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Trispecific killer engager 161519 enhances natural killer cell function and provides anti-tumor activity against CD19-positive cancers

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Cancer biology & Medicine 2020年第4期17卷 1026-1038页

作者： Ying Cheng Xiaodong Zheng Xuefu Wang Yongyan Chen Haiming Wei Rui Sun Zhigang Tian Haoyu Sun Hefei National Laboratory for Physical Sciences at Microscale The CAS Key Laboratory of Innate Immunity and Chronic DiseaseSchool of Basic Medical SciencesDivision of Life Sciences and MedicineInstitute of ImmunologyUniversity of Science and Technology of ChinaHefei 230027China Research Unit of NK cell Study Chinese Academy of Medical SciencesBeijing 100864China

Objective:Natural killer(NK)cells have gained considerable attention due to their potential in treating"cold tumors,"and are therefore considered as one of the new strategies for curing cancer,by using worldwide development of their new possibilities and interventions with NK cell-related therapeutic products.Methods:We constructed a trispecific killer engager(TriKE)consisting of anti-CD16,IL-15,and anti-CD19.This TriKE was designed to attract CD19^(+)tumor cells to CD16^(+)NK cells,whereas IL-15 sustained the proliferation,development,and survival of NK cells.Results:Treatment with 161519 TriKE in the presence of CD19^(+)targets upregulated expression of CD69,CD107 a,TRAIL,IFN-γ,and TNF-α in NK cells,and significantly improved the proliferation and cytotoxicity of NK cells.NK cells"armed"with 161519 TriKE showed stronger cytolysis against CD19+targets compared with that of"unarmed"NK cells.A preclinical model of b-cell lymphoma in human peripheral blood mononuclear cell-reconstituted xenograft mice showed significant inhibition of tumor growth and prolonged overall survival after treatment with 161519 TriKE,when compared with that in control mice or mice treated with 1619 biKE.Combined use of IL-2 was a more effective treatment with 1619 biKE,when compared with that using 161519 TriKE.Conclusions:The newly generated 161519 TriKE enhanced the proliferation,activation,cytokine secretion,and cytotoxicity of NK cells in the presence of CD19+tumor cells.The 161519 TriKE aided inhibition of tumor growth and prolonged the overall survival of murine xenografts,and could be used to treat CD19-positive cancers.

关键词： Trispecific antibody trispecific killer engager(TriKE) NK cell b-cell lymphoma tumor immunotherapy

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Safety and efficacy of obinutuzumab in Chinese patients with b-cell lymphomas: a secondary analysis of the GERSHWIN trial

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Cancer Communications 2018年第1期38卷 335-343页

作者： Yan Qin Yuqin Song Zhixiang Shen Xin Du Wei Ji Wanling Hsu Jun Zhu Yuankai Shi Department of Medical Oncology Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted DrugsNational Cancer Center/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021P.R.China Department of lymphoma Beijing Cancer HospitalPeking UniversityBeijing 100142P.R.China Department of Hematology Ruijin HospitalShanghai Jiaotong UniversityShanghai 200025P.R.China Department of Hematology Guangdong General Hospital/Guangdong Academy of Medical SciencesGuangzhou 510030GuangdongP.R.China Clinical Science Shanghai Roche Pharmaceuticals LtdShanghai 201203P.R.China Statistics Roche(China)Holding LtdShanghai 201203P.R.China

background:Patients with relapsed/refractory b-cell lymphomas have limited treatment options.GERSHWIN is an open-label,single-arm,phase Ib study of obinutuzumab monotherapy in Chinese patients with histologically docu-mented CD20+relapsed/refractory chronic lymphocytic leukemia(CLL),diffuse large b-cell lymphoma(DLbCL),or follicular lymphoma(FL).The primary outcome measure of pharmacokinetics has been previously reported.We now present data on the secondary endpoint measures(e.g.,safety,and efficacy and pharmacodynamics).Methods:Patients received 1000 mg obinutuzumab intravenously on days 1,8,and 15 of cycle 1(CLL patients;first dose split over 2 days),and on day 1 of cycles 2-8.Each cycle lasted for 21 days;the treatment period was 24 weeks.All subjects receiving at least one dose of obinutuzumab were included in the analysis of safety,efficacy,as well as pharmacodynamics.Results:A total of 48 patients(>18 years of age)were enrolled(CLL:12;DLbCL:23;FL:13).The subjects received a median of two lines of anticancer treatment prior to the enrollment.Thirty-five patients(72.9%)had at least one adverse event(AE).The most frequent AE was infusion-related reactions(15 patients;31.3%),followed by pyrexia(11 patients;22.9%).Treatment-related AEs were reported in 28 patients(58.3%),and included one death(interstitial lung disease).End-of-treatment(EoT)response rate was 33.3%.best overall response rate was 47.9%.Most CLL patients achieved a partial response at EoT(58.3%).CD19+depletion occurred in 75.0%of the patients with CLL,and all patients with FL and DLbCL.Conclusions:The safety and efficacy of obinutuzumab monotherapy in Chinese patients with b-cell lymphomas were similar to that observed in previous studies in non-Chinese patients;no new safety signals were observed.

