Our study suggests that HPD is more common with PD-1/PD-L1 inhibitors compared with chemotherapy in pretreated patients with NSCLC and is also associated with high metastatic burden and poor prognosis in patients treated with PD-1/PD-L1 inhibitors. Additional studies are needed to determine the molecular mechanisms involved in HPD.

IMPORTANCECheckpoint inhibitors targeting programmed cell death 1 or its ligand (PD-L1) as monotherapies or in combination with anti-cytotoxic T-lymphocyte-associated antigen 4 have shown clinical activity in patients with metastatic non-small cell lung cancer.OBJECTIVE To compare durvalumab, with or without tremelimumab, with chemotherapy as a first-line treatment for patients with metastatic non-small cell lung cancer. DESIGN, SETTING, AND PARTICIPANTSThis open-label, phase 3 randomized clinical trial (MYSTIC) was conducted at 203 cancer treatment centers in 17 countries. Patients with treatment-naive, metastatic non-small cell lung cancer who had no sensitizing EGFR or ALK genetic alterations were randomized to receive treatment with durvalumab, durvalumab plus tremelimumab, or chemotherapy. Data were collected from July 21, 2015, to October 30, 2018.INTERVENTIONS Patients were randomized (1:1:1) to receive treatment with durvalumab (20 mg/kg every 4 weeks), durvalumab (20 mg/kg every 4 weeks) plus tremelimumab (1 mg/kg every 4 weeks, up to 4 doses), or platinum-based doublet chemotherapy. MAIN OUTCOMES AND MEASURESThe primary end points, assessed in patients with Ն25% of tumor cells expressing PD-L1, were overall survival (OS) for durvalumab vs chemotherapy, and OS and progression-free survival (PFS) for durvalumab plus tremelimumab vs chemotherapy. Analysis of blood tumor mutational burden (bTMB) was exploratory.

Background:Circulating tumour cells (CTCs) can provide information on patient prognosis and treatment efficacy. However, there is no universal method to detect CTC currently available. Here, we compared the performance of two CTC detection systems based on the expression of the EpCAM antigen (CellSearch assay) or on cell size (ISET assay).Methods:Circulating tumour cells were enumerated in 60 patients with metastatic carcinomas of breast, prostate and lung origins using CellSearch according to the manufacturer's protocol and ISET by studying cytomorphology and immunolabelling with anti-cytokeratin or lineage-specific antibodies.Results:Concordant results were obtained in 55% (11 out of 20) of the patients with breast cancer, in 60% (12 out of 20) of the patients with prostate cancer and in only 20% (4 out of 20) of lung cancer patients.Conclusion:Our results highlight important discrepancies between the numbers of CTC enumerated by both techniques. These differences depend mostly on the tumour type. These results suggest that technologies limiting CTC capture to EpCAM-positive cells, may present important limitations, especially in patients with metastatic lung carcinoma.

Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC)is the third most frequent virus-associated human malignancy. How this tumor escapes immune recognition despite the expression of several viral antigens has remained poorly understood. Our previous in vitro studies have shown that NPC cells release exosomes containing high amounts of galectin-9, a ligand of the membrane receptor Tim-3, which is able to induce apoptosis in mature Th1 lymphocytes.Here, we sought to determine whether galectin-9-carrying exosomes were produced in NPC patients and whether such exosomes might play a role in the immune evasion of NPC cells. We report that galectin-9-containing exosomes are selectively detected in plasma samples from NPC patients and mice xenografted with NPC tumors. The incorporation into exosomes protects galectin-9 against proteolytic cleavage but retains its Tim-3-binding capacity. Importantly, NPC exosomes induce massive apoptosis in EBVspecific CD4 ؉ cells used as a model of target T cells. This effect is inhibited by both anti-Tim-3 and antigalectin-9 blocking antibodies. These results indicate that blocking galectin-9/Tim-3 interaction in vivo might alleviate the Th1-suppressive effect of NPC exosomes and sustain antitumoral T-cell responses and thereby improve clinical efficacy of immunotherapeutic approaches against NPC. (Blood. 2009;113:1957-1966 IntroductionNasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated malignancy and the third most frequent virus-associated human malignancy after hepatocarcinomas and cervix carcinomas. Each year, approximately 80 000 new cases are diagnosed worldwide. The geographic distribution of NPC is not uniform. It is relatively rare in European and North American countries. Very high incidence foci are found in South China, especially in Guandong and Guangxi provinces (25-40 per 100 000 per year). 1 Areas of intermediate incidence (approximately 3-8 per 100 000 per year) include a large number of developing or emerging countries, especially in North and Central Africa (Tunisia, Algeria, Morocco, Somalia, and Kenya) and in Southeast Asia (Philippines, Vietnam, Indonesia).NPC is an epithelial malignancy with a complex etiology involving viral, environmental, and hereditary factors. Except for some very rare cases of atypical highly differentiated NPC occurring in Western countries, the intact EBV genome is always contained in the nuclei of all malignant cells. 2,3 Many of the approximately 80 EBV genes are silent, but several viral RNAs and proteins are consistently expressed in NPC and contribute to the malignant phenotype. 4 NPC oncogenesis also requires a variable assortment of cellular genetic or epigenetic alterations. 5 Another important biologic feature of NPC is the presence of a massive lymphoid infiltrate in the primary tumor. This infiltrate contains mostly T lymphocytes and a minority of B cells, monocytes, dendritic cells, and eosinophils. The abundant production by malignant NPC cells of inflammatory cytokines, including interle...

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