Cytokine Release Syndrome

Cytokine release syndrome (CRS) is one of the most problematic issues in cancer immunotherapy. Originally extremely rare, the incidence of CRS is rapidly increasing, especially with the development of new agents and combination immunotherapy. CRS has given great problems to patients treated with CAR-T, which has been successful in blood born cancers, but carried huge risk. We also began seeing it in more patients, with bulky disease when using combination immunotherapy directly injected into the tumor. Basically, it is a condition caused when the immune cells produce a large amount of immune-stimulating substances called cytokines in response to mounting an immune attack, in this case, against cancer. It seems the larger amount of cancer burden the patient has, the higher the risk there is for CRS. The immune system is used to attacking things that relatively small, such as a viral or bacterial infection that does not have much mass, but cancer tumors can be larger than one of your organs. When the body attacks something so massive it is not without potential consequences.

Symptoms of CRS typically include fatigue, fever, loss of appetite, vomiting, low blood pressure, seizure, headache, and confusion. This is very similar to the symptoms associated with severe infections and sepsis. Fatigue, fever and loss of appetite can be common in immunotherapy, as well, but CRS progresses to these other symptoms, often starting with low blood pressure. For me, this was the major drawback of immunotherapy. I feel it is one reason that it is best to treat patients as early as possible, before their disease becomes too bulky, since increased tumor burden is a risk factor. Other thoughts are to use chemotherapy, radiation, or ablation to reduce tumor volume first, though often this is not possible. However, thankfully, recently some major breakthroughs have been made. They may not eliminate the problem, but hopefully they will make it manageable in most cases.

In a study published in Nature Medicine, May 2018 by Norelli, et al. they showed that cells of the immune system called monocytes produce Interleukin 1(IL-1) and Interleukin 6(IL-6) causing CRS in a specific mouse model. Importantly, the study showed that IL-1 seems to be the source of associated neurotoxicity in CRS. This type of toxicity is normally the most dangerous and fatal aspect.

Besides supportive care, the typical treatments for CRS are steroids, histamine blockers, and potentially the IL-6 blocking agent Tocilizumab. However, this last treatment has not been as successful as hoped, especially in a case where neurological symptoms have developed. Norelli, et al. showed that IL-1 seemed to start this whole cascade and was responsible for the neurological toxicity. This led them to show that the IL-1 blocking drug Anakinra did have success in preventing the neurological related toxicity. This was in the animal model, but it is important enough that we should consider using this therapy in patients right away. Thankfully, Anakinra is already FDA-approved for treatment of rheumatoid arthritis, so it can be used off-label in the U.S.

Reference: Shimabukuro-Vornhagen, A. a.-B. (2018). Cytokine release syndrome. Journal for immunotherapy of cancer, 1-14.

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