关键词： Obinutuzumab b-cell lymphoma Chronic lymphocytic leukemia Chinese patients

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Primary mucosa-associated lymphoid tissue lymphoma in the midbrain:A case report

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World Journal of Clinical Cases 2021年第22期9卷 6566-6574页

作者： Yong-Rui Zhao Rong-Hua Hu Rui Wu Jian-Kun Xu Department of Radiation Oncology Xuanwu HospitalCapital Medical UniversityBeijing 100053China Department of Hematology Xuanwu HospitalCapital Medical UniversityBeijing 100053China Department of Pathology Peking University Third HospitalSchool of Basic Medical SciencesPeking University Health Science CenterBeijing 100191China

bACKGROUND Primary non-dural central nervous system mucosa-associated lymphoid tissue(MALT)lymphoma is a rare indolent b-cell lymphoma,with only a few reported cases worldwide.CASE SUMMARY A 33-year-old man presented with a 5-mo history of left blepharoptosis and a 4-mo history of right limb numbness and weakness.Magnetic resonance imaging showed a significantly enhanced mass in the left midbrain.Subsequent positron emission tomography revealed that the lesion had increased glucose uptake.A stereotactic robotic biopsy supported a diagnosis of MALT lymphoma.Then he was treated with radiation therapy(30Gy/15F),which resulted in complete remission.We also review the literature on brain parenchymal-based MALT lymphoma,including the clinical presentation,treatment options,and outcomes.CONCLUSION Although there is no consensus on the optimal treatment for this rare disease,patients can respond well when treated with radiotherapy alone.

关键词： Mucosa-associated lymphoid tissue lymphoma b-cell lymphoma Central nervous system brain parenchyma Radiotherapy Case report

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Progressively Enlarging Goiter:Case Reports of Primary Thyroid lymphoma and Literature Review

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Current Medical Science 2020年第3期40卷 518-522页

作者： Xia-ming LIU De-lin MA Gang YUAN Jun-hui XIE Department of Urology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China Department of Endocrinology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China

Primary thyroid lymphoma(PTL)is an exceptionally rare and highly aggressive potentially curable malignant disease.We report three typical cases of PTL referred to our hospital.All three cases had long history of Hashimoto’s thyroiditis,and presented with progressively enlarging neck mass.The first two cases were confirmed by surgical biopsy to be diffuse large b cell lymphoma,and received radiotherapy combined with chemotherapy,or received only chemotherapy.The third case was confirmed by core needle biopsy to be mucosa-associated lymphoid tissue lymphoma,and received radiotherapy.In summary,confirmation of PTL diagnosis is essential for further clinical decisions.Core biopsy should be one of the most important methods to make the diagnosis of PTL,while the use of fine needle aspiration cytology alone is still limited in diagnosing PTL.

关键词： primary thyroid lymphoma b-cell lymphoma Hashimoto’s thyroiditis fine needle aspiration cytology core needle biopsy

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Cross-talk between Myc and p53 in b-cell lymphomas

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Chronic Diseases and Translational Medicine 2019年第3期5卷 139-154页

作者： Li Yu Tian-Tian Yu Ken H.Young Department o f Hematology The Second Affiliated Hospital to Nanchang UniversityNanchangJiangxi 330006China Hematopathology Division and Pathology Department Duke University School of MedicineDurhamNC 27710USA Duke University Medical Center and Cancer Institute DurhamNC 27710USA

Myc and p53 proteins are closely associated with many physiological cellular functions,including immune response and lymphocyte survival,and are expressed in the lymphoid organs,which are sites for the development and activation of b-cell malignancies.Genetic alterations and other mechanisms resulting in constitutive activation,rearrangement,or mutation of MYC and TP53 contribute to the development of lymphomas,progression and therapy resistance by gene dysregulation,activation of downstream anti-apoptotic pathways,and unfavorable microenvironment interactions.The cross-talk between the Myc and p53 proteins contributes to the inferior prognosis in many types of b-cell lymphomas.In this review,we present the physiological roles of Myc and p53 proteins,and recent advances in understanding the pathological roles of Myc,p53,and their cross-talk in lymphoid neoplasms.In addition,we highlight clinical trials of novel agents that directly or indirectly inhibit Myc and/or p53 protein functions and their signaling pathways.Although,to date,these trials have failed to overcome drug resistance,the new results have highlighted the clinical efficiency of targeting diverse mechanisms of action with the goal of optimizing novel therapeutic opportunities to eradicate lymphoma cells.

