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XELOX(capecitabine plus oxaliplatin)plus bevacizumab(anti-VEGF-A antibody)with or without adoptive cell immunotherapy in the treatment of patients with previously untreated metastatic colorectal cancer:a multicenter,open-label,randomized,controlled,phase 3 trial

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Signal Transduction and Targeted Therapy 2024年第5期9卷 2104-2113页

作者： Qiu-Zhong Pan Jing-Jing Zhao Liang Liu Dong-Sheng Zhang Li-Ping Wang Wen-Wei Hu De-Sheng Weng Xiang Xu Yi-Zhuo Li Yan Tang Wei-Hong Zhang Jie-Yao Li Xiao Zheng Qi-Jing Wang Yong-Qiang Li Tong Xiang Li Zhou Shuang-Ning Yang Chen Wu Rong-Xing Huang Jia He Wei-Jiao Du Lu-Jun Chen Yue-Na Wu Bin Xu Qiong Shen Yi Zhang Jing-Ting Jiang Xiu-Bao Ren Jian-Chuan Xia State Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for CancerCollaborative Innovation Center for Cancer MedicineSun Yat-Sen University Cancer CenterGuangzhouGuangdong 510060PR China Department of Biotherapy Sun Yat-Sen University Cancer CenterGuangzhouGuangdong 510060PR China Tianjin Medical University cancer Institute and hospital National Clinical Research Center for CancerTianjin 300060PR China Key Laboratory of cancer Immunology and Biotherapy Tianjin 300060PR China Department of Biotherapy/Immunology Tianjin Medical University Cancer Institute and HospitalTianjin 300060PR China Department of Medical Oncology Sun Yat-sen University Cancer CenterGuangzhou 510060PR China Department of Oncology the First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052PR China Department of Tumor Biological Treatment the Third Affiliated Hospital of Soochow UniversityChangzhouJiangsu 213003PR China Jiangsu Engineering research center for Tumor Immunotherapy ChangzhouJiangsu 213003PR China Institute for Cell Therapy of Soochow University ChangzhouJiangsu 213003PR China Department of Stem Cell&Regenerative Medicine State Key Laboratory of TraumaBurn and Combined InjuryDaping HospitalArmy Medical UniversityChongqing 400042PR China Imaging Diagnosis and Interventional center Sun Yat-sen University Cancer CenterGuangzhouGuangdong 510060PR China

Fluoropyrimidine-based combination chemotherapy plus targeted therapy is the standard initial treatment for unresectable metastatic colorectal cancer(mCRC),but the prognosis remains poor.This phase 3 trial(clinicalTrials.gov:NCT03950154)assessed the efficacy and adverse events(AEs)of the combination of PD-1 blockade-activated DC-CIK(PD1-T)cells with XELOX plus bevacizumab as a first-line therapy in patients with mCRC.A total of 202 participants were enrolled and randomly assigned in a 1:1 ratio to receive either first-line XELOX plus bevacizumab(the control group,n=102)or the same regimen plus autologous PD1-T cell immunotherapy(the immunotherapy group,n=100)every 21 days for up to 6 cycles,followed by maintenance treatment with capecitabine and bevacizumab.The main endpoint of the trial was progression-free survival(PFS).The median follow-up was 19.5 months.Median PFS was 14.8 months(95%CI,11.6-18.0)for the immunotherapy group compared with 9.9 months(8.0-11.8)for the control group(hazard ratio[HR],0.60[95%CI,0.40-0.88];p=0.009).Median overall survival(OS)was not reached for the immunotherapy group and 25.6 months(95%CI,18.3-32.8)for the control group(HR,0.57[95%CI,0.33-0.98];p=0.043).Grade 3 or higher AEs occurred in 20.0%of patients in the immunotherapy group and 23.5%in the control groups,with no toxicity-associated deaths reported.The addition of PD1-T cells to first-line XELOX plus bevacizumab demonstrates significant clinical improvement of PFS and OS with well tolerability in patients with previously untreated mCRC.

