Biomarkers of cytokine release syndrome and neurotoxicity related to CAR-T cell therapy

Abstract

Severe cytokine release syndrome (CRS) and neurotoxicity following chimeric antigen receptor T cell (CAR-T) therapy can be life-threatening in some cases, and management of those toxicities is still a great challenge for physicians. Researchers hope to understand the pathophysiology of CRS and neurotoxicity, and identify predictive biomarkers that can forecast those toxicities in advance. Some risk factors for severe CRS and/or neurotoxicity including patient and treatment characteristics have been identified in multiple clinical trials of CAR-T cell therapy. Moreover, several groups have identified some predictive biomarkers that are able to determine beforehand which patients may suffer severe CRS and/or neurotoxicity during CAR-T cell therapy, facilitating testing of early intervention strategies for those toxicities. However, further studies are needed to better understand the biology and related risk factors for CRS and/or neurotoxicity, and determine if those identified predictors can be extrapolated to other series. Herein, we review the pathophysiology of CRS and neurotoxicity, and summarize the progress of predictive biomarkers to improve CAR-T cell therapy in cancer.

Tocilizumab for Treatment of Severe COVID-19 Patients: Preliminary Results from SMAtteo COvid19 REgistry (SMACORE)

“…Although COVID-19 pathogenesis is still unclear, some patients with a severe disease have laboratory evidence of a systemic inflammation similar to cytokine release syndrome (CRS) [11,12]. CRS is characterized by a sharp increase of a large number of proinflammatory cytokines, among which IL-6 plays a pivotal role [11][12][13]. Therefore, blocking the IL-6 pathway might reduce the vigorous inflammatory response in COVID-19 [11].…”

A Modeling Framework to Characterize Cytokine Release upon T‐Cell–Engaging Bispecific Antibody Treatment: Methodology and Opportunities

“…However, due to large intersubject variabilities in patients’ sensitivity to develop CRS, a general threshold for cytokine levels associated with severe CRS has yet to be established. Nevertheless, serum cytokine levels were suggested as biomarkers for CRS due to the underlying pathophysiology characterized by elevated inflammatory cytokines and systemic inflammation . In the current report, a quantitative modeling framework was developed for characterizing the cytokine profiles upon T‐BsAb treatment, with the goal to facilitate the design of priming dose strategies to minimize CRS toxicities.…”

T lymphocytes as therapeutic arsenal for patients with hematological malignancies

“…As CRs to CARs are invariably accompanied by severe toxicity, recently developed animal models have shown mechanistic dissection and prevention of toxicity without hampering therapeutic efficacy by using IL-6-receptor and IL-1-receptor antagonists [116,117]. Algorithms and grading scales have been developed to aid the clinical management of these patients and include administration of steroids [118] and the interleukin six blocking antibodies, tocilizumab (FDA approved) [119 & ] and siltuximab [120]. TCR-transduced T cells are another therapeutic platform based on genetically modified cells to recognize malignant cells in the context of an HLArestricted and epitope-specific manner.…”