Just like that, another terrific medical advance. I figured things would pick up after Labor Day, but sheesh!
Five patients, aged 18-24, with the autoimmune disorder SLE (systemic lupus erythematosus) enrolled in a last-ditch, “compassionate-use” trial because they had not responded to conventional treatments and likely were headed for multiple organ failure and possibly death. Each was given a single dose of their own re-engineered T cells. Within three months, all five patients had essentially no symptoms of lupus and continued this way even after immunosuppressive drugs were stopped. As of now, they’re all still living normal lives again and have suffered no significant side effects. It’s hard to imagine a better trial outcome than that!
This is the work of Georg Schett and numerous collaborators in Germany, and you can read all about it in the September 15 issue of Nature Medicine. It’s behind a paywall, but if you go to Nicoletta Lanese’s on-point LiveScience article on this topic, you’ll see she’s managed to include a gift link to the journal article that lets you view it for free.
In lupus, which affects about 8 million people worldwide, we have a major problem with B cells. So first let’s review what they do. Each B cell makes its own random antibody and puts that out on its surface. Maybe it’ll stick to something, and maybe it won’t, but the average human has about 10 billion different B cells floating around. If a B cell’s antibody does happen to stick to something, that’s a signal that there may be an invader in the body. That B cell is then empowered by a helper T cell to start dividing and making lots more of its antibody:
If an invader like a virus or bacterium is tagged by antibodies, then white blood cells (macrophages) will soon arrive on the scene and literally eat the tagged invader for lunch.
B cells mature within the bone marrow, and occasionally a B cell will concoct an antibody that sticks to something harmless that is normally found in the human body, like DNA. In most people, B cells like that get destroyed before they get out into circulation. But in people with lupus, something goes wrong there, and B cells that tag normal human components get loose. This is a big problem because the immune system can then start attacking anything: kidneys, heart, lungs, skin, etc. This leads to organ damage and severe fatigue. It’s totally debilitating and can get to the point where it’s life-threatening.
So how can we stop these crazy miswired B cells? Well, there’s another type of immune cell called the T cell, and its job is to kill other cells that have been compromised by, say, a virus or harmful mutation. But these crazy B cells appear outwardly normal — they’re just doing their jobs, right? — so T cells don’t go after them.
If we could use T cells to get rid of all of someone’s B cells, though, would that even leave a functional human being? When you face existential questions like this, you are in “compassionate-use” territory. These are last-gasp efforts that frankly don’t often go very well.
We can at least convince T cells to attack B cells. A unique protein called CD19 is found on the surface of all B cells, so we’ve got ourselves a target for the T cells to go after. We isolate a batch of the patient’s own T cells and enable them to produce, out on their own surfaces, an antibody fragment that will stick to CD19.
The yellow protein in the figure above (the chimeric antigen receptor, or “CAR”) has our antibody fragment at the top, while the long “stick” part below it pokes down into the T cell. At the bottom end of that “stick” is an activator that lets the T cell know when the antibody fragment has latched onto something. So CAR is basically a switch that will flip on to let our T cell know it has found a CD19 (a B cell) and that it’s time to get to work.
We can insert the CAR genes into the patient’s T cells with the help of a lentivirus (RNA virus). We slip the code for the CAR genes into the virus RNA and infect our T cells with it. The virus then makes DNA out of its own RNA and integrates that DNA into the genome of our T cells, and they in turn treat the CAR genes as their own and follow their instructions. Now we have a batch of “CAR-T cells”, which we inject back into the patient.
This is actually a very eventful and exciting time for CAR-T cell therapy, because it is showing promise in treating lymphoma, leukemia, and multiple myeloma, all of which involve B cells or their derivatives that are multiplying out of control. At least six CAR-T cell therapies have already been approved by the FDA for these disorders, and we’re already on at least the 5th generation of CAR switch design, and they keep getting more effective.
In lymphoma and leukemia patients, we have to remember that the number of B cells is very large, because they are dividing like crazy. But in lupus, the problem isn’t the number of B cells; the problem is what they’re attacking. So T cells directed against B cells in SLE shouldn’t be overwhelmed by sheer numbers; they might be able to wipe them out almost entirely.
But the big question is: What’s going to happen to patients whose B cells all get killed? Will their B cells eventually come back? And when they do, will they just turn wacko again and start attacking organs?
Fortunately, the answers seem to be, respectively, ‘they’ll be fine’, ‘yes’ and ‘no’. The patients all experienced a gradual regeneration of B cells, and these turned out to be “naive” B cells, meaning a random collection ready to scout for invaders and not the person’s own organs. Before the treatment, the patients had been cranking out antibodies against their own DNA, but three months afterwards, all of the patients’ levels of anti-DNA antibodies were virtually zero, indistinguishable from background.
An immune system reboot!
Schett said of the lupus patients in this trial:
For them, this is really a breakthrough. It's a single shot of CAR T cells, and patients stop all treatments. We were really surprised [at] how good this effect is.
Pretty impressive, considering we didn’t even understand the cause of SLE until 2015.
This approach will be tested in larger lupus trials, of course, but it might also turn out to be effective in other autoimmune disorders such as rheumatoid arthritis and multiple sclerosis. We must keep in mind that every autoimmune disease is sure to have its own idiosyncracies, and Schett’s surprise is indicative of how unpredictable it all can be.
But the discovery that B cells can apparently be reset to “manufacturer’s specs” could go a very long way. It sure did for five patients who were staring into the abyss just months ago, but who now look like they have full lives ahead of them once again, in which to make their own discoveries.