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1.
Ruihua Xu Fenghua Wang Qi Li Jianhua Shi Lin Shen Qingyuan Zhang Xianglin Yuan Yi Jiang Nong Xu Ye Chen Xichun Hu Xiaoyan Lin Shujun Yang Chao Ren 《The lancet oncology》2017
Background
Patients with unresectable or recurrent nasopharyngeal cancer who have disease progression after standard therapy have few treatment options and represent an important, unmet medical need. Nasopharyngeal cancer is closely associated with Epstein-Barr virus (EBV) infection and has been reported to have high concentrations of PD-L1 expression and tumour-infiltrating lymphocytes, which indicate a potential implication of PD-1 blockade in the treatment of nasopharyngeal cancer. JS001, a humanised recombinant IgG4 antibody against PD-1, selectively blocks the interactions of PD-1, with its ligands PD-L1 and PD-L2, and promotes antigen-specific T-cell activation. Results of a phase 1 study of JS001 treatment in Chinese patients with heavily pretreated solid tumours have shown an acceptable safety profile in doses up to 10 mg/kg once every 2 weeks until progressive disease, intolerance, withdrawal of consent, or investigator decision. Here we report the safety and efficacy of JS001 in a phase 1b/2 clinical study.Methods
We did this open-label, phase 1b/2, clinical study in Chinese patients with refractory or metastatic nasopharyngeal cancer received JS001 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity. All patients with measurable disease were assessed for clinical response every 8 weeks according to the immune-related Response Evaluation Criteria In Solid Tumors (iRECIST) criteria. Tumour PD-L1 expression, plasma EBV DNA concentration, and additional potential predictive biomarkers were monitored for correlation with clinical response. This study is registered with ClinicalTrials, number NCT02915432.Findings
Between Dec 29, 2016, and June 19, 2017, we enrolled 48 patients with nasopharyngeal cancer. Of 23 evaluable patients, the median age was 46 years (range 33–70), 81% were male, and EBV serology tested positive in 92%. Adverse events occurred in 46 (96%) of 48 patients, which were mostly grade 1 or 2. Grade 3 and worse adverse events occurred in 17 patients (35%), including abnormal liver function (n=6, 13%), dysphagia (n=2, 4%), and pulmonary infection (n=2, 4%). Rapid and deep clinical responses were observed. Seven patients (15%) had partial responses while ten patients (21%) achieved stable disease, with the proportion of patients who achieved an objective response of 30% and a disease control of 73%. The responses seemed unrelated to PD-L1 expression status on tumour biopsy.Interpretation
JS001 treatment has shown good clinical activity in heavily pretreated patients with nasopharyngeal cancer and a manageable safety profile. We plan to enrol 54 patients with nasopharyngeal cancer to further monitor the safety and efficacy of JS001 treatment.Funding
Shanghai Science and Technology Innovation Fund. 相似文献2.
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Theodore W Laetsch Steven G DuBois Leo Mascarenhas Brian Turpin Noah Federman Catherine M Albert Ramamoorthy Nagasubramanian Jessica L Davis Erin Rudzinski Angela M Feraco Brian B Tuch Kevin T Ebata Mark Reynolds Steven Smith Scott Cruickshank Michael C Cox Alberto S Pappo Douglas S Hawkins 《The lancet oncology》2018,19(5):705-714
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Hussein A Tawbi Melissa Burgess Vanessa Bolejack Brian A Van Tine Scott M Schuetze James Hu Sandra D&#x;Angelo Steven Attia Richard F Riedel Dennis A Priebat Sujana Movva Lara E Davis Scott H Okuno Damon R Reed John Crowley Lisa H Butterfield Ruth Salazar Jaime Rodriguez-Canales Shreyaskumar Patel 《The lancet oncology》2017,18(11):1493-1501
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Yirui Zhai Honglian Ma Zhouguang Hui Lujun Zhao Dongming Li Jun Liang Xiaozhen Wang Liming Xu Bo Chen Yu Tang Runye Wu Yujin Xu Ming Chen Luhua Wang 《The lancet oncology》2017
Background
Concurrent chemoradiotherapy is the standard treatment for unresectable stage III non-small lung cancer, with frequently unsatisfactory results. We aimed to evaluate the efficacy and safety of the addition of continuous intravenous infusion of recombinant human endostatin (Endostar) to concurrent chemoradiotherapy.Methods
We did this prospective, phase 2 study (HELPER) in patients with inoperable stage III non-small-cell lung cancer (defined by the American Joint Committee on Cancer 7th edn staging system) with an E performance score of 0–2; diagnoses were made on the basis of pathology or cytology results. All enrolled patients received thoracic radiation at doses of 60–66 Gy and continuous intravenous infusions of Endostar (7·5 mg/m2 per 24h, 120 h continuously, 120 h per cycle; from day ?5 to day ?1, days 10–13, days 24–28, and days 38–42). Additionally, patients received two cycles of etoposide (50 mg/m2; days 1–5 and days 29–33) plus cisplatin (50 mg/m2; day 1, 8, 29, and 36). The primary endpoint was progression-free survival and the secondary endpoints were objective response, overall survival, local recurrence-free survival, and toxicities.Findings
From November, 2012, to June, 2015, 73 patients were enrolled and 67 patients were evaluable. 56 patients were male and 11 patients were female. The median age was 59 years (range 31–69). Most patients (44, 66%) had squamous cell carcinoma. 27 patients (40%) had stage IIIa disease, and 40 (60%) had stage IIIb disease. Severe adverse events were observed in two patients (one had massive haemoptysis and one had pneumonia). The most common adverse event was leucopenia (96%; 45% were grade 3–4). The complete response was 12% and partial response was 64%. The median follow-up time was 37·1 months (range 20·1–52·1). The median overall survival was 34·7 months (21·9–47·4), progression-free survival was 13·3 months (5·5–21·0), and local recurrence-free survival was 27·1 months. Progression-free survival was 51% at 1 year, 35% at 2 years, and 28% at 3 years, overall survival was 82% at 1 year, 60% at 2 years, and 48% at 3 years, and local recurrence-free survival was 73% at 1 year, 55% at 2 years, and 50% at 3 years.Interpretation
For patients with unresectable stage III non-small-cell lung cancer, continuous intravenous human recombinant endostatin in combination with concurrent chemoradiotherapy is an effective treatment with tolerable toxicities. A phase 3 study is warranted.Funding
None. 相似文献8.
