Dr David L. Porter Discusses Side Effects of CAR-T Cell Therapy
CAR-T cell treatment can have a number of side effects, with the most serious being cytokine release syndrome, according to David L. Porter, MD, of the University of Pennsylvania Health System. However, there are some promising therapies like interleukin-6 blockers that can reverse this reaction.
Transcript (slightly modified) What are the most significant side effects of treatment with CAR-T cells and how can these side effects be managed?
There are a number of side effects with the CAR-T cells. Some of the more common and manageable side effects are things like B cell aplasia. When we target CD19 we also kill normal B cells. That leaves patients with hypogammaglobulinemia, or the inability to make normal antibodies. That can be managed with replacement of antibodies through intravenous immunoglobulin infusions periodically, for instance. As of yet, it does not seem to leave patients susceptible to many typical or unusual infections.
Another side effect that we’ve seen is something called tumor lysis syndrome, this is something that happens when you kill large amounts of cancer cells all at the same time and they release their contents into the bloodstream. It is a side effect on some level, you might say that that’s a manifestation of very, very effective therapy. If you can anticipate it there is good therapy to prevent it, and if it develops, good therapy to treat it.
The most unique and most difficult side effect is something called a cytokine release syndrome. When the T cells see their target they become activated and they start proliferating. They’re very active, they proliferate, they start releasing cytokines, and they begin to activate other immune cells as well. All of these activated immune cells release cytokines into the bloodstream, and this can make patients very, very sick.
It almost always starts with a fever and can escalate over time to very, very severe flu-like syndrome, with other complications. Patients will have progressively high fevers, they can get as high as 104, 105 degrees and even higher. And as this progresses, patients develop myalgias and arthralgias, muscle aches and bone and joint aching that really has been quite severe in some cases. They may develop nausea or diarrhea, but as it even further progresses the most dangerous aspects are very low blood pressure, dangerous hypotension. There are a number of patients that may need to be on pressors, medicine to increase their blood pressure, they need to be cared for in an ICU. And they develop a capillary leak syndrome where fluid can leak into various tissues including the lungs, causing hypoxia, making it difficult to breathe.
Early on in development of this therapy, we learned what some of these cytokines were causing these bad side effects. One of the central cytokines to this reaction is a cytokine called interleukin-6, or IL-6, and it turns out there are medications that block activity of interleukin-6. We have learned that in most cases, when patients do develop this side effect of cytokine release syndrome, treatment with an anti-IL-6 therapy, anti-IL-6 antibody for instance or an anti-IL-6 receptor antibody, can rapidly reverse this reaction in a matter of an hour or two.
And in fact there are now clinical trials being developed trying to understand how to best use these reversing agents, these blocking agents. Whether they can be used earlier before patients get sick, or do we need to wait until patients are becoming unstable to use the therapy. And we will learn that, I think over the next year or two, how to best intervene for this and other side effects as well.