RA Drug May Reduce Toxicity Caused By CAR T Treatment

While the development of chimeric antigen receptors (CAR) T-cell therapy has changed the landscape of cancer treatment and was named “Advance of the Year” by the American Society of Clinical Oncology for 2018, the treatment can also cause side effects that can be challenging to prevent and difficult to treat, such as cytokine release syndrome (CRS).

The symptoms caused by CRS vary from a rash or fever to neurotoxicity. Last year, the FDA expanded the indications of tocilizumab (Actemra) from its original designation of rheumatoid arthritis (RA) treatment to treating CRS in patients undergoing CAR T treatment. Tocilizumab works by blocking interleukin-6 (IL-6), an inflammatory cytokine. Though oncologists have been able to use this inhibitor to some success in patients receiving CAR T treatment, it doesn’t always provide relief from symptoms.

Recently, 2 studies published in Nature Medicine discovered another rheumatoid arthritis drug that could help treat CRS.

The first study¹ investigated the effect of anakinra (Kineret) on patients if administered prior to receiving CAR T therapy. Unlike tocilizumab, anakinra targets the IL-1 cytokine and is able to cross the blood-brain barrier, potentially limiting the toxic side effects of CRS. During the study, researchers noticed that IL-1 cytokines were present well before IL-6, and IL-1 actually induces the production of more IL-6. When the mice being studied were given anakinra, they had significantly improved overall survival, and researchers discovered that targeted intervention against IL-1 may help to successfully treat toxicity caused by CAR T-cell treatment.

Similarly, the second study² also investigated the role of IL-1 in connection to CRS. Researchers in this trial found that IL-1, IL-6, and nitric oxide produced by recipient macrophages can counteract CRS. The mouse models used in the study were also treated with anakinra, and it was found to be more effective than simply targeting IL-6.

The next step in determining the safety and efficacy of this approach in treating CRS is to begin to study the treatment in human clinical trials. Additionally, researchers hypothesized that these results could potentially lead to a CAR T treatment that has an IL-1 inhibitor built into the genetically modified immune cells.

References

1. Norelli M, Camisa B, Barbiera G, et al. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat Med. 2018; 24:739-748. doi: 10.1038/s41591-018-0036-4.

2. Giavridis T, van der Stegan S, Eyquem J, Hamieh M, Piersigilli A, Sadelain M. CAR T cell-induced cytokine released syndrome is mediated by macrophages and abated by IL-1 blockade. Nat Med. 2018; 24:731-738. doi: 10.1038/s41591-018-0041-7.