You've probably seen the headlines about a new experimental treatment for leukemia. For once, the excitement seems justified - this is a remarkable and very promising result, and it's worth taking a close look at it.
As reported in the New England Journal of Medicine, a patient in this study had been diagnosed with chronic lymphoid leukemia (CLL) since 1996. In this condition, B cells proliferate uncontrollably, piling up in the bone marrow and the lymph nodes. This patient had run through several courses of chemotherapy over the years. He would go for periods with no signs of disease, but it would always come back (in harder-to-treat form, naturally). By the time of this study, he was in bad shape and running out of options. Those, frankly, are the patients who are appropriate to enroll in a trial like this one - you want to treat cancer with what we know can treat it before going to something that might well not work at all (or might even make things worse).
And this particular idea had not shown as much promise in the past as everyone had hoped, despite being immunologically reasonable. The idea is to take T-cells from the patient and modify them to express a new antigen receptor, then infuse them back in and let them go to work on the tumor cells. But previous attempts to do this (against lymphoma, ovarian cancer, and neuroblastoma) hadn't had much effect, since the modified T cells had apparently not proliferated once back in the patient. Without the cells taking off on their own, it really doesn't seem feasible to infuse enough of them from outside to show a significant effect.
In this case, the chimeric antigen receptor (CAR) was designed to go after CD19, a surface protein found on all B-cells. That's as solid a target as you could find for treating CLL, but without something new, trying to have engineered T cells clear them out would very likely fall short in this case as well. But this time, the T-cells were outfitted (via a lentivirus vector) not only with the anti-CD19 CAR, but with signaling domains from CD3-zeta and CD137. These are known to be involved with (respectively) coupling surface antigen recognition to intracellular processes and with T-cell proliferation in general. Animal studies had suggested that this combination could deliver a more robust response from the T-cells after being sent back.
And a robust response is what happened. Before treatment, the patient was given a drug regiment to deplete his lymphocytes (in order to give the new T cells a clear field to work in), and at that point his bone marrow was found to be widely infiltrated by cancerous B cells. He then went through three consecutive days of infusions with his own T cells, 5% of which had been modified. Nothing untoward happened during this stage. And in fact, it doesn't appear as if much at all happened for a couple of weeks, which must have had everyone wondering.
But on day 14, the patient started experiencing chills and fever, followed by nausea and enough severe flu-like symptoms to send him into the hospital. Blood work showed no evidence of infection, but large increases in uric acid, lactate dehydrogenase, and other factors, with signs of kidney damage as well. But this was actually good news. Because at this same time, more than20% of his circulating lymphocytes turned out to be the engineered T cells, which had indeed proliferated and were vigorously going after the B cells of the leukemia. (At this point, it wouldn't surprise me if the folks running the study were beginning to wonder what they'd turned loose). The patient's kidneys were, in fact, having a hard time keeping up with the amount of cellular debris that they were being asked to sweep out of the blood stream; he lost over a kilo of cancerous cells.
On day 23, there was no evidence of CLL in the patient's bone marrow. The swollen lymph glands had resolved, and a CT scan confirmed that the masses seen before treatment had disappeared. None of the cancerous B-cell types that were present before the therapy (two clones, both with mutations in p53) could be detected. Ten months later, they still can't. As far as can be told, this case of refractory leukemia has been completely cured.
Two of the three patients treated in this fashion showed this effect - the third still shows signs of leukemia in the bone marrow, but appears to be asymptomatic. Most interestingly, it appears that the T-cell effect is persistent, and may continue as a "surveillance" mechanism in the treated patients.
Now, this is all excellent news, because this sort of therapy can be adapted to a wide variety of tumors. The main requirement is that there is some sort of surface antigen that's specific to the tumor type, but that still leaves you with a wide field to work in. It's important to note, though, that in one way this experiment did something quite strange: it worked much better than anyone expected. The dose of engineered T cells was much smaller than used in previous trials, and was deliberately chosen to be on the low side because no one was quite sure what to expect. Given the response, that was certainly a good move. I've no idea what would have happened if the therapy had been more aggressive, but it couldn't have been good.
I hope, though, that everyone involved is enjoying this as much as possible, because this is a rare event indeed. Having things go suddenly, crazily right in a clinical trial is a once-in-a-career thing, if ever. The field of immunological cancer therapy has been given a huge boost, and now all the other groups working in the area have a huge motivation to spur them on. This is potentially some of the best oncology news in years, so let's hope that it continues to work out.