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Alex S. Woodell
A warm breeze whips by as you notice a peculiar set of clouds forming in the distance. These cumulus clouds are tall with bumpy protrusions that flatten out near the top to form a silhouette of a giant anvil. As condensation builds in these behemoths, the bright sunlight dims to a pale twilight. Flashes of light arc across the sky, illuminating a dark horizon. CRACK! A sharp blast captures your full attention as the hairs on your arms begin to raise. A storm is coming! But the storm we discuss today takes place not in the sky, but within your own body.
In my last article, we discussed the fundamentals of chimeric antigen receptor T cell (CAR-T) therapy and the problem of T cell exhaustion. In this follow up article, we will continue to explore the limitations of CAR-T therapy by examining a potentially life-threatening side effect that affects 70 to 90 percent of patients receiving this intervention. Cytokine release syndrome (CRS), commonly referred to as a cytokine storm, is caused by an immune response that flares out of control ⎯ much like a thunderstorm on a humid summer afternoon. Patients describe CRS as having a severe case of the flu with symptoms including fever, fatigue, and body aches. So what exactly are cytokines? I’m glad you asked.
Cytokines are small proteins secreted by cells that allow them to communicate with their neighbors, sort of like a cellular handshake. Free cytokines bind to receptors on the surface of neighboring cells, which can cause a variety of different responses depending on the type of cytokine and target cell. A specific family of cytokines, called interleukins, act as the primary immune regulators. Originally named after the immune cells that secrete them (leukocytes), they are now known to be produced by a variety of different cell types including T cells. During CAR-T therapy, patients receive a large infusion of engineered T cells to combat tumors. However, these T cells also release massive amounts of interleukins which elicit an inflammatory response that causes the flu-like symptoms described by patients. Thus, CRS is quite literally caused by an overproduction of cytokines.
Reducing the severity of CRS is critical for the safety of patients undergoing CAR-T therapy. To identify new therapeutic targets for CRS, one group developed a mouse model that shows symptoms within the first two to three days after CAR-T infusion. Using this model, they found that CRS severity appears to be dependent on the presence of two interleukins, IL-1 and IL-6. Interestingly, these interleukins were produced primarily by macrophages recruited to the tumor microenvironment following CAR-T infusion rather than T cells themselves. In an effort to eliminate CRS in these mice, they generated new CAR-Ts that also produce an IL-1 blocker. By using this new construct, they were able to completely prevent CRS-related mortality, while preserving the tumor-killing effect. If these results are translatable to humans, this will mark a huge milestone in CAR-T development.
In the final article of this series, we will discuss the most significant barrier to the success of CAR-T therapy ⎯ relapse. This typically occurs due to poor T cell persistence and/or tumor antigen loss. Both prongs of this causal fork will be explored in this exciting finale.
Giavridis, Theodoros, et al. “CAR T Cell–Induced Cytokine Release Syndrome Is Mediated by Macrophages and Abated by IL-1 Blockade.” Nature Medicine, vol. 24, no. 6, 2018, pp. 731–738., doi:10.1038/s41591-018-0041-7.