CART Cell Toxicities: New Insight into Mechanisms and Management
Authors Anas Zahid1, ORCID, Elizabeth L. Siegler2, 3, Saad S. Kenderian2, 3, 4, 5, *, ORCID 1 College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, U.A.E 2 T Cell Engineering, Mayo Clinic, Rochester, MN, USA 3 Division of Hematology, Mayo Clinic, Rochester, MN, USA 4 Department of Immunology, Mayo Clinic, Rochester, MN, USA 5 Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA * Corresponding author. Email: Kenderian.saad@mayo.edu Corresponding Author Saad S. Kenderian Received 4 September 2020, Accepted 22 October 2020, Available Online 23 November 2020.
Abstract T cells genetically engineered with chimeric antigen receptors (CART) have become a potent class of cancer immunotherapeutics. Numerous clinical trials of CART cells have revealed remarkable remission rates in patients with relapsed or refractory hematologic malignancies. Despite recent clinical success, CART cell therapy has also led to significant morbidity and occasional mortality from associated toxicities. Cytokine release syndrome (CRS) and Immune effector cell-associated neurotoxicity syndrome (ICANS) present barriers to the extensive use of CART cell therapy in the clinic. CRS can lead to fever, hypoxia, hypotension, coagulopathies, and multiorgan failure, and ICANS can result in cognitive dysfunction, seizures, and cerebral edema. The mechanisms of CRS and ICANS are becoming clearer, but many aspects remain unknown. Disease type and burden, peak serum CART cell levels, CART cell dose, CAR structure, elevated pro-inflammatory cytokines, and activated myeloid and endothelial cells all contribute to CART cell toxicity. Current guidelines for the management of toxicities associated with CART cell therapy vary between clinics, but are typically comprised of supportive care and treatment with corticosteroids or tocilizumab, depending on the severity of the symptoms. Acquiring a deeper understanding of CART cell toxicities and developing new management and prevention strategies are ongoing. In this review, we present findings in the mechanisms and management of CART cell toxicities.
7.1. Cytokine-directed therapy: IL-6, IL-1, GM-CSF IL-6 is associated with severe CRS after CART cell therapy, and tocilizumab, a monoclonal antibody against IL-6R, was approved by the FDA for the management of CRS [50]. Tocilizumab had originally been used to treat rheumatoid and juvenile arthritis but has also shown effectiveness in reducing CRS-associated symptoms after the infusion of CART cells [18]. The dosage suggested by the FDA is 8 mg/kg for adult patients and 12 mg/kg for patients who have a weight lower than 30 kg.
Recent studies suggest that IL-1, produced by activated macrophages, plays a key part in eliciting CRS and ICANS. Anakinra, an IL-1 antagonist which is clinically available but not yet FDA approved for CART-associated toxicities, may lessen both CRS and ICANS after CART cell therapy [51,52]. Anakinra reduces the effect of IL-1a and IL-1ß by competing for IL-1R binding and, in the clinic, 1–2 mg/kg/day is administered via subcutaneous injection [53]. Anakinra was able to effectively mitigate CRS and ICANS while maintaining CART cell antitumor efficacy in preclinical studies [50,53,54]. A recent clinical study showed promising results regarding the use of anakinra to alleviate CART-associated toxicities in large B-cell lymphoma [55]. Results from a phase I anti-CD22 CART cell trial showed that anakinra was associated with favorable outcomes when used in patients who developed hemophagocytic lymphohistiocytosis-like manifestations [56]. The ongoing clinical trials exploring the use of anakinra (NCT04432506, NCT04359784, NCT04148430, and NCT04205838), may show additional promising outcomes.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is produced by activated CART cells and stimulates myeloid cells, suggesting a role in CRS development. IL-6, a major cytokine implicated in CRS, is produced by tumor-resident myeloid cells, which are dependent on GM-CSF [57]. The Rosenberg group revealed that GM-CSF levels are highest during the initial phases of CRS [58]. Moreover, excess GM-CSF can cause ICANS and cerebral edema [59]. Initial GM-CSF surges are linked to more severe CRS [60]. A study conducted by Sterner et al. showed that neutralization of GM-CSF with lenzilumab or with CRISPR gene editing does not prevent antitumor functions of anti-CD19 CART cells in vitro or in vivo. In addition, effective control of leukemia and enhancement of CART cell proliferation was sustained in vivo after GM-CSF neutralization with lenzilumab. In an ALL patient-derived xenograft model of CRS and ICANS, neutralization of GM-CSF led to a decrease in myeloid and T cell infiltration in the central nervous system and a substantial reduction of neuroinflammation and CRS [61]. A study conducted by Sachdeva et al. [62] showed that GM-CSF neutralization with antibodies or with TALEN gene editing in CART cells eliminates macrophage production of CRS-associated cytokines, including IL-6, IL-8, and MCP-1. Anti-GM-CSF therapies have potential to reduce severe adverse effects and improve the safety profile of CART cell therapies while preserving anti-tumor activity.
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