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Zhitao Ying Xiaoyu Xiang Yuqin Song Ning Ding Yufu Lin Wen Zheng Xiaopei Wang Ningjing Lin Meifeng Tu Yan Xie Chen Zhang Weiping Liu Lijuan Deng Yanling Liu Yunqiang Yue Xueyun Yu Hanzhi Liu Panpan Duan Jun Zhu 《The lancet oncology》2017
Background
Patients with relapsed or refractory B-cell non-Hodgkin lymphoma have poor outcomes with the available strategies. Based on the promising results seen in patients treated with anti-CD19 CAR T-cell therapy in relapsed or refractory B-cell non-Hodgkin lymphoma, we initiated a phase 1 study to evaluate the safety and efficacy in patients. Autologous T cells were genetically modified to express a chimeric antigen receptor consisting of an anti-CD19-scFv domain with CD3ζ and 4–1BB signalling domains.Methods
We did this phase 1 study in patients with relapsed or refractory B-cell non-Hodgkin lymphoma in Peking University Cancer Hospital, Beijing, China. Patients received a CAR T-cell infusion after a conditioning regimen of cyclophosphamide (250 mg/m2) and fludarabine (25 mg/m2) daily for 3 days. Three CAR T cell doses were tested: 5?×?104 CAR T cells/kg, 1?×?105 CAR T cells/kg, and 1?×?106 CAR T cells/kg. Primary endpoints included safety and pharmacokinetics of CAR T cells. Secondary endpoints include complete response, overall response, and duration of response per International Working Group Criteria. This trial is registered at ClinicalTrials, number NCT02842138.Findings
As of March 2017, 14 patients were enrolled and ten patients, with a median age of 37 years (range 24–68) underwent response evaluation. Of the ten evaluable patients, four were women, six were men, three had follicular lymphoma, and seven had diffuse large B-cell lymphoma. The median number of previous therapies was 2·5 (range 2–7). The first group of three patients (two with follicular lymphoma and one with diffuse large B-cell lymphoma) received 5?×?104 CAR T cells/kg. Two patients with follicular lymphoma achieved partial remission on day 28, and one of these patients achieved complete remission 3 months later. The second group of three patients (one with follicular lymphoma and two with diffuse large B-cell lymphoma) received 1?×?105 CAR T cells/kg. The patient with follicular lymphoma achieved partial remission on day 28. The last group of four patients (all were diagnosed with diffuse large B-cell lymphoma) received 1?×?106 CAR T cells/kg. Three patients (75%) achieved partial remission on day 28. One patient attained progressive disease on day 28, and died 10 days later due to disease progression. A significant CAR T-cell expansion was detected in this case. On day 26, 26·8% of the patient's peripheral blood mononuclear cells were CAR T cells. PD1 expression was significant in her expanded CAR T cells. 78·3% of CD8-positive CAR T cells and 71·4% of CD4-positive CAR T cells expressed PD1 on day 26, as compared with 22% and 42% on day 13, respectively in the same patient. Increased PD1-expressing CAR T cells were also found in other patients' peripheral blood. No serious adverse event was observed in any patient. Two patients had mild fever (grade 1–2). In-vivo expansion of CAR T cells was detected in all patients between day 14–28. All responding patients were still in remission at the last follow-up (range 2·5–9·0 months).Interpretation
This study demonstrated early promising activity of anti-CD19 CAR T cells in patients with relapsed or refractory B-cell non-Hodgkin lymphoma. The toxicities of cytokine release syndrome were mild and manageable. Our study also provided the first clinical evidence that expanded CAR T cells could express PD1. Blocking PD1 pathway might enhance the effector function of CAR T cells and improve the clinical outcomes of CAR T-cell therapy.Funding
Marino Biotechnology Co, Ltd. 相似文献10.
