Tocilizumab, but not dexamethasone, prevents CRS without affecting antitumor activity of bispecific antibodies
Open Access
- 20 December 2019
- journal article
- research article
- Published by BMJ in Journal for ImmunoTherapy of Cancer
- Vol. 8 (1), e000621
- https://doi.org/10.1136/jitc-2020-000621
Abstract
Bispecific antibodies (bsAb) and chimeric antigen receptor (CAR) T cells allow for antibody guided recruitment of T cells against tumors. Both are successfully used for treatment of CD19 expressing leukemias, but may cause cytokine release syndrome (CRS) as a major dose-limiting side effect. For CRS prevention, steroids are recommended prior to bsAb treatment, despite their well-known lymphotoxic activity. The IL-6 receptor antibody tocilizumab is established for treatment of CRS induced by CAR T cells, but was not considered for CRS prevention in bsAb therapy. We here compared the influence of dexamethasone and tocilizumab on bsAb-mediated T cell proliferation and tumor lysis in vitro and in vivo and found that dexamethasone profoundly inhibited T cell proliferation and antitumor activity as induced by two different bsAb, particularly at low effector:target ratios, whereas tocilizumab did not affect efficacy. When we applied tocilizumab early during treatment of three patients with a newly developed PSMAxCD3 bsAb, significant CRS attenuation despite high IL-6 serum levels was observed. Thus, early IL-6 blockade may reduce the undesired sequelae of CRS upon bsAb therapy without affecting therapeutic activity, allowing in turn for safe application of effective doses.Keywords
Funding Information
- Wilhelm Sander-Stiftung (2007.115.3)
- Deutsche Krebshilfe (111828, 70112914)
- Helmholtz Validation Fund (OPTIMAB)
- Deutsche Forschungsgemeinschaft (SA1360/7-3, SA1360/9-1)
- Germany's Excellence Strategy (EXC 2180/1)
- Deutschen Konsortium für Translationale Krebsforschung
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