Any chance we have to stick it to cancer is a positive. There will never be a single magic bullet, because cancer is really a large number of diseases, so we need all the tools we can get. One of the general approaches that has advanced quite a bit over the last several years is helping the immune system to be better equipped to fight a particular patient’s form of cancer. There are a number of ways to go about that, but we now have a new approach to add to the arsenal that is quite elegant and a bit sly.
Dr. Ravindra Majeti and his team at Stanford University School of Medicine have found a way to take a patient’s own cancer cells and directly convert them into immune cells — to “switch teams”, in effect, with all their idiosyncracies remaining in place. This way the immune system gains a whole lot of information about exactly which targets to recognize and attack in that particular patient’s cancer, so that a therapeutic design does not need to rely on best guesses.
They demonstrated a potent stimulation of essentially customized T cells both in live mice and in cultured human cells. In mice, this led to a complete eradication of leukemia and even a strong response against solid tumors.
“When we first saw the data showing clearance of the leukemia in the mice with working immune systems, we were blown away,” said Majeti. “We couldn’t believe it worked as well as it did. What’s more, we showed that the immune system remembered what these cells taught them. When we reintroduced cancer to these mice over 100 days after the initial tumor inoculation, they still had a strong immunological response that protected them.”
They discuss their promising results in the March 1 issue of Cancer Discovery. I thank Dr. Majeti for sending me a reprint of the article.
In order to leverage the immune system to fight cancer, you need to alert T cells to know what it is they’re supposed to attack. One main way they get that signal is from macrophages — the classic “white blood cells”. A macrophage goes around the body patrolling like a malleable little amoeba until it sees something it doesn’t recognize, like a bacterium or cancer cell. The macrophage engulfs and digests that offending thing, chops up its proteins into small peptides, and displays them out on its surface, attached to an adapter called major histocompatibility complex II (MHC II).
Above we see a “helper T cell”, which has a protein called CD4 out on its surface. CD4 hooks up with MHC II, lining up the T cell receptor with the peptide the macrophage has presented. If it’s a match (and a few other things also check out), the T cell gets activated and starts dividing so its progeny can go hunt down anything displaying this peptide throughout the body.
Another type of T cell is the “killer (or cytotoxic) T cell”, which has CD8 on its surface. CD8 hooks up with MHC I, which is found on the surface of all human cell types that have a nucleus, including macrophages. Macrophages can activate both killer T cells and helper T cells.
While killer T cells can go out and kill any cell displaying a peptide that fits into their receptors, and that’s obviously very useful, helper T cells are the key to triggering pretty much everything else in the immune system. All that could fill a textbook, so let’s leave it at this:
Helper T cells are arguably the most important cells in adaptive immunity, as they are required for almost all adaptive immune responses. They not only help activate B cells to secrete antibodies and macrophages to destroy ingested microbes, but they also help activate cytotoxic T cells to kill infected target cells. As dramatically demonstrated in AIDS patients, without helper T cells we cannot defend ourselves even against many microbes that are normally harmless.
So macrophages are a huge part of alerting the immune system to trouble. They’re good at patrolling the body and finding things that shouldn’t be there, but if an infection or malignancy grows fast enough, they may not be able to keep up. Or if there’s a tumor within solid tissue, they may not be able to reach it very well. How can we help macrophages find and deal with invaders better and faster?
One pretty intriguing answer, believe it or not, is to take a bunch of cancer cells from a particular patient, whether blood-borne or from a tumor, and turn them into macrophages. Suddenly you have an army of macrophages that already contain every peculiar offending protein that the patient’s cancer has, which will be different for every patient. These macrophages will chop up the offending proteins and display them on their surfaces so that T cells are taught exactly the right combination of stuff to go after.
You could not even have thought this way 20 years ago.
But we’ve gotten a lot better recently at converting certain types of cells into other types by identifying the control factors responsible for cell identity and changing their levels. At first you needed stem cells to do that, but now it’s possible in many cases to change one type of cell into another without even needing stem cells at all. This called “lineage reprogramming”.
Majeti and his team took advantage of recent advances in this area, along with their own diabolical scheming abilities, to basically turn cancer cells into zombie narcs that give the whole game away. If you install two genes for controller proteins called C/EBPα and PU.1 into cancer cells, you get them to morph into cells that act very much like macrophages. That is, they chop up all the weird proteins inside of them and display them out on the surface with MHC II — and teach T cells juuust the right combination of things to attack.
Here’s what happens when you do that to mouse leukemia cells:
The morphology of these cells obviously changes, and they also start making proteins that macrophages typically make. But the crazy thing is, when you feed them E. coli bacteria, they start eating them! These cancer cells have turned into white blood cells! This does not seem like especially good news for cancer.
Now imagine unleashing these cells back on the cancer. That’s what they did in the mice where they got these leukemia cells from. Wanna see leukemia disappear completely?
This figure is a survival graph. Doxycycline (Dox) was the chemical inducer that made the engineered leukemia cells produce proteins that would turn them into macrophages. “DT” is diphtheria toxin, which in this line of mice actually depletes dendritic cells, a major component of the immune system.
The mice that didn’t get the doxycycline treatment (actually “Doxycycline Chow” — yum) all died within two weeks. But the treated mice, regardless of whether DT set their immune systems back, just kept chewing on their plastic igloos. 100% survival? Are you kidding me? Those four stars on the graph mean that the chances of this being statistically significant are greater than 99.9999%. Ya think??
Even solid tumors treated in this way gave results to ponder. Here is the comparison, for example, for fibrosarcoma:
And the approach worked in cultured human cells as well. They applied it to B cell acute lymphoblastic leukemia (B-ALL) as a first example because this lab had recently shown that those cells could be reprogrammed into macrophages in a similar way to mouse cells (or even more simply, by pounding them with a certain combination of cytokines for a week), and importantly that once reprogrammed they not only act like macrophages but also lose their malignancy and don’t act like cancer cells anymore.
It’s very interesting that there’s one other type of human cancer, acute promyelocytic leukemia (APL) that actually gets cured in 95% of cases by reprogramming, but the reprogramming part just sort of happens when you treat the disease with retinoic acid and arsenic trioxide. Not exactly sophisticated, but hey, it works. We’ll take it. And we’ll also take heart in the fact that this general reprogramming approach has precedent, and if only we can figure out how to apply it to other cancers, it stands a real chance of being extremely effective. We’ve seen it.
So the reprogrammed B-ALL cells started making the machinery to put chopped-up peptides out on the surface within MHC II. And these newly macrophage-ish cells could indeed stimulate T cells specifically geared to attack B-ALL cells at levels comparable to genuine antigen-presenting cells like real macrophages and much better than simply exposing T cells to actual B-ALL cells. Turncoats! Not only that, but when antibodies to MHC II were added, the T-cell activation stopped, meaning it wasn’t just some fluke, but that the right mechanism was responsible.
If this approach can work in humans, it certainly would have leukemia as one of its first targets, but even if it didn’t make enough headway against solid tumors (most things don’t), it could still be very valuable in halting metastasis, giving other treatments and/or surgeries time to deal with the solid tumor.
As I always say in these kinds of diaries, I’m not trying to claim that this is a magic solution to all cancer or that it’s guaranteed to work or that nobody has ever had an idea like this before. I’m just here to point out promising examples from the field to try and show what researchers out there are thinking and where they seem to be making real progress. And they really are.