慢性淋巴细胞白血病
细胞毒性T细胞
伊布替尼
布鲁顿酪氨酸激酶
CD19
免疫学
细胞毒性
抗体依赖性细胞介导的细胞毒性
癌症研究
外周血单个核细胞
抗体
免疫系统
医学
化学
作者
Maissa Mhibik,Erika M. Gaglione,David Eik,Ellen K Kendall,Amy Blackburn,Keyvan Keyvanfar,Maria Joao Baptista,Inhye E. Ahn,Clare Sun,Junpeng Qi,Christoph Rader,Adrian Wiestner
出处
期刊:Blood
[American Society of Hematology]
日期:2021-11-11
卷期号:138 (19): 1843-1854
被引量:11
标识
DOI:10.1182/blood.2020009686
摘要
Bruton tyrosine kinase inhibitors (BTKis) are a preferred treatment of patients with chronic lymphocytic leukemia (CLL). Indefinite therapy with BTKis, although effective, presents clinical challenges. Combination therapy can deepen responses, shorten treatment duration, and possibly prevent or overcome drug resistance. We previously reported on a CD19/CD3-bispecific antibody (bsAb) that recruits autologous T-cell cytotoxicity against CLL cells in vitro. Compared with observations with samples from treatment-naïve patients, T cells from patients being treated with ibrutinib expanded more rapidly and exerted superior cytotoxic activity in response to the bsAb. In addition to BTK, ibrutinib also inhibits interleukin-2 inducible T-cell kinase (ITK). In contrast, acalabrutinib, does not inhibit ITK. Whether ITK inhibition contributes to the observed immune effects is unknown. To better understand how BTKis modulate T-cell function and cytotoxic activity, we cultured peripheral blood mononuclear cells (PBMCs) from BTKi-naive and ibrutinib- or acalabrutinib-treated CLL patients with CD19/CD3 bsAb in vitro. T-cell expansion, activation, differentiation, and cytotoxicity were increased in PBMCs from patients on treatment with either BTKi compared with that observed for BKTi-naïve patients. BTKi therapy transcriptionally downregulated immunosuppressive effectors expressed by CLL cells, including cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and CD200. CTLA-4 blockade with ipilimumab in vitro increased the cytotoxic activity of the bsAb in BTKi-naïve but not BTKi-treated PBMCS. Taken together, BTKis enhance bsAb-induced cytotoxicity by relieving T cells of immunosuppressive restraints imposed by CLL cells. The benefit of combining bsAb immunotherapy with BTKis needs to be confirmed in clinical trials.
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