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Anti-metabolic agent pegaspargase plus PD-1 antibody sintilimab for first-line treatment in advanced natural killer T cell lymphoma

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1665-1674页

作者： Jie Xiong Shu Cheng Xiao Gao Shan-He Yu Yu-Ting Dai Xin-Yun Huang Hui-Juan Zhong Chao-Fu Wang Hong-Mei Yi Hao Zhang Wei-Guo Cao Rong Li Wei Tang Yan Zhao Peng-Peng Xu Li Wang Wei-Li Zhao Shanghai Institute of Hematology State Key Laboratory of Medical GenomicsNational Research Center for Translational Medicine at ShanghaiRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina department of Nuclear Medicine Shanghai Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina department of Pathology Shanghai Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina department of Otolaryngology Shanghai Rujin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina department of Radiation Shanghai Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina department of Hematology Navy Medical Center of PLAShanghaiChina pole de recherches sino-francais en science du vivant et genomique Laboratory of Molecular PathologyShanghaiChina

Natural killer T cell lymphoma(NKTCL)is highly aggressive,with advanced stage patients poorly responding to intensive chemotherapy.To explore effective and safe treatment for newly diagnosed advanced stage NKTCL,we conducted a phase ll study of anti-metabolic agent pegaspargase plus PD-1 antibody sintilimab(NCT04096690).Twenty-two patients with a median age of 51 years(range,24-74)were enrolled and treated with induction treatment of pegaspargase 2500 IU/m2 intramuscularly on day 1 and sintilimab 200 mg intravenously on day 2 for 6 cycles of 21 days,followed by maintenance treatment of sintilimab 200 mg for 28 cycles of 21 days.The complete response and overall response rate after induction treatment were 59%(95%Cl,43-79%)and 68%(95%Cl,47-84%),respectively.With a median follow-up of 30 months,the 2 year progression-free and overall survival rates were 68%(95%Cl,45-83%)and 86%(95%Cl,63-95%),respectively.The most frequently grade 3/4 adverse events were neutropenia(32%,n=7)and hypofibrinogenemia(18%,n=4),which were manageable and led to no discontinuation of treatment.Tumor proportion score of PD-L1,peripheral blood high-density lipoprotein cholesterol,and apolipoprotein A-l correlated with good response,while PD-1 on tumor infiltrating lymphocytes and peripheral Treg cells with poor response to pegaspargase plus sintilimab treatment.In conclusion,the chemo-free regimen pegaspargase plus sintilimab was effective and safe in newly diagnosed,advanced stage NKTCL.Dysregulated lipid profle and immunosuppressive signature contributed to treatment resistance,providing an alternative therapeutic approach dual targeting fatty acid metabolism and CTLA-4 in NKTCL.

关键词： killer metabolism lymphoma

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Polymorphisms of microsomal triglyceride transfer protein in different hepatitis B virus-infected patients

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World Journal of Gastroenterology 2008年第35期14卷 5454-5460页

作者： Zhi-Tao Yang Xin-Xin Zhang Xiao-Fei Kong Dong-Hua Zhang Shen-Ying Zhang Jie-Hong Jiang Qi-Ming Gong Gen-Di Jin Zhi-Meng Lu pole sino-francais de recherches en science du vivant et genomique Ruijin Hospital 197 Ruiiin Er Road Shanghai 200025 China department of Infectious Diseases Ruijin Hospital 197 Ruijin Er Road Shanghai 200025 China

AIM: To identify the two polymorphisms of microsomal triglyceride transfer protein (MTP) gene in the Chinese population and to explore their correlation with both hepatitis B virus (HBV) self-limited infection and persistent infection. MetHODS: A total of 316 subjects with self-limited HBV infection and 316 patients with persistent HBV infection (195 subjects without familial history), matched with age and sex, from the Chinese Han population were enrolled in this study. Polymorphisms of MTP at the promoter region -493 and at H297Q were determined by the allele specific polymerase chain reaction (PCR). RESULTS: The ratio of males to females was 2.13:1 for each group and the average age in the self-limited and chronic infection groups was 38.36 and 38.28 years, respectively. None of the allelic distributions deviated significantly from that predicted by the Hardy-Weinberg equilibrium. There was a linkagedisequilibrium between H297Q and -493G/T (D’ = 0.77). As the χ2 test was used, the genotype distribution of MTP -493G/T demonstrated a significant difference between the self-limited infection group and the entire chronic group or the chronic patients with no family history (χ2 = 8.543, P = 0.015 and χ2 = 7.199, P = 0.019). The allele distribution at the MTP-493 position also demonstrated a significant difference between the study groups without family history (χ2 = 6.212, P = 0.013). The T allele emerged as a possible protective factor which may influence the outcomes of HBV infection (OR: 0.59; 95% CI: 0.389-0.897). CONCLUSION: The polymorphism of the MTP gene, T allele at -493, may be involved in determining the HBV infection outcomes, of which the mechanism needs to be further investigated.

