Toxicity Induced by a Bispecific T Cell–Redirecting Protein Is Mediated by Both T Cells and Myeloid Cells in Immunocompetent Mice

髓系细胞 毒性 髓样 细胞生物学 细胞 免疫学 生物 癌症研究 化学 医学 内科学 遗传学
作者
Claire Godbersen-Palmer,Tiffany A. Coupet,Zakaria Grada,Samuel C. Zhang,Charles L. Sentman
出处
期刊:Journal of Immunology [American Association of Immunologists]
卷期号:204 (11): 2973-2983 被引量:16
标识
DOI:10.4049/jimmunol.1901401
摘要

Abstract Bispecific T cell engagers have demonstrated clinical efficacy; however, their use can be accompanied by severe toxicity. Mechanistic understanding of these toxicities is limited by a lack of suitable immunocompetent preclinical models. In this study, we describe an immunocompetent mouse tumor model that exhibits bispecific T cell engager–induced toxicity and recapitulates key features similar to those in human cytokine release syndrome. In this study, toxicity occurred between the second and fourth injections of an NK Group 2D bispecific T cell engager protein. Symptoms were transient, peaking 3–4 h after treatment and resolving by 8 h. Mice developed weight loss, elevated plasma cytokines, a significant reduction in spleen white pulp, and lymphocyte infiltration in the liver. Systemic cellular immune changes also occurred; notably, an increase in CD8+ T cell activation, an increase in myeloid cells in the blood, and a population of Ly-6Cint monocytes (CD11b+Ly-6G−F4/80−) emerged in the liver and spleens of bispecific protein–treated mice. IFN-γ was primarily produced by CD8+ T cells in the spleen and was required for the observed changes in both T cell and myeloid populations. Rag deficiency, IFN-γ deficiency, or depletion of either CD4+ or CD8+ T cells prevented toxicity, whereas perforin deficiency, GM-CSF deficiency, or modulation of the myeloid population through clodronate-mediated depletion showed a partial abrogation of toxicity. Together, these findings reveal that T cell activation by a bispecific T cell engager leads to changes in the host myeloid cell population, both of which contribute to treatment induced toxicity in immunocompetent mice.
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