Xiupeng Ye1, Meijing Liu2, Cuicui Lv3, Yeqiong Li1, Lan Chen1, Jin Zhang1, Juan Mu3, Qi Deng3. 1. 159438People's Hospital of Ningxia Hui Autonomous Region, Yinchuan City, China. 2. National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, 74566The First Affiliated Hospital of Soochow University, Suzhou, China. 3. Department of Hematology, 66571Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China.
Abstract
Background and Objects: Bruton's tyrosine kinase inhibitors are commonly used and effective for lymphoma and chronic lymphocytic leukemia (CLL). Ibrutinib might improve the effect of anti-cluster of differentiation 19 (CD19) chimeric antigen receptor (CD19 CAR) T-cell therapy in lymphoma, but the effects of zanubrutinib combined with CAR-T cells is unclear. Methods: We selected a low effect-target ratio (E:T = 1:3) to study this synergistic effect in vitro. The programed cell death protein 1 (PD-1) expression in CD19 CAR-T cells and immune phenotype of T lymphocytes were analyzed by flow cytometry (FCM). We selected CD19 CAR-T cells of a patient with diffuse large B cell lymphoma (DLBCL) to study the synergistic effect of zanubrutinib with CAR-T cells by bioluminescence imaging monitoring. The CD19 CAR-T cells expansion in mice was compared by FCM. Results: Zanubrutinib and ibrutinib had dose-dependent toxicity on both CAR-T cells and lymphoma cells. But there was no significant synergistic effect of the CD19 CAR-T cells combined with zanubrutinib/ibrutinib in vitro. The PD-1 expression in CD19 CAR-T cells increased when the CD19 CAR-T cells were co-cultured with Raji cells and decreased when ibrutinib was added in culture, but zanubrutinib had no such effect. The extinction of luciferase expression was more obvious in the polytherapy group of ibrutinib and CD19 CAR-T cell than that in the other groups. Moreover, the proportion of CAR-T cells in the combination therapy group of CD19 CAR-T cells and ibrutinib was higher than that of the polytherapy group of CD19 CAR-T cells with zanubrutinib group. The synergistic effect could be observed obviously in mice receiving ibrutinib combined with CD19 CAR-T cells. But zanubrutinib cannot perform joint therapy effect either in vitro or in mice. Conclusion: Zanubrutinib might have no joint therapy effect with CD19 CAR-T cells neither in vitro nor in mice, but the mechanism of different curative effects requires our further research and exploration.
Background and Objects: Bruton's tyrosine kinase inhibitors are commonly used and effective for lymphoma and chronic lymphocytic leukemia (CLL). Ibrutinib might improve the effect of anti-cluster of differentiation 19 (CD19) chimeric antigen receptor (CD19 CAR) T-cell therapy in lymphoma, but the effects of zanubrutinib combined with CAR-T cells is unclear. Methods: We selected a low effect-target ratio (E:T = 1:3) to study this synergistic effect in vitro. The programed cell death protein 1 (PD-1) expression in CD19 CAR-T cells and immune phenotype of T lymphocytes were analyzed by flow cytometry (FCM). We selected CD19 CAR-T cells of a patient with diffuse large B cell lymphoma (DLBCL) to study the synergistic effect of zanubrutinib with CAR-T cells by bioluminescence imaging monitoring. The CD19 CAR-T cells expansion in mice was compared by FCM. Results: Zanubrutinib and ibrutinib had dose-dependent toxicity on both CAR-T cells and lymphoma cells. But there was no significant synergistic effect of the CD19 CAR-T cells combined with zanubrutinib/ibrutinib in vitro. The PD-1 expression in CD19 CAR-T cells increased when the CD19 CAR-T cells were co-cultured with Raji cells and decreased when ibrutinib was added in culture, but zanubrutinib had no such effect. The extinction of luciferase expression was more obvious in the polytherapy group of ibrutinib and CD19 CAR-T cell than that in the other groups. Moreover, the proportion of CAR-T cells in the combination therapy group of CD19 CAR-T cells and ibrutinib was higher than that of the polytherapy group of CD19 CAR-T cells with zanubrutinib group. The synergistic effect could be observed obviously in mice receiving ibrutinib combined with CD19 CAR-T cells. But zanubrutinib cannot perform joint therapy effect either in vitro or in mice. Conclusion: Zanubrutinib might have no joint therapy effect with CD19 CAR-T cells neither in vitro nor in mice, but the mechanism of different curative effects requires our further research and exploration.
Authors: Stephen J Schuster; Michael R Bishop; Constantine S Tam; Edmund K Waller; Peter Borchmann; Joseph P McGuirk; Ulrich Jäger; Samantha Jaglowski; Charalambos Andreadis; Jason R Westin; Isabelle Fleury; Veronika Bachanova; S Ronan Foley; P Joy Ho; Stephan Mielke; John M Magenau; Harald Holte; Serafino Pantano; Lida B Pacaud; Rakesh Awasthi; Jufen Chu; Özlem Anak; Gilles Salles; Richard T Maziarz Journal: N Engl J Med Date: 2018-12-01 Impact factor: 91.245
Authors: Zi-Xun Yan; Li Li; Wen Wang; Bin-Shen OuYang; Shu Cheng; Li Wang; Wen Wu; Peng-Peng Xu; Muharrem Muftuoglu; Ming Hao; Su Yang; Mu-Chen Zhang; Zhong Zheng; James Li; Wei-Li Zhao Journal: Clin Cancer Res Date: 2019-08-23 Impact factor: 12.531
Authors: Idit Sagiv-Barfi; Holbrook E K Kohrt; Debra K Czerwinski; Patrick P Ng; Betty Y Chang; Ronald Levy Journal: Proc Natl Acad Sci U S A Date: 2015-02-17 Impact factor: 11.205
Authors: David L Porter; Wei-Ting Hwang; Noelle V Frey; Simon F Lacey; Pamela A Shaw; Alison W Loren; Adam Bagg; Katherine T Marcucci; Angela Shen; Vanessa Gonzalez; David Ambrose; Stephan A Grupp; Anne Chew; Zhaohui Zheng; Michael C Milone; Bruce L Levine; Jan J Melenhorst; Carl H June Journal: Sci Transl Med Date: 2015-09-02 Impact factor: 17.956
Authors: Fotios Mpekris; Chrysovalantis Voutouri; James W Baish; Dan G Duda; Lance L Munn; Triantafyllos Stylianopoulos; Rakesh K Jain Journal: Proc Natl Acad Sci U S A Date: 2020-02-03 Impact factor: 11.205