关键词： PD1 immunotherapy bevacizumab

Heavy-atom engineered hypoxia-responsive probes for precisive photoacoustic imaging and cancer therapy

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Chinese Chemical Letters 2024年第4期35卷 316-320页

作者： Ling-Ling Wu Xiangchuan Meng Qingyang Zhang Xiaowan Han Feiya Yang Qinghua Wang Hai-Yu Hu Nianzeng Xing Department of Urology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China State Key Laboratory of Bioactive Substances and Function of Natural Medicine Institute of Materia MedicaPeking Union Medical College and Chinese Academy of Medical SciencesBeijing 100050China

Photoacoustic agents combining photodynamic therapy(PDT) and photothermal therapy(PTT) functions have emerged as potent theranostic agents for combating cancer. The molecular approaches for enhancing the near-infrared(NIR)-absorption and maximizing non-radiative energy transfer are essential for effective photoacoustic imaging(PAI) and therapy applications. In addition, such molecules with high specificity and affinity to cancer cells are urgently needed, which would further decrease the side effect during treatments. In this study, we applied a heavy-atom engineering strategy and introduced p-aminophenol,-thio, and-seleno moieties into NIR heptamethine cyanine(Cy7) skeleton(Cy7-X-NH_(2), X = O, S, Se) to significantly increase photothermal conversion efficiency for PTT and promote intersystem crossing for PDT.Additionally, we designed a series of nitroreductase(NTR)-activated photoacoustic probes(Cy7-X-NO_(2),X = O, S, Se), and target hypoxic tumors with NTR overexpression. Our prostate cancer targeting probe,Cy7-Se-NO_(2)-KUE, exhibited specific tumor photoacoustic signals and effective tumor killing through outstanding synergistic PTT/PDT in vivo. These findings highlighted a versatile strategy for cancer photoacoustic diagnosis and enhanced phototherapy.

关键词： Heavy-atom effect Phototherapy Photoacoustic imaging Hypoxia-responsive Prostate cancer

Molecular classification of small cell lung cancer subtypes:Characteristics,prognostic factors,and clinical translation

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Chinese Medical Journal 2024年第2期137卷 130-139页

作者： Hanfei Guo Wenqian Li Ye Guo Naifei Chen Jiuwei Cui cancer center The First Hospital of Jilin UniversityChangchunJilin 130021China

Small cell lung cancer(SCLC)is a highly malignant tumor with a very poor prognosis;therefore,more effective treatments are urgently needed for patients afflicted with the disease.In recent years,emerging molecular classifications based on key transcription factors of SCLC have provided more information on the tumor pathophysiology,metastasis,immune microenvironment,and acquired therapeutic resistance and reflected the intertumoral heterogeneity of the various SCLC phenotypes.Additionally,advances in genomics and single-cell sequencing analysis have further revealed the high intratumoral heterogeneity and plasticity of the disease.Herein,we review and summarize these recent lines of evidence and discuss the possible pathogenesis of SCLC.

关键词： Small cell lung carcinoma Molecular classification Tumor heterogeneity Drug resistance Transcription factors Genomics Phenotype Prognosis

Identification of telomere maintenance gene variations related to lung adenocarcinoma risk by genome-wide association and whole genome sequencing analyses

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cancer Communications 2024年第2期44卷 287-293页

