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.