Thursday, August 13, 2009

Tumor Immunology Is A Waste of Time

Ian York recently wrote some interesting stuff about the interesting case of the transmissible tumours that are spreading in Tasmanian devils. The question is how are these tumours transmitted from one host to the next without being rejected by the immune system. He points out some pretty compelling evidence that this is not due to MHC homogeneity amongst the devil population. Therefore, the tumors are persisting despite being MHC mistmatched. In contrast, if you were to transplant normal tissue from one devil to another, it would be rejected by the recipient's immune system. And yet, for these tumors this is not the case. Apparently the same is true of a totally different type of canine transmissible tumor.

We shouldn't find this all that surprising. Tumor cells evolve resistance to almost anything you can throw at them, things that would kill normal cells. Their continued existence demands mechanisms of resistance to death by many diverse types of stimuli. There's only so many ways to kill a cell, so evolved resistance to one stimulus is often cross-protective against many others. The result is that everything down to the most fundamental metabolic processes of the cancer cell are adapted to surviving adversity. In light of this, you would predict T cells would have a hard time killing cancer cells.

Anyhow whatever the mechanism of resistance, all this is enough to convince me that tumor immunologists should give up on trying to make vaccines or other therapeutics that try to cure cancer by targeting "tumor" antigens. If tumors can escape MHC rejection, a natural, more specific and much more robust phenomenon, I find it impossible to believe that effective therapy will ever achieved by artificially stimulating the immune system to attack weak and largely self antigens. I suspect smart immunologists already know this.

UPDATE: In a follow-up post, York points out an important difference between transmitted and spontaneous tumors I hadn't fully considered. That is, the transmitted tumors have a much longer evolutionary history that spans multiple host generations, whereas a spontaneous tumor's evolution follows a blind alley that ends when the host dies. Therefore there has perhaps been greater opportunity for immune evading characteristics to emerge in what may be a more genetically diverse population of transmitted tumors. If this were true, the kinds of non-transmitted tumors we'd like to vaccinate against in humans wouldn't necessarily be as difficult to get the body to reject. At any rate, York remains optimistic re tumor immunology and promises to elaborate so stay tuned...


13 comments:

rob said...

Smart immunologists work on oncolytic viruses.

Anonymous Coward said...

Yeah it always struck we as an odd approach, I mean if there is a good antigen, and the immune system has failed to react to it, what makes you think a vaccine would work? But I wonder if perhaps it would work in prevention, before the cancer evolves the ability to evade the immune system. Like Gardasil but with a self-antigen.

Bayman said...

Gardasil is a good example, probably the reason it has worked where all other vaccines have failed is that it's actually a vaccine against a pathogen, not tumor cells.

@Rob. Are you suggesting that infecting Tasmanian devil tumors with a virus would induce immunological rejection, despite the fact that MHC rejection has already failed?

rob said...

I guess I'm suggesting something you already know. Because these tumour cells have evolved to evade immunological rejection they may also lack the ability to recruit the immune system to fight off a virus infection.
The Tasmanian devil cancer might be a great animal model. Too bad those things look like they would rip my face off.

Bayman said...

Whoa shit. I was digging the Taz-tumor model until that thing opened its mouth!!! Those things are biting machines.

Maybe someone could breed the mean out of them...or select for a transmissible mouse tumour. I guess some of our implanted tumour models are kind of like that as they have been derived from serially mouse-passaged tumors...Although I don't know if any were passaged amongst MHC heterogeneous populations, like these wild Taz-tumors...

iayork said...

Rob:
I guess I'm suggesting something you already know. Because these tumour cells have evolved to evade immunological rejection they may also lack the ability to recruit the immune system to fight off a virus infection.

Tumor immune evasion (like viral immune evasion) isn't necessarily and all-or-none phenomenon. It isn't as if the tumor is 100% resistant, so you have to crank up the immune response by an infinite amount to control the tumor. If the immune system kills 99% of new cancer cells, the cancer may still end up growing rapidly enough for detection. But all you'd need to do is bump up the immune response by 2% and then you'd get it under control.

Too bad those things look like they would rip my face off.

Most popular pictures of them show them looking ferocious, but if you start looking through Flickr for un-posed shots, they're mostly peaceful-looking, fairly cute little guys.

rob said...

@iayork
yeah, I understand the logic. I think the point of the post is there isn't much evidence that it works. The devil tumours suggest that cancer can evade even the most fundamental aspects of immunological recognition.

..."peaceful-looking, fairly cute" facing-ripping little guys..
I think there is a reason that they have a cancer that spreads through them biting each others faces!

iayork said...

