Menée in vitro et à l'aide de plusieurs modèles murins de tumeur, cette étude met en évidence l'intérêt d'une stratégie thérapeutique consistant à injecter dans la tumeur des exosomes recombinants dont la membrane, recouverte de glycoprotéines virales, fusionne avec celle des cellules cancéreuses

Xenogenization of tumor cells by fusogenic exosomes in tumor microenvironment ignites and propagates antitumor immunity

Kim, Gi Beom ; Nam, Gi-Hoon ; Hong, Yeonsun ; Woo, Jiwan ; Cho, Yakdol ; Kwon, Ick Chan ; Yang, Yoosoo ; Kim, In-San

Many cancer patients not responding to current immunotherapies fail to produce tumor-specific T cells for various reasons, such as a lack of recognition of cancer cells as foreign. Here, we suggest a previously unidentified method for xenogenizing (turning self to non-self) tumors by using fusogenic exosomes to introduce fusogenic viral antigens (VSV-G) onto the tumor cell surface. We found that xenogenized tumor cells were readily recognized and engulfed by dendritic cells; thereby, tumor [...]

Menée à l'aide de lignées cellulaires, de modèles murins et d'échantillons tumoraux puis menée sur des patients atteints d'un cholangiocarcinome extrahépatique, cette étude chinoise met en évidence l'intérêt d'une perfusion au niveau des canaux biliaires de microvésicules dérivées de cellules tumorales et chargées en méthotrexate pour traiter une obstruction biliaire liée à la tumeur

Methotrexate-loaded tumour-cell-derived microvesicles can relieve biliary obstruction in patients with extrahepatic cholangiocarcinoma

Gao, Yunfeng ; Zhang, Hui ; Zhou, Nannan ; Xu, Pingwei ; Wang, Jianxiong ; Gao, Yuan ; Jin, Xun ; Liang, Xiaoyu ; Lv, Jiadi ; Zhang, Yamin ; Tang, Ke ; Ma, Jingwei ; Zhang, Huafeng ; Xie, Jing ; Yao, Fang ; Tong, Weimin ; Liu, Yuying ; Wang, Ximo ; Huang, Bo

Most patients with cholangiocarcinoma (CCA) develop extrahepatic malignant biliary obstructions, which require palliative drainage to normalize bilirubin levels and to improve the patients’ overall survival. Here, we report that the infusion of methotrexate-containing plasma-membrane microvesicles derived from apoptotic human tumour cells into the bile-duct lumen of patients with extrahepatic CCA mobilized and activated neutrophils and relieved biliary obstruction in 25% of the patients. [...]

Menée in vitro et in vivo, cette étude met en évidence l'intérêt d'une endopeptidase couplée à un fragment de la toxine diphtérique pour cliver les protéines RAS activées (qu'elles soient mutées ou non) et inhiber la croissance tumorale

An engineered chimeric toxin that cleaves activated mutant and wild-type RAS inhibits tumor growth

Vidimar, Vania ; Beilhartz, Greg L. ; Park, Minyoung ; Biancucci, Marco ; Kieffer, Matthew B. ; Gius, David R. ; Melnyk, Roman A. ; Satchell, Karla J. F.

RAS oncoproteins have long been considered among the most elusive drug targets in cancer research. At issue is the lack of accessible drug-binding sites and the extreme affinity for GTP. Covalent inhibitors against the KRAS G12C mutant have shown early clinical promise; however, targeting the other oncogenic RAS mutants across three RAS isoforms has proven challenging. Inhibition of activated wild-type RAS in the absence of canonical RAS mutations is also highly desirable in certain tumors. [...]

Menée in vitro, à l'aide de xénogreffes et sur des patients atteints d'une leucémie myéloïde aiguë traitée par agents hypométhylants, cette étude démontre que le ciblage de l'antigène CD70 à l'aide du cusatuzumab élimine les cellules souches cancéreuses

Targeting CD70 with cusatuzumab eliminates acute myeloid leukemia stem cells in patients treated with hypomethylating agents

Riether, Carsten ; Pabst, Thomas ; Höpner, Sabine ; Bacher, Ulrike ; Hinterbrandner, Magdalena ; Banz, Yara ; Müller, Rouven ; Manz, Markus G. ; Gharib, Walid H. ; Francisco, David ; Bruggmann, Rémy ; van Rompaey, Luc ; Moshir, Mahan ; Delahaye, Tim ; Gandini, Domenica ; Erzeel, Ellen ; Hultberg, Anna ; Fung, Samson ; de Haard, Hans ; Leupin, Nicolas ; Ochsenbein, Adrian F.

Acute myeloid leukemia (AML) is driven by leukemia stem cells (LSCs) that resist conventional chemotherapy and are the major cause of relapse1,2. Hypomethylating agents (HMAs) are the standard of care in the treatment of older or unfit patients with AML, but responses are modest and not durable3–5. Here we demonstrate that LSCs upregulate the tumor necrosis factor family ligand CD70 in response to HMA treatment resulting in increased CD70/CD27 signaling. Blocking CD70/CD27 signaling and [...]

Menée sur des patients atteints d'un mésothéliome et menée à l'aide de deux modèles murins, cette étude met en évidence l'intérêt de l'immunotoxine anti-mésothéline LMB-100 pour améliorer l'efficacité antitumorale des anticorps anti-PD1

Enhanced efficacy of mesothelin-targeted immunotoxin LMB-100 and anti–PD-1 antibody in patients with mesothelioma and mouse tumor models

Jiang, Qun ; Ghafoor, Azam ; Mian, Idrees ; Rathkey, Daniel ; Thomas, Anish ; Alewine, Christine ; Sengupta, Manjistha ; Ahlman, Mark A. ; Zhang, Jingli ; Morrow, Betsy ; Steinberg, Seth M. ; Pastan, Ira ; Hassan, Raffit

Mesothelioma is a rare but difficult-to-treat cancer, which usually recurs after chemotherapy and only occasionally responds to checkpoint inhibitor immunotherapy. During a clinical trial of an immunotoxin targeting the mesothelin protein in this cancer, Jiang et al. observed that immunotoxin-treated patients showed promising responses to immune checkpoint inhibitors, particularly if their tumors expressed the relevant checkpoint. The authors characterized the immune responses in the treated [...]