作者： Kouya Shiraishi Atsushi Takahashi Yukihide Momozawa Yataro Daigo Syuzo Kaneko Takahisa Kawaguchi Hideo Kunitoh Shingo Matsumoto Hidehito Horinouchi Akiteru Goto Takayuki Honda Kimihiro Shimizu Masahiro Torasawa Daisuke Takayanagi Motonobu Saito Akira Saito Yuichiro Ohe Shun-ichi Watanabe Koichi Goto Masahiro Tsuboi Katsuya Tsuchihara Sadaaki Takata Tomomi Aoi Atsushi Takano Masashi Kobayashi Yohei Miyagi Kazumi Tanaka Hiroyuki Suzuki Daichi Maeda Takumi Yamaura Maiko Matsuda Yoko Shimada Takaaki Mizuno Hiromi Sakamoto Teruhiko Yoshida Yasushi Goto Tatsuya Yoshida Taiki Yamaji Makoto Sonobe Shinichi Toyooka Kazue Yoneda Katsuhiro Masago Fumihiro Tanaka Megumi Hara Nobuo Fuse Satoshi S.Nishizuka Noriko Motoi Norie Sawada Yuichiro Nishida Kazuki Kumada Kenji Takeuchi Kozo Tanno Yasushi Yatabe Kuniko Sunami Tomoyuki Hishida Yasunari Miyazaki Hidemi Ito Mitsuhiro Amemiya Hirohiko Totsuka Haruhiko Nakayama Tomoyuki Yokose Kazuyoshi Ishigaki Toshiteru Nagashima Yoichi Ohtaki Kazuhiro Imai Ken Takasawa Yoshihiro Minamiya Kazuma Kobayashi Kenichi Okubo Kenji Wakai Atsushi Shimizu Masayuki Yamamoto Motoki Iwasaki Koichi Matsuda Johji Inazawa Yuichi Shiraishi Hiroyoshi Nishikawa Yoshinori Murakami Michiaki Kubo Fumihiko Matsuda Yoichiro Kamatani Ryuji Hamamoto Keitaro Matsuo Takashi Kohno Division of Genome Biology National Cancer Center Research InstituteTokyoJapan Department of clinical Genomics National Cancer Center Research InstituteTokyoJapan Laboratory for Statistical Analysis Center for Integrative Medical SciencesRIKENYokohamaJapan Department of Genomic Medicine Research InstituteNational Cerebral and Cardiovascular CenterOsakaJapan Laboratory for Genotyping Development Center for Integrative Medical SciencesRIKENYokohamaJapan center for Antibody and Vaccine Therapy Research HospitalInstitute of Medical ScienceThe University of TokyoTokyoJapan Department of Medical Oncology and cancer center and Center for Advanced Medicine against CancerShiga University of Medical ScienceOtsuJapan Division of Medical AI research and Development National Cancer Center Research InstituteTokyoJapan center for Genomic Medicine Graduate School of MedicineKyoto UniversityKyotoJapan Department of Medical Oncology Japanese Red Cross Medical CenterTokyoJapan Department of Thoracic Oncology National Cancer Center Hospital EastJapan Department of Thoracic Oncology National Cancer Center HospitalTokyoJapan Department of Cellular and Organ Pathology Graduate School of MedicineAkita UniversityAkitaJapan Department of Respiratory Medicine Tokyo Medical and Dental UniversityBunkyo-kuTokyoJapan Division of General Thoracic Surgery Department of SurgeryShinshu University School of MedicineMatsumotoNaganoJapan Department of General Surgical Science Division of General Thoracic SurgeryGunma University Graduate School of MedicineIntegrative Center of General SurgeryGunma University HospitalGunmaJapan Department of Gastrointestinal Tract Surgery Fukushima Medical University School of MedicineFukushimaJapan StaGen Co. LtdTokyoJapan Division of Thoracic Surgery National Cancer Center HospitalTokyoJapan Department of Thoracic Surgery National Cancer Center Hospital EastChibaJapan Division of Translational Informatics Exploratory Oncology Research and Clinical Trial Center(EPOC

Dear editor,Lung carcinoma is responsible for the highest fatal-ity rate among cancer-related deaths globally,with lung adenocarcinoma(LADC)emerging as the prevailing sub-type.

关键词： adenocarcinoma lung Lung

Pan-cancer immunogenic death analysis identifies key roles of CXCR3 and CCL18 in hepatocellular carcinoma

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Genes & Diseases 2024年第2期11卷 568-570页

作者： Jia Guo Xin Sun Guowei Pan Ce Li Xin He Xiaofang Che Zan Teng Xiujuan Qu Yunpeng Liu Bowen Yang Department of Medical Oncology Provincial Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning ProvinceLiaoning Provincial Clinical Research Center for CancerClinical Cancer Research Center of ShenyangThe First Hospital of China Medical UniversityShenyangLiaoning 110001China research center for Universal Health School of Public HealthChina Medical UniversityShenyangLiaoning 110122China

Immunogenic death is a form of programmed cell death that is common in the development and progression of cancer.However,its impact on tumor progression differs depending on the location of the tumor.Meanwhile,it also plays an important role in antitumor immunity because the process of immunogenic death can release substances that activate immunity.1 Therefore,in this study,the key mechanism of mediating immunogenic death in hepatocellular carcinoma(HCC)was found from the excavation of the immunogenic death characteristics of pan-cancer and the in-depth investigation of its effects on different tumor types(Fig.1A).

关键词： death CXCR3 immunity

A preliminary study on rectal dose reduction associated with hyaluronic acid implantation in brachytherapy for prostate cancer

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Asian Journal of Urology 2024年第2期11卷 286-293页

作者： Tairo Kashihara Yuka Urago Hiroyuki Okamoto Mihiro Takemori Hiroki Nakayama Shohei Mikasa Tetsu Nakaichi Kotaro Iijima Takahito Chiba Junichi Kuwahara Satoshi Nakamura Weishan Chang Yoshiyuki Matsui Hiroshi Igaki Department of Radiation Oncology National Cancer Center Hospital5-1-1 TsukijiChuo-kuTokyoJapan Radiation Safety and Quality Assurance Division National Cancer Center Hospital5-1-1 TsukijiChuo-kuTokyoJapan Department of Radiological Sciences Graduate School of Human Health SciencesTokyo Metropolitan University7-2-10 Higashi-OguArakawa-kuTokyoJapan Department of Radiological Technology National Cancer Center Hospital5-1-1 TsukijiChuo-kuTokyoJapan Department of Urological Oncology National Cancer Center Hospital5-1-1 TsukijiChuo-kuTokyoJapan

