Neurotoxicity and Cytokine Release Syndrome After Chimeric Antigen Receptor T Cell Therapy: Insights Into Mechanisms and Novel Therapies

Abstract

Chimeric antigen receptor T (CART) cell immunotherapy has been remarkably successful in treating certain relapsed/refractory hematological cancers. However, CART cell therapy is also associated with toxicities which present an obstacle to its wider adoption as a mainstay for cancer treatment. The primary toxicities following CART cell administration are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). New insights into the mechanisms of these toxicities have spurred novel treatment options. In this review, we summarize the available literature on the clinical manifestations, mechanisms, and treatments of CART-associated CRS and ICANS.

Dual-Target Car-Ts With on- and off-Tumour Activity May Override Immune Suppression in Solid Cancers: A Mathematical Proof of Concept

“…These side effects of the treatment can be life-threatening in a subset of patients. However, tocilizumab and corticosteroids have been used to manage these toxicities, enabling CD19 CAR-T cells to be administered without obvious compromise in efficacy [49,50]. Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 7 December 2020 doi:10.20944/preprints202012.0166.v1…”

Toxicities of Chimeric Antigen Receptor T Cell Therapy in Multiple Myeloma: An Overview of Experience From Clinical Trials, Pathophysiology, and Management Strategies

“…As previously mentioned, the excessive cytokine release from CAR T cells and/ or other immune cells might cause endothelial activation, and might subsequently contribute to severe CRS with hemodynamic instability, capillary leak, and consumptive coagulopathy (71,84). Since activated macrophages are considered as the main source of pro-inflammatory cytokines, secondary hemophagocytic lymphohistocytosis/macrophage activation syndrome (HLH/MAS) could be an accompanying event during CRS (88,89). Indeed, some patients with CRS do meet the HLH-2004 diagnostic criteria (90).…”

“…In the most of the CAR T cell trials, patients receive LDC prior to CAR T cell infusion to create a favorable environment for CAR T cells (23)(24)(25). However, LDC is also associated with more frequent and more severe CRS and/or ICANS (89). Additionally, cytopenias, i.e., anemia, thrombocytopenia, leukopenia, and neutropenia, following LDC and/or CAR T cell infusion occur in the vast majority of the patients ( Table 1).…”

“…Moreover, as endothelial damage is regarded as a major "driver" in CRS and/or ICANS, endothelial protection using defibrotide, an approved agent for treatment of venoocclusive disease following SCT, might be an option for CAR T cell-related toxicities (151,152). Clinical investigation is currently underway (89). Recently, Mestermann et al have reported that the tyrosine kinase inhibitor dasatinib can reversibly inhibit the cytolytic activity, cytokine production, and proliferation of CAR T cells in vitro and in vivo, suggesting that dasatinib could potentially be an option to alleviate CRS and/or ICANS after CAR T cell therapy (153).…”

Current Immunotherapy Approaches in Non-Hodgkin Lymphomas

“…As with classical mAbs, frequency and severity of CRS after CAR T-cells or bsAbs is dependent both on the product and the treated disease. On a pathophysiological level, CRS seems to be mediated by T-lymphocyte and myeloid cell interactions [ 209 ]. Upon contact with the tumor cells, T-cells secrete inflammatory cytokines such as TNF-α and IFN-γ, which in turn stimulate secretion of IL-1, IL-6, inducible nitric oxide synthase (iNOS) and other cytokines by monocytes and macrophages.…”