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Jennifer L McQuade Carrie R Daniel Kenneth R Hess Carmen Mak Daniel Y Wang Rajat R Rai John J Park Lauren E Haydu Christine Spencer Matthew Wongchenko Stephen Lane Dung-Yang Lee Mathilde Kaper Meredith McKean Kathryn E Beckermann Samuel M Rubinstein Isabelle Rooney Luna Musib Michael A Davies 《The lancet oncology》2018,19(3):310-322
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Hagop Kantarjian Farhad Ravandi Nicholas J Short Xuelin Huang Nitin Jain Koji Sasaki Naval Daver Naveen Pemmaraju Joseph D Khoury Jeffrey Jorgensen Yesid Alvarado Marina Konopleva Guillermo Garcia-Manero Tapan Kadia Musa Yilmaz Gautam Bortakhur Jan Burger Steven Kornblau Elias Jabbour 《The lancet oncology》2018,19(2):240-248
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Rodabe N Amaria Peter A Prieto Michael T Tetzlaff Alexandre Reuben Miles C Andrews Merrick I Ross Isabella C Glitza Janice Cormier Wen-Jen Hwu Hussein A Tawbi Sapna P Patel Jeffrey E Lee Jeffrey E Gershenwald Christine N Spencer Vancheswaran Gopalakrishnan Roland Bassett Lauren Simpson Rosalind Mouton Jennifer A Wargo 《The lancet oncology》2018,19(2):181-193
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Jie Shen Zheng-Yun Zou Li-Feng Wang Jing Yan Wei-Wei Kong Fan-Yan Meng Fang-Jun Chen Juan Du Jie Shao Qiu-Ping Xu Ru-Tian Li Jia Wei Xiao-Ping Qian Bao-Rui Liu 《The lancet oncology》2017
Background
We aimed to investigate a new treatment method for the treatment of advanced hepatocellular carcinoma. The method was a cellular immune therapy based on personalised peptide vaccination (PPV-DC-CTL) combined with radiotherapy.Methods
We did a phase 1 study in which patients with advanced hepatocellular carcinoma who were not eligible for surgery, as confirmed by multidisciplinary consultation, were treated with precise radiotherapy combined with PPV-DC-CTL in the Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, Nanjing, China. To personalise the vaccine, the peptide candidate library, including mutated peptides and highly expressed peptides, was established according to the gene mutation and expression spectra of hepatocellular carcinoma and previous studies about PPV. Peptides for vaccination of every patient were selected from the peptide candidate library, with the consideration of the pre-existing immunity of the host before vaccination. The assay of peptide-specific IFN-γ production was used to define pre-existing immunity. Side-effects were measured with a haemogram. This study is registered with the Chinese Clinical Trial Registry, number ChiCTR-OIC-16010025.Findings
A total of nine patients with advanced hepatocellular carcinoma were admitted. Four patients had multiple liver metastases (liver lesions more than three pieces), one patient had liver metastasis and portal vein tumour thrombosis, one patient had lung and bone metastases, two patients had liver and lung metastases, and one patient had liver metastasis and peritoneal metastasis. Following radiotherapy and 1–3 cycles of PPV-DC-CTL treatment, AFP concentrations were significantly reduced in six patients compared with baseline concentrations, and imaging assessment of the lesions showed a partial response in three of the patients and stable disease in the other three patients. An objective response was achieved in 33% and disease control in 66%. This regimen was found to be safe and well tolerated because none of the patients developed liver or kidney side-effects. Only one patient developed grade 2 bone marrow suppression, and the other patients had no significant side-effects.Interpretation
Radiotherapy combined with PPV-DC-CTL provides a new therapeutic strategy for patients with advanced hepatocellular carcinoma, which is well tolerated, safe, feasible, and effective.Funding
National Natural Science Foundation of China, Jiangsu Provincial Medical Youth Talent, and the Key Medical Science and Technology Development Project of Nanjing. 相似文献18.
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Funda Meric-Bernstam Herbert Hurwitz Kanwal Pratap Singh Raghav Robert R McWilliams Marwan Fakih Ari VanderWalde Charles Swanton Razelle Kurzrock Howard Burris Christopher Sweeney Ron Bose David R Spigel Mary S Beattie Steven Blotner Alyssa Stone Katja Schulze Vaikunth Cuchelkar John Hainsworth 《The lancet oncology》2019,20(4):518-530
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Baohui Han Kai Li Qiming Wang Yizhuo Zhao Li Zhang Jianhua Shi Zhehai Wang Yin Cheng Jianxing He Yuankai Shi Weiqiang Chen Xiuwen Wang Yi Luo Kejun Nan Faguang Jin Baolan Li Yinlan Chen Jianying Zhou Donglin Wang 《The lancet oncology》2017