Objectives: Hydrogel spacer (HS) was developed to reduce rectal toxicities caused by radiotherapy, but has been reported to cause major adverse events. Our institute has attempted to introduce a hyaluronic acid (HA) as an alternative spacer. This study aimed to compare rectal doses and geometric distributions between the HS and HA implantation in prostate cancer.Methods: HS and HA were inserted in 20 and 18 patients undergoing high-dose brachytherapy, respectively. The rectum spacer volumes injected were 10 mL and 22 mL, respectively. In the treatment planning system, 13.5 Gy was administered with common catheter positions. The rectal dose indices were assessed between the spacer groups for dosimetry evaluation. Distances between the prostate and rectum and configurations of the spacers were compared.Results: The mean doses irradiated to 0.1 and 2 mL of the rectum were 10.45 Gy and 6.71 Gy for HS, and 6.73 Gy and 4.90 Gy for HA (p<0.001). The mean minimum distances between the prostate and rectum were 1.23 cm and 1.79 cm for HS and HA, respectively (p<0.05). Geometrical configuration comparisons revealed that HA has a higher ability to expand the space than HS.Conclusion: The rectal dose reduction ability of HA is significantly greater than that of HS, suggesting its potential as a new spacer.

关键词： Brachytherapy Hyaluronicacid Hydrogel Prostaticneoplasm Radiotherapy

Estrogen receptor beta suppresses the androgen receptor oncogenic effects in triple-negative breast cancer

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Chinese Medical Journal 2024年第3期137卷 338-349页

作者： Feng Xu Kun Xu Lingling Fan Xintong Li Yiqiu Liu Fang Yang Chengjun Zhu Xiaoxiang Guan Department of Oncology The First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu 210029China Department of Oncology Jiangsu Cancer HospitalThe Affiliated Cancer Hospital of Nanjing Medical UniversityJiangsu Institute of Cancer ResearchNanjingJiangsu 210009China The Comprehensive cancer center of Nanjing Drum Tower hospital Affiliated Hospital of Medical SchoolNanjing UniversityNanjingJiangsu 210008China Jiangsu Key Lab of cancer Biomarkers Prevention and TreatmentCollaborative Innovation Center for Personalized Cancer MedicineNanjing Medical UniversityNanjingJiangsu 211166China

Background:Triple-negative breast cancer(TNBC)is an aggressive type of breast cancer associated with poor prognosis and limited treatment options.The androgen receptor(AR)has emerged as a potential therapeutic target for luminal androgen receptor(LAR)TNBC.However,multiple studies have claimed that anti-androgen therapy for AR-positive TNBC only has limited clinical benefits.This study aimed to investigate the role of AR in TNBC and its detailed mechanism.Methods:Immunohistochemistry and TNBC tissue sections were applied to investigate AR and nectin cell adhesion molecule 4(NECTIN4)expression in TNBC tissues.Then,in vitro and in vivo assays were used to explore the function of AR and estrogen receptor beta(ERβ)in TNBC.Chromatin immunoprecipitation sequencing(ChIP-seq),co-immunoprecipitation(co-IP),molecular docking method,and luciferase reporter assay were performed to identify key molecules that affect the function of AR.Results:Based on the TNBC tissue array analysis,we revealed that ERβand AR were positive in 21.92%(32/146)and 24.66%(36/146)of 146 TNBC samples,respectively,and about 13.70%(20/146)of TNBC patients were ERβpositive and AR positive.We further demonstrated the pro-tumoral effects of AR on TNBC cells,however,the oncogenic biology was significantly suppressed when ERβtransfection in LAR TNBC cell lines but not in AR-negative TNBC.Mechanistically,we identified that NECTIN4 promoter–42 bp to–28 bp was an AR response element,and that ERβinteracted with AR thus impeding the AR-mediated NECTIN4 transcription which promoted epithelial–mesenchymal transition in tumor progression.Conclusions:This study suggests that ERβfunctions as a suppressor mediating the effect of AR in TNBC prognosis and cell proliferation.Therefore,our current research facilitates a better understanding of the role and mechanisms of AR in TNBC carcinogenesis.