关键词：乙型肝炎病毒遗传多样性神经元体细胞甘油三酸酯转移蛋白

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CREBBP/EP300 mutations promoted tumor progression in diffuse large B-cell lymphoma through altering tumorassociated macrophage polarization via FBXW7-N0TCHCCL2/ CSF1 axis

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Signal Transduction and Targeted Therapy 2021年第2期6卷 482-495页

作者： Yao-Hui Huang Kun Cai Peng-Peng Xu Li Wang Chuan-Xin Huang Ying Fang Shu Cheng Xiao Jian Sun Feng Liu Jin-Yan Huang Meng-Meng Ji Wei-Li Zhao Shanghai Istitute of Hematology State Key Laboratory of Medical GenomicsNational Research Center for Translational Medicine at ShanghaiRulin Hospital Afliated to Shanghai Jiao Tong University School of MedicineShanghaiChina School of Life sciences and Biotechnology.Shanghai Jiao Tong Universiy ShanghalChina department of Immunobiology and Microbiology Shanghai Istitute of ImmunologyShanghai Jiao Tong University School of MedicineShanghaiChina pole de recherches sino francais en science du vivant et genomique Laboratory of Molecular PathologyShanghalChina

Epigenetic alterations play an important role in tumor progression of diffuse large B-cell lymphoma(DL BCL).However,the biological relevance of epigenetic gene mutations on tumor microenvironment remains to be determined.The core set of genes relating to histone methylation(KMT2D,KMT2C,EZH2),histone acetylation(CREBBP,EP300),DNA methylation(Tet2),and chromatin remodeling(ARID1A)were detected in the training cohort of 316 patients by whole-genome/exome sequencing(WGS/WES)and in the validation cohort of 303 patients with newly diagnosed DL BCL by targeted sequencing.Their correlation with peripheral blood immune cells and clinical outcomes were assessed.Underlying mechanisms on tumor microenvironment were investigated both in vitro and in vivo.Among all 619 DLBCL patients,somatic mutations in KMT2D(19.5%)were most frequently observed,followed by mutations in ARID1A(8.7%),CREBBP(8.4%),KMT2C(8.2%),Tet2(7.8%),EP300(6.8%),and EZH2(2.9%).Among them,CREBBP/EP300 mutations were signifcantly associated with decreased peripheral blood absolute lymphocyte-to-monocyte ratios,as well as inferior progression-free and overall survival.In B-lymphoma cells,the mutation or knockdown of CREBBP or EP300 inhibited H3K27 acetylation,downregulated FBXW7 expression,activated the NOTCH pathway,and downstream CCL2/CSF1 expression,resulting in tumor-associated macrophage polarization to M2 phenotype and tumor cell proliferation.In B-lymphoma murine models,xenografted tumors bearing CREBBP/EP300 mutation presented lower H3K27 acetylation,higher M2 macrophage recruitment,and more rapid tumor growth than those with CREBBP/EP300 wild-type control via FBXW7-NOTCH-CCL2/CSF1 axis.Our work thus contributed to the understanding of aberrant histone acetylation regulation on tumor microenvironment as an alternative mechanism of tumor progression in DLBCL.

关键词： FBXW7 P300 macrophage

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Presence of multiple abnormal immunologic markers is an independent prognostic factor of diffuse large B-cell lymphoma

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Frontiers of Medicine 2019年第1期13卷 94-103页

作者： Yiwen Cao Zhenhua Liu Wen Wu Ying Qian Qin Shi Rong Shen Binshen Ouyang Pengpeng Xu Shu Cheng Jin Ye Yiming Lu Chaofu Wang Chengde Yang Li Wang Weili Zhao State Key Lahoratory of Medical Genomics Shanghai Institute of HematologyRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200025China State Key Lahoratory of Medical Genomics Shanghai Institute of HematologyRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200025China department of Pathology Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200025China pole de recherches sino-francais en science du vivant et genomique Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200025China department of Rheumatology Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200025China

Autoimmune diseases (ADs) increase the risk of non-Hodgkin's lymphoma and contribute to poor prognosis of patients. However, the association between immunologic markers and clinical outcome has rarely been investigated. This study aims to analyze the prognostic value of pretreatment immunologic markers in newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL). We retrospectively reviewed the data on 502 patients with DLBCL treated in our institution from January 2013 to March 2018. Survival functions were estimated using Kaplan Meier method and Cox regression model. The 3-year progression free survival (PFS) and overall survival (OS) rates were 70.2% and 80.9%, respectively, and the complete remission (CR) rate was 78.1%. Among the patients, those with multiple (≥3) abnormal immunologic markers had significantly shorter 3-year PFS (52.7% vs. 77.3%, P ence of multiple abnormal immunologic markers and the elevated serum levels of lactate dehydrogenase were the independent adverse prognostic factors for PFS (P= 0.008, P dependent adverse prognostic factor for PFS (P= 0.001) and age > 60 years for OS (P= 0.014). In conclusion, the immunologic status was closely related to lymphoma progression, and this study provides new insights into the risk stratification of patients with DLBCL.

关键词： immunologic marker diffuse large B-cell lymphoma prognosis

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