HOUSTON – Cytokine release syndrome and neurotoxicity frequently occur with CD19-directed chimeric antigen receptor (CAR) T-cell immunotherapies, but targetable factors for mitigating the risk and effects of these complications are emerging, according to Cameron Turtle, MBBS, PhD.
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Frozen T cells of a cancer patient
These factors include infused CAR T-cell dose, bone marrow disease burden, immune response, and the lymphodepletion regimen used, Dr. Turtle, of Fred Hutchinson Cancer Research Center, Seattle, said at the Transplantation & Cellular Therapies Meetings. This list is based on an analysis of several studies that included a total of 195 patients with B-cell malignancies who were treated with defined-composition CD19 CAR T cells.
In a 2016 study included in the analysis, for instance, Dr. Turtle and his colleagues found that CD19 CAR T cells administered to adults with B-cell acute lymphoblastic leukemia (B-ALL) after lymphodepletion chemotherapy were “remarkably potent.” Remission was achieved in 27 of 29 patients (J Clin Invest. 2016 Jun 1;126[6]:2123-38).
However, the study also established that high CAR T-cell doses and tumor burden increased the risk of severe cytokine release syndrome (CRS) and neurotoxicity, Dr. Turtle said at the meeting, held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
“Importantly, we identified serum biomarkers that allow testing of early intervention strategies in the patients who have the highest risk of toxicity,” he said.
Dr. Turtle explained that significantly higher peak interleuken-6 (IL-6) and interferon (IFN)-gamma levels were seen after CAR T-cell infusion in patients with high bone marrow tumor burden and in patients requiring treatment in an intensive care unit (ICU).
ICU care correlated with a higher percentage of bone marrow blasts before lymphodepletion chemotherapy, he added.
Elevations of serum C-reactive protein (CRP) and ferritin also correlated with bone marrow disease burden and with the occurrence of severe CRS requiring ICU care, he said, noting that ferritin and CRP levels declined after tocilizumab or corticosteroid therapy.
In addition, all patients in the study who developed neurotoxicity had evidence of CRS. Peak levels of IL-6, IFN-gamma, ferritin, and CRP were significantly higher in those who developed grade 3 or higher neurotoxicity. Further, serum IL-6 and IFN-gamma concentrations on day 1 after infusion were significantly higher in those who required ICU care and in those who subsequently developed grade 4 neurotoxicity than in patients who developed grade 3 neurotoxicity.
Multivariate analysis indicated that serum IL-6 concentration of more than 30 pg/mL on day 1 and the total number of CD19+ cells in bone marrow before therapy were independent predictors of subsequent development of grade 3 or higher neurotoxicity.
Notably, serum IL-6 of more than 30 pg/mL on day 1 identified all patients in the study who subsequently developed grade 4 or higher neurotoxicity, Dr. Turtle and his colleagues noted.
“The findings suggested that evaluation of serum IL-6 concentration early after CAR T-cell infusion might be useful for identifying patients at high risk of severe neurotoxicity and to evaluate early intervention approaches,” he said.