Scientists at Italy’s San Raffaele Institute have identified circulating monocytes as the molecular players responsible for the release of interleukins 1 and 6, which leads to the life-threatening cytokine release syndrome often seen associated with CAR-T therapy.
Although chimeric antigen receptor T (CAR-T) cell therapy is showing promising results in clinical trials for cancers and other life-threatening diseases, cytokine release syndrome (CRS) and neurotoxicity associated with the therapy pose a major risk.
Clinical manifestations of severe CRS develop few days after the CAR-T therapy and include high fever, respiratory and cardiovascular insufficiency. If left untreated, it can lead to the death of the patient.
Although interleukins (IL-1 and IL-6) were shown to be responsible for producing CRS, the players generating interleukins were not known yet. In the present study published in Nature Medicine, Dr Attilio Bondanza and team at Italy’s San Raffaele Hospital Scientific Institute identified circulating monocytes, rather than CAR-T cells, as the major contributors of IL-1 and IL-6.
The team used a humanized mouse model which recapitulated symptoms of CRS and neurotoxicity following CAR-T infusion. CAR-T cells specific for CD44v6, an antigen overexpressed on acute myeloid leukemia and multiple myeloma were used in the study.
Results showed that CAR-T cell mediated clearance of cancer in these transgenic mice was followed by high fever and increased IL-6 levels, which are hallmarks of CRS. The syndrome could be prevented by monocyte depletion or by using tocilizumab, an IL-6 blocker. However, blocking IL-6 with tocilizumab was still not sufficient to treat the delayed neural toxicity in mice. Instead anakinra, the IL-1 receptor antagonist, could abolish both CRS and neurotoxicity resulting in significant leukemia-free survival.
Thus, the study shows monocyte-derived IL-1 and IL-6 as the major contributors for CRS associated with CAR-T therapy and provides preliminary evidence that targeted therapy against IL-1 could help overcome toxicities of CAR-T therapy.
Source: Norelli M et al., Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nature Medicine, June 2018. DOI