关键词： b-cell lymphoma p53 Myc Molecular mechanisms Targeted therapy

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bAFF受体TACI融合蛋白的表达纯化与功能研究

BAFF受体TACI融合蛋白的表达纯化与功能研究

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作者：孟祥斌天津大学

学位级别：硕士

b细胞活化因子（b cell activating factor,bAFF）属于肿瘤坏死因子超家族的一员。它是外周b细胞存活的重要因子。在动物模型中,bAFF的过表达会导致自身免疫病样症状的发生。研究发现,在不同类型的自身免疫性疾病患者的血清中,bAFF的含... 详细信息

b细胞活化因子（b cell activating factor,bAFF）属于肿瘤坏死因子超家族的一员。它是外周b细胞存活的重要因子。在动物模型中,bAFF的过表达会导致自身免疫病样症状的发生。研究发现,在不同类型的自身免疫性疾病患者的血清中,bAFF的含量是明显升高的。近期研究还发现bAFF还与部分肿瘤疾病的发生有关。因此,bAFF的拮抗剂可能成为治疗自身免疫疾病和某些肿瘤的新型药物。由于bAFF和受体TACI具有高亲和力,可特异性识别bAFF并与之结合,因此体外构建表达的TACI可中和体内过表达的bAFF,抑制b细胞的增殖和活化,缓解和治疗与bAFF相关的自身免疫病和b细胞肿瘤。本课题的研究为开发bAFF拮抗剂治疗bAFF相关疾病提供了实验基础。本课题研究方法:对bAFF受体TACI融合蛋白原核表达与纯化,在体外研究TACI对b系淋巴瘤细胞增殖的影响,并初步分析了TACI抑制肿瘤细胞系增殖的机理。主要研究结果: （一）TACI融合蛋白原核表达纯化:本实验室已将钓取的TACI基因片段连接到原核表达载体pET-32a上。将重组正确的质粒转化大肠杆菌Rosetta,获得TACI表达工程菌。经IPTG诱导,融合蛋白利用镍金属螯合琼脂糖凝胶亲和层析柱纯化。（二）TACI抑制b系淋巴瘤细胞系细胞的增殖:某些b系淋巴瘤细胞系表达bAFF及其受体,并且通过自分泌bAFF来促进肿瘤细胞的增殖。可溶性TACI蛋白能够通过特异性阻断bAFF抑制b系淋巴瘤细胞系的增殖,并且具有剂量依赖性。（三）TACI抑增殖的机理:TACI能够将Daudi细胞阻滞在DNA合成期（即S期） ,而且具有一定的剂量依赖性。TACI对Daudi细胞增殖抑制作用,主要是通过调控细胞周期,而非凋亡达到抑增殖效果。

关键词： bAFF TACI-Trx b-cell lymphoma 融合蛋白拮抗剂

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Trispecific killer engager 161519 enhances natural killer cell function and provides anti-tumor activity against CD19-positive cancers

Trispecific killer engager 161519 enhances natural killer ce...

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第十四届全国免疫学学术大会

作者： Ying Cheng Rui Sun Haoyu Sun Zhigang Tian University of Science and Technology of China

Objective:Natural killer(NK) cells have gained considerable attention due to their potential in treating "cold tumors," and are therefore considered as one of the new strategies for curing cancer,by using worldwide development of their new possibilities and interventions with NK cell-related therapeutic products.Methods:We constructed a trispecific killer engager(TriKE) consisting of anti-CD16,IL-1 5,and anti-CD19.This TriKE was designed to attract CD19 tumor cells to CD16 NK cells,whereas IL-15 sustained the proliferation,development,and survival of NK cells.Results:Treatment with 161519 TriKE in the presence of CD19 targets upregulated expression of CD69,CD107 a,TRAIL,IFN-γ,and TNF-α in NK cells,and significantly improved the proliferation and cytotoxicity of NK cells.NK cells "armed" with 161519 TriKE showed stronger cytolysis against CD19 targets compared with that of "unarmed" NK cells.A preclinical model of b-cell lymphoma in human peripheral blood mononuclear cell-reconstituted xenograft mice showed significant inhibition of tumor growth and prolonged overall survival after treatment with 161519 TriKE,when compared with that in control mice or mice treated with 1619 biKE.Combined use of IL-2 was a more effective treatment with 1619 biKE,when compared with that using 161519 TriKE.Conclusions:The newly generated 16151 9 TriKE enhanced the proliferation,activation,cytokine secretion,and cytotoxicity of NK cells in the presence of CD19 tumor cells.The 161519 TriKE aided inhibition of tumor growth and prolonged the overall survival of murine xenografts,and could be used to treat CD19-positive cancers.

关键词： Trispecific antibody trispecific killer engager（TriKE） NK cell b-cell lymphoma tumor immunotherapy

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