Mené sur 50 patients atteints d'une tumeur stromale gastrointestinale de stade métastatique, cet essai de phase II évalue l'efficacité, du point de vue de la survie sans progression, et la toxicité du cabozantinib, après l'échec de l'imatinib et du sunitinib

Activity and safety of the multi-target tyrosine kinase inhibitor cabozantinib in patients with metastatic gastrointestinal stromal tumour after treatment with imatinib and sunitinib: European Organisation for Research and Treatment of Cancer phase II trial 1317 ‘CaboGIST’

Schöffski, Patrick ; Mir, Olivier ; Kasper, Bernd ; Papai, Zsuzsanna ; Blay, Jean-Yves ; Italiano, Antoine ; Benson, Charlotte ; Kopeckova, Katerina ; Ali, Nasim ; Dileo, Palma ; LeCesne, Axel ; Menge, Franka ; Cousin, Sophie ; Wardelmann, Eva ; Wozniak, Agnieszka ; Marreaud, Sandrine ; Litière, Saskia ; Zaffaroni, Facundo ; Nzokirantevye, Axelle ; Vanden Bempt, Isabelle ; Gelderblom, Hans

Background : Gastrointestinal stromal tumour (GIST) is commonly treated with tyrosine kinase inhibitors (TKIs), but most patients ultimately develop secondary resistance. Cabozantinib, a multi-targeted TKI inhibitor, has activity in patient-derived GIST mouse xenograft models and can overcome compensatory MET signalling occurring on TKI treatment. European Organisation for Treatment of Cancer (EORTC) 1317 ‘CaboGIST’ assessed the safety and activity of cabozantinib in patients with GIST who had [...]

Mené sur 86 patients atteints d’une tumeur solide de stade avancé, cet essai de phase I évalue la dose maximale tolérée du futibatinib (un inhibiteur de FGFR1-4) et analyse ses caractéristiques pharmacodynamiques et pharmacocinétiques

Phase 1, First-in-Human Study of Futibatinib, a Highly Selective, Irreversible FGFR1–4 Inhibitor in Patients with Advanced Solid Tumors

R.Bahleda, F.Meric-Bernstam, L.Goyal, B.Tran (et al.)

Background : Futibatinib is an oral, irreversible, highly selective fibroblast growth factor receptor (FGFR)1–4 inhibitor with potent preclinical activity against tumors harboring FGFR aberrations. This first-in-human, phase 1 dose-escalation trial (NCT02052778) evaluates the safety and pharmacokinetics/pharmacodynamics of futibatinib in advanced solid tumors. Patients and methods : Following a standard 3+3 dose-escalation design, eligible patients with advanced solid tumors refractory to [...]

Mené sur 35 patientes atteintes d’un cancer récidivant de l’ovaire, cet essai de phase II évalue l’efficacité, du point de vue du taux de réponse globale, d’un traitement combinant olaparib et durvalumab

Combination of PARP Inhibitor Olaparib, and PD-L1 Inhibitor Durvalumab, in Recurrent Ovarian Cancer: a Proof-of-Concept Phase II Study

Erika J. Lampert, Alexandra Zimmer, Michelle Padget, Ashley Cimino-Mathews

Purpose: Preclinical studies suggest PARP inhibition (PARPi) induces immunostimulatory micromilieu in ovarian cancer thus complementing activity of immune checkpoint blockade. We conducted a phase II trial of PARPi olaparib and anti–PD-L1 durvalumab and collected paired fresh core biopsies and blood samples to test this hypothesis.Patients and Methods: In a single-center, proof-of-concept phase II study, we enrolled women aged ?18 with recurrent ovarian cancer. All patients were immune [...]

Mené sur 60 patients atteints d’un adénocarcinome pulmonaire de stade avancé et présentant une mutation HER2, cet essai de phase II évalue l’efficacité, du point de vue du taux de réponse objective, et la toxicité du pyrotinib, après l’échec d’une chimiothérapie à base de sels de platine

Pyrotinib in HER2-Mutant Advanced Lung Adenocarcinoma After Platinum-Based Chemotherapy: A Multicenter, Open-Label, Single-Arm, Phase II Study

Caicun Zhou, Xingya Li, Qiming Wang, Guanghui Gao, Yiping Zhang, Jianhua Chen (et al.)

PURPOSE : Targeted therapies against non–small-cell lung cancer (NSCLC) harboring HER2 mutations remain an unmet need. In this study, we assessed the efficacy and safety of pyrotinib in patients with HER2-mutant advanced NSCLC in a prospective, multicenter, open-label, single-arm, phase II study. PATIENTS AND METHODS : Patients with stage IIIB or IV HER2-mutant lung adenocarcinoma who were previously treated with platinum-based chemotherapy were enrolled to receive pyrotinib at a dose of 400 [...]

Mené sur 444 patients atteints d’un cancer du poumon non à petites cellules de stade avancé, cet essai de phase II évalue l’efficacité, du point de vue de la survie globale, et la toxicité du durvalumab en traitement de troisième ligne ou au-delà

Final overall survival and safety update for durvalumab in third- or later-line advanced NSCLC: the phase II ATLