I don't think my friends at the CAR-T and Follicular Non-Hodgkin's Lymphoma blog have gotten to this one yet, but they'll forgive me if I look at it first.
Some folks at MD Anderson, along with colleagues at some other institutions, have published "Chimeric Antigen Receptor T-cell Therapy — Assessment and Management of Toxicities" -- a plan for watching and responding to the potentially fatal side effects that can come with CAR-T therapy.
CAR-T has been in the news in the last few weeks because the FDA approved the treatment for some Leukemia patients. CAR-T thrapy involves removing a patient's T Cells (part of the immune system that attacks invaders) and changing them so they can recognize cancer cells as invaders and take care of them. The results in clinical trials have been excellent -- good enough to justify FDA approval, with more approvals possible in the future (including one, potentially, for some Follicular Lymphoma patients).
The problem with CAR-T is some of the side effects. In a way, CAR-T can work too well.
The potential side effect that causes the biggest problem is Cytokine-Release Syndrome, or CRS. CAR-T has been called a "living cancer treatment," because unlike something like chemical treatment, T Cells do their job by not just attacking invaders, but by overwhelming them -- when they sense an invader, they signal to other T Cells to attack. So an effective response means a whole army going against the invaders.
Those T Cells are activated by Cytokines, which are proteins whose job is to signal cells. The problem is, the Cytokines signal the T Cells, which then produce more Cytokines. Which signal more T Cells. Which produce more Cytokines.
The body can usually keep this cycle in check, so it doesn't cause too many problems. But sometimes it can't do that. And this results in CRS. The body is overwhelmed by Cytokines and T Cells. At best, it can make the patient feel really horrible (like having the flu, I have read). At worst, it can be fatal, and there has been at least one patient in a CAR-T trial who has died as a result.
Another side effect is neurotoxicity, or toxicity that affects the nervous system. CAR-T treatment can cause a specific type of neurotoxicity called CAR-T-cell-Related Encephalopathy Syndrome, or CRES. This affects the brain in particular.
These very nasty side effects have been dealt with since CAR-T treatments (and other Immunotherapies) have been in trials.
The folks at MD Anderson and their colleagues looked at published studies and about 100 patients to develop a system for identifying CAR-T side effects early, and dealing with them quickly before too much damage occurs. Cytokine release Syndrome does not have to be fatal, but it does have to be treated quickly to keep the worst from happening.
The system involves monitoring the patient for symptoms, grading the symptoms (determining how severe they are), and treating immediately. The treatment could involve "aggressive supportive care, anti-IL-6 therapy, and/or corticosteroids for severe cases." Anti-IL-6 are antibodies that target the Interleukin-6 Cytokine. Corticosteroids are commonly used to stop allergic reactions. Basically, the treatments are used to slow down the immune system response.
Interestingly, one researcher who was not part of this team pointed out that other approaches are also being used in other places, and that the ways to deal with CAR-T side effects are still evolving.
So while there is no guarantee that the system will stop a CRS reaction, but I find it comforting that there is a system being recommended. Lots of very good minds worked together for this, and it sounds like even more good minds will keep working to make it better.
Hi Bob
ReplyDeleteAnother CAR-T side effect is low immunoglobulins. My wife received an NIH CAR-T infusion in March 2016 and must get an IVIG infusion when her IgG drops below 400. So far she has received an IVIG infusion about every four months. Tiredness for about a week following an infusion is her only IVIG side effect. IVIG infusions are necessary to preclude life-threatening infections and they are expensive.
William
Hi Bob,
ReplyDeleteActually we did cover this topic a bit back on Sept. 23. Only we didn't do nearly as thorough a job as you did! The link we had for this story was buried with a bunch of other stories, with very little side commentary. So thanks for raising awareness of this important issue when considering the CAR-T option.
I myself spent 5 days in ICU with CRS symptoms about 10 days after my CAR-T infusion. I recovered with no residual symptoms, and actually have no memory of it, but I suppose there are no guarantees, so this decision should certainly not be taken lightly.
Keep up the great coverage, I look forward to every post!
-- Ben
William, yes low Immunoglobins are another side effect. The article focused on those two big ones -- I think they are the ones that are less easily managed and potentially cause more problems that need to be dealt with very quickly. The important thing is, plans are in place to manage them, making the treatment more attractive.
ReplyDeleteBob
Thank, Ben. I do remember you talking about your CRS experience. And I did see the links on your blog -- somehow I missed this one.
ReplyDeleteThanks to you (and William) for keeping us all up to date on CAR-T.
Bob
Hi Bob
ReplyDeleteI recently read another CAR-T article (I cannot remember the source) that said you do not have to get CAR-T side effects (e.g., CRS) to have a CAR-T CR. Like Ben, Gretchen got a CR from CAR-T but unlike Ben she did not get CRS.
William
When I was reading up on CRS, I saw something that said CRS is more likely in a healthy immune system. That makes sense; if your system is working properly, it will more likely have that super-response, which might lead to CRS. A weakened immune system that isn't working as well won't "do it's job," which is a way a good thing, since it won't lead to that particular side effect. But I take your point -- there's no guarantee that CRS will happen from CAR-T. I guess that's the point of that research -- trying to identify early on who is likely to have that response, and treat it as quickly as possible.
ReplyDeleteIt's a fascinating treatment, and one that it seems like we are likely to see for a while, eventually in improved form.
Bob
There also seems to be a pretty strong correlation with degree of "tumor burden" and CRS. In my case, my last CT scan before CAR-T infusion showed bulky lymph nodes and and a large mass in my abdomen, and I was experiencing pleural effusions and edema from the lymphoma. Perhaps patients who enroll in CAR-T before their lymphomas become quite so extreme will experience less (and perhaps none!) CRS.
ReplyDelete-- Ben
Very interesting. I wonder if the strategy right now is to hold off and use CAR-T as a second-line or salvage therapy? The ZUMA trial, which includes FL patients, includes the requirement that patients are refractory to chemo. I don't know if there are any trials going on for this as a first-line treatment or not.
ReplyDeleteHey, all of the rest of you reading these comments -- I hope you find all of this as fascinating as I do. All the more reason to go to https://fnhlben.wordpress.com/ and read more on the topic.
Bob
Bob
ReplyDeleteMy (VERY, VERY, non-expert) opinion is that CAT-T is considered a "last chance saloon" treatment. Reasonably often it has significant side effects. However, it beats having your spouse choose a tombstone. In addition, I've heard it costs $400,000 to $500,000 per series of treatments. That's why it's prudent to "save" it for the last seconds of the game when the appropriate approach is to throw a "Hail Mary" pass. (Even if you're not Catholic).
Hi Bob
ReplyDeleteIn my September 29 post I should have mentioned that Gretchen had a low tumor burden which could have been the reason for she did not have CRS.
William