CAR-T: What's Next?

The medical journal Cancers published an article recently called "CAR-T: What is Next?"

I thought it was pretty interesting, given what I wrote in my last post -- that experts were kind of torn about when to give CAR-T to Follicular Lymphoma patients, given some of its limitations (like its potential effects on Quality of Life). 

This article, by three authors from King's College in London, is a review of how CAR-T is used, not just in FL, or even in blood cancers, but in solid cancers, too. And as the title suggests, it also looks at the future of CAR-T, and how researchers are working to overcome some of its limitations. As the authors point out, one of the limitation is the dangerous side effect called Cytokine Release Syndrome, the body's response to a surge of immune cells. But another is a lack of durability for patients with some cancers, where as many as 60% of patients receiving CAR-T will relapse. Basically, CAR-T has limitation in both of the areas that cancer treatments are evaluated by -- how effective they are, and how safe they are.

Of course, every cancer treatment has limitations on how effective and safe they are. If they didn't have limitations, then we'd all be cured, with no side effects. It seems to me that this is an issue for CAR-T because it holds so much promise. 

It turns out there are a whole lot of attempts by researchers to make CAR-T more effective and more safe. If you look at the article, focus on Table 2, which gives a summary of all of those attempts. It's too big a table to copy here, but I want to mention a few of the research approaches that are discussed. 

•  To try to make CAR-T more effective, researchers are developing Artificial Antigen-Presenting Cells (AAPCs). CAR-T works by training T Cells (a kind of immune cell) to recognize the cancer cells. When the cancer cells are gone, the T Cells might die off, since the threat is gone. It is possible that, if there is a relapse, those trained T Cells aren't around anymore to go after the cancer cells. In this research, AAPCs are given to the patient after relapse. these might be "fake cancer cells" or other substances that stimulate the trained T Cells, so those trained cells don't die off. If an actual relapse happens, those T cells will be ready to recognize them and go after them.
• Other research combines CAR-T with Bi-Specifics. A Bi-specific works by bringing a cancer cell and T Cell next to each other, making it easier on the T Cell. Researchers are trying to develop B-specifics that would seek out the specific T cells that have been trained in the CAR-T process, making them even more effective.
• Still other research is trying to develop variations on CAR-T. There are lots of immune cells in the body besides T Cells, and they can be even more powerful. So some researchers are trying to develop treatments like CAR-NK (training Natural Killer cells they way T Cells are trained now) and CAR-M (using Macrophages in place of T cells).
  
• Other research is focused on safety, trying to reduce the side effects that come with CAR-T. One problem with CAR-T is that once it starts working, it's hard to control. That's why Cytokine Release Syndrome is a problem -- it's a side effect of having too strong an immune response. In a weird way, it's almost as if CAR-T is working too well. T cells work in two ways -- they kill the cancer cell, but then also signal the body to create more T cells. So one strategy to help with safety is to separate those two functions -- keep the "kill the cancer cell" part, but not the "signal the body to make so many that the patient gets CRS" part. Another strategy is to add something to the T Cell as it is being trained that will act as a kind of brake. If signs of CRS are starting, doctors can give the patient another treatment that will tell the T cells to slow down, and thus avoid CRS.
  

I'm not trying to give a complete list of the research being done to improve CAR-T -- there is a while lot more that is discussed in the article. But I think it's pretty fantastic that there is so much work being done on this. Oncologists are very excited about the possibilities of CAR-T; as I've mentioned before, CAR-T and Bi-specifics seem to be the two things that get doctors most excited these days. And patients are just as excited -- I see lots of discussion in online groups for FL patients about CAR-T being "The Cure."

As this article makes clear, that might be a little premature. We're not there yet. But I love that there's so much work being done to move us in that direction -- far more than I was aware of. Lots of reasons for hope.