关键词： Androgen receptor Estrogen receptor beta Triple-negative breast cancer NECTIN4 Oncogenic effects Tumor progression

The activity and immune dynamics of PD-1 inhibition on high-risk pulmonary ground glass opacity lesions:insights from a single-arm,phase II trial

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Signal Transduction and Targeted Therapy 2024年第5期9卷 2202-2214页

作者： Bo Cheng Caichen Li Jianfu Li Longlong Gong Peng Liang Ying Chen Shuting Zhan Shan Xiong Ran Zhong Hengrui Liang Yi Feng Runchen Wang Haixuan Wang Hongbo Zheng Jun Liu Chengzhi Zhou Wenlong Shao Yuan Qiu Jiancong Sun Zhanhong Xie Zhu Liang Chenglin Yang Xiuyu Cai Chunxia Su Wei Wang Jianxing He Wenhua Liang Department of Thoracic Surgery and Oncology the First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou Institute of Respiratory HealthState Key Laboratory of Respiratory DiseaseNational Clinical Research Center for Respiratory DiseaseGuangzhouChina Medical Department Genecast Biotechnology Co.LtdWuxiChina Department of Radiation Oncology the First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina Department of Respiratory Medicine the First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou Institute of Respiratory HealthState Key Laboratory of Respiratory DiseaseNational Clinical Research Center for Respiratory DiseaseGuangzhouChina Department of Cardiothoracic Surgery Affiliated Hospital of Guangdong Medical UniversityZhanjiangChina Department of Thoracic Surgery National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital&Shenzhen HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeShenzhenChina Department of VIP Inpatient Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South ChinaSun Yat-sen UniversityGuangzhouChina Department of Medical Oncology Shanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghaiChina

Immune checkpoint inhibitors targeting the programmed cell death-1(PD-1)protein significantly improve survival in patients with advanced non-small-cell lung cancer(NSCLC),but its impact on early-stage ground-glass opacity(GGO)lesions remains unclear.This is a single-arm,phase II trial(NCT04026841)using Simon’s optimal two-stage design,of which 4 doses of sintilimab(200 mg per 3 weeks)were administrated in 36 enrolled multiple primary lung cancer(MPLC)patients with persistent high-risk(Lung-RADS category 4 or had progressed within 6 months)GGOs.The primary endpoint was objective response rate(ORR).T/B/NK-cell subpopulations,TCR-seq,cytokines,exosomal RNA,and multiplexed immunohistochemistry(mIHC)were monitored and compared between responders and non-responders.Finally,two intent-to-treat(ITT)lesions(pure-GGO or GGO-predominant)showed responses(ORR:5.6%,2/36),and no patients had progressive disease(PD).No grade 3-5 TRAEs occurred.The total response rate considering two ITT lesions and three non-intent-to-treat(NITT)lesions(pure-solid or solid-predominant)was 13.9%(5/36).The proportion of CD8^(+)T cells,the ratio of CD8^(+)/CD4^(+),and the TCR clonality value were significantly higher in the peripheral blood of responders before treatment and decreased over time.Correspondingly,the mIHC analysis showed more CD8^(+)T cells infiltrated in responders.Besides,responders’cytokine concentrations of EGF and CTLA-4 increased during treatment.The exosomal expression of fatty acid metabolism and oxidative phosphorylation gene signatures were down-regulated among responders.Collectively,PD-1 inhibitor showed certain activity on high-risk pulmonary GGO lesions without safety concerns.Such effects were associated with specific T-cell re-distribution,EGF/CTLA-4 cytokine compensation,and regulation of metabolism pathways.

关键词： lesions metabolism doses

Manufacturing CAR-NK against tumors: Who is the ideal supplier?

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Chinese Journal of cancer research 2024年第1期36卷 1-16页

作者： Feifei Guo Yi Zhang Jiuwei Cui The First hospital of Jilin University Cancer CenterChangchun 133021China

Chimeric antigen receptor-natural killer(CAR-NK) cells have emerged as another prominent player in the realm of tumor immunotherapy following CAR-T cells. The unique features of CAR-NK cells make it possible to compensate for deficiencies in CAR-T therapy, such as the complexity of the manufacturing process, clinical adverse events, and solid tumor challenges. To date, CAR-NK products from different allogeneic sources have exhibited remarkable anti-tumor effects on preclinical studies and have gradually been applied in clinical practice.However, each source has advantages and disadvantages. Selecting a suitable source may help maximize CAR-NK cell efficacy and increase the feasibility of clinical transformation. Therefore, this review discusses the development and challenges of CAR-NK cells from different sources to provide a reference for future exploration.

关键词： CAR-NK cells cord blood iPSC NK-92 cells peripheral blood