress somebody. The thing in stake might be even our lives. I wanted that the people be fully aware of the mechanism generating the occurrence and development of malign affections, as well as the main liable agent so that the human being may redirect and adapt its efficient, preventive defense strategy against malignity.
    It is not easy to carry out such a complex scientific research in an inaccessible field, located beyond the knowledge limits and to succeed revealing some unknown biological mechanism of malign cells and vulnerable „key” points of their behavior which might be selectively attacked.
    I am not an English speaker, I have no support and the translation and editing costs are large, especially to support and continue the fundamental applicative scientific activity of tumor cells.
    I am sorry that such new information and solutions cannot reach the audience much more quickly in order to improve, to test them legally and to obtain the copyrights license.
    While most people is waiting, hoping for years to have something new which may heal them, this new information stays hidden within my papers and documents, having no chance to be known and useful. I am looking for a suggestion and help in order to reveal them to the world, to continue the activity and release one of the four books named „Life beyond all” which includes everything about malign cells and their fighting against (400 pag.).
    Thank you for your attention and support.

    Sincerely yours,
    The author of these works
    Nicolae Gheorghe


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