I think the point of the post is there isn't much evidence that it works.

No, I disagree. There's tons of evidence that anti-tumor immunity works, and in fact there's tons of evidence that it works in therapeutic treatment of natural human tumors. What hasn't happened yet is consistent success, or even predictably inconsistent success. The message from human clinical trials seems to be that anti-tumor immunity works very well against some, perhaps even many, tumors, but not all; and we're not yet able to understand which are which.

But that's a far cry from "not working".

c said...

that picture hurts my heart.

Bayman said...

The message from human clinical trials seems to be that anti-tumor immunity works very well against some, perhaps even many, tumors, but not all;

Ok, I can go along with that. This might describe some of the successes that have been achieved with Rosenberg-esque adoptive therapies for example. If you define success to mean "tumor regression at all costs". Which is a fair definition I suppose if we're talking about cancer therapy in general; chemo clearly is often successful but never ideal if the goal is to be specific in targeting disease.

However my understanding is that success in clinical adoptive therapy correlates with the induction of autoimmune toxicities. Vitiligo in the case of melanoma and and lots of nastiness as the immune system is revved up to such an extent that nearly as much damage is exacted on healthy organs as tumors.

To me, these kinds of results just support the notion that human tumors are just not antigenic. And that you cannot therefore vaccinate against cancer. A successful vaccination, like a flu shot, is not usually a near-death experience because it harnesses the specificity of the immune system in distinguishing self from non-self. You don't seem to have to crank up the immune system anywhere near the point of non-specific mayhem to get protective immunity to a virus or tissue rejection.

I agree that anything that "works" is a step forward when we're talking about a deadly disease, and it's great that highly aggressive immunotherapy benefits a limited subset of patients.

But I guess what I find lacking is evidence that the real idea behind cancer vaccines is a realistic goal, that it really is possible to harness the tremendous specificity of the immune system against cancer cells. But maybe my expectations are just too high.

iayork said...

Which is a fair definition I suppose if we're talking about cancer therapy in general; chemo clearly is often successful but never ideal if the goal is to be specific in targeting disease.

Interesting comparison. You probably know that several recent papers strongly suggest that chemo actually works by breaking tolerance, and it's not the chemo per se that eliminates the tumor, it's the immune response that's induced by the cell death. (See http://www.iayork.com/MysteryRays/index.php?s=chemo and especially http://www.iayork.com/MysteryRays/2009/02/24/more-chemotherapy-and-tumor-immunity/ for more, with references.)

As I say, I don't think that tumors are non-antigenic. I think they have reduced antigenicity. It's a quantitative, not a qualititative, change, and so it needs a quantitative, not a qualitative change in immunization. I don't think it would be surprising that so far, the push is way too far; that doesn't mean that there's not a happier mean.

The vitiligo associated with recponse to melanoma may be a special case -- not all tumor antigens are shared by normal cells. It's a complicated issue, of course.

rob said...

@iayork
I actually hadn't read that literature before and the mouse model data is convincing that there is an adaptive immune component to tumour elimination. The clinical stuff is just correlation, am I right?
There is definitely an adaptive immune component to tumour rejection. We have seen this in our lab too (coincidentally(?) using the SAME mouse model as the nature med paper).
But does this argue that a cancer vaccine is a viable approach for treatment of naturally occurring human tumours? Is it not possible that the tumour microenvironment is much too immunosuppressive for such a strategy to have any chance at all? Again those crazy devil tumours suggest that tumour immune evasion can be pretty successful.
I don't read that kind of literature much, I probably should, so thanks for pointing it out.

iayork said...

The clinical stuff is just correlation, am I right?

Most of the trials are relatively small. I'm not sure if there are large-scale phase III trials ongoing. But the small-scale trials, done on people with cancers that have resisted treatment, have resulted in some spectacular cures. I don't really think there's any doubt that immune therapy of tumors has worked -- it's not mere coincidence when tumors that are invariably fatal abruptly disappear permanently after vaccination. It's very clear that tumor-induced immune suppression is not invariably insurmountable.

As I say, it hasn't worked consistently, and immune suppression may be part of that. But even so, that doesn't mean it's an impossible problem. Apart from the fact that some cases have succeeed, it's at least theoretically possible to overcome immune supression. For example, the work with anti-CTLA4 and other ways of overcoming immune suppression is directed at exactly that.

Arguing from the natural outcome of disease, that treatment is futile, is a fairly short-sighted approach. By that argument no treatment of any serious disease would ever be possible.