Any chance we have of sticking with cancer is positive. There will never be one magic bullet, because cancer is really a lot of diseases, so we need all the tools we can get. One of the general approaches that has advance much in recent years has helped the immune system be better equipped to fight a particular patient’s form of cancer. There are a number of ways to do this, but now we have a new approach to add to the arsenal that’s quite elegant and a little sneaky.
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 convert them directly into immune cells — to “change teams”, indeed, with all their idiosyncrasies remaining in place. In this way, the immune system gets a lot of information about the exact targets to recognize and attack in that particular patient’s cancer, so that a therapeutic design need not rely on the best hypotheses.
They demonstrated potent stimulation of essentially personalized T cells in both live mice and cultured human cells. In mice, this directed to complete eradication of leukemia and even a strong response against solid tumors.
“When we first saw the data showing the elimination of leukemia in mice with functioning immune systems, we were blown away,” Majeti said. “We couldn’t believe it worked so well. Moreover, we have shown that the immune system remembers what these cells have taught it. When we reintroduced the cancer into these mice more than 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 Discovery of cancer. I thank Dr. Majeti for sending me a reprint of the article.
In order to harness the immune system to fight cancer, you need to alert the T cells to know what they are supposed to attack. One of the main ways they get this signal is through macrophages – the classic “white blood cells”. A macrophage roams the body, patrolling like a small, malleable amoeba until it sees something it doesn’t recognize, such as a bacteria or cancer cell. The macrophage engulfs and digests this offending thing, cuts its proteins into small peptides and displays them 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 on its surface. CD4 connects to MHC II, aligning the T cell receptor with the peptide that the macrophage has presented. If it’s a match (and a few other things to check as well), the T cell is activated and begins dividing so that its offspring can hunt down anything displaying that peptide throughout the body.
Another type of T-lymphocyte is the “killer (or cytotoxic) T-lymphocyte”, which has CD8 on its surface. CD8 connects to MHC I, which is found on the surface of all types of human cells 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 integrates into their receptors, and that’s obviously very helpful, helper T cells are the key to triggering just about everything else in the immune system. Anything that could fill a textbook, so let’s leave it to This:
Helper T cells are arguably the most important cells in adaptive immunity, as they are required for nearly 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 against even many microbes that are normally harmless.
Macrophages therefore play an important role in alerting the immune system in the event of a problem. They’re good at patrolling the body and finding things that shouldn’t be there, but if an infection or malignancy develops quickly enough, they may not be able to keep up. Or if there is a tumor in solid tissue, they may not be able to get to it very well. How can we help macrophages find and deal with invaders better and faster?
A rather intriguing answer, believe it or not, is to take a group of cancer cells from a particular patient, whether bloodborne or from a tumor, and turn them into macrophages. Suddenly you have an army of macrophages that already contain all of the patient’s particular cancer offending proteins, which will be different for each patient. These macrophages will chop up the offending proteins and display them on their surfaces so that the T cells learn exactly the right combination of things to look for.
You wouldn’t even have thought that 20 years ago.
But we have got much better recently to convert certain types of cells into other types by identifying the control factors responsible for cell identity and modifying their levels. At first you needed stem cells to do this, but now it is possible in many cases to transform one type of cell into another without even needing stem cells at all. This is called “lineage reprogramming”.
Majeti and her team took advantage recent advances in this area, along with their own evil plot abilities, to essentially turn cancer cells into zombie narcs that give the game away. If you install two genes for controller proteins called C/EBPα and PU.1 in cancer cells , you turn them into cells that act very similarly to macrophages. In other words, they chop up all the weird proteins inside them and display them on the surface with MHC II – and teach T cells the right combination of things to attack.
Here’s what happens when you do this on mouse leukemia cells:
The morphology of these cells obviously changes and they also start making proteins that macrophages typically make. But the craziest thing is when you feed them E.coli bacteria, they start eating them! These cancer cells have turned into white blood cells! That doesn’t sound like good news for cancer.
Now imagine releasing these cells onto the cancer. This is what they did in mice from which they obtained these leukemic cells. Want to see leukemia disappear completely?
This figure is a survival graph. Doxycycline (Dox) was the chemical inducer that caused the modified leukemic cells to produce proteins that turned them into macrophages. “DT” is diphtheria toxin which, in this line of mice, exhaust dendritic cells, a major component of the immune system.
The mice that did not receive the doxycycline treatment (actually “Doxycycline Chow” – yum) all died within two weeks. But the treated mice, whether or not DT delayed their immune systems, continued to chew on their plastic igloos. 100% survival? Are you kidding me? Those four stars on the graph mean that the chances of it being statistically significant are greater than 99.9999%. You think ??
Even solid tumors so treated gave results to ponder. Here is the comparison, for example, for fibrosarcoma:
And the approach also worked in cultured human cells. They applied it to B-cell acute lymphoblastic leukemia (B-ALL) as a first example because this lab had recently show that these cells could be reprogrammed into macrophages in the same way as mouse cells (or even more simply, by hammering them with a certain combination of cytokines for a week), and especially that once reprogrammed, they not only act like macrophages, but also lose their malignancy and no longer act like cancer cells.
It is very interesting that there is another type of human cancer, acute promyelocytic leukemia (APL) which is actually cured 95% of the time by reprogramming, but the reprogramming part is kind of arrived when treating the disease with retinoic acid and arsenic trioxide. Not exactly fancy, but hey, it works. We will take it. And we will 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 has a real chance of being extremely effective. We have seen it.
So the reprogrammed B-ALL cells started making the machinery to put chopped peptides on the surface in the MHC II. And these newly macrophage cells could indeed stimulate T cells specifically designed to attack B-ALL cells at levels comparable to true antigen-presenting cells like true macrophages and much better than simply exposing T cells to B-cells. ALL real. Defectors! Not only that, but when antibodies to MHC II were added, T cell activation stopped, meaning it wasn’t just a fluke, but the good mechanism was responsible.
If this approach can work in humans, it would certainly have leukemia as one of its first targets, but even if it hasn’t made enough headway against solid tumors (most things don’t) , it could still be very helpful in stopping metastases. , allowing time for other treatments and/or surgeries to treat the solid tumor.
As I always say in these kinds of journals, I’m not trying to pretend that this is a magic bullet for all cancers or that it’s guaranteed to work or that no one has ever had such an idea previously. I’m just here to point out promising examples from the field to try to show what researchers are thinking and where they seem to be making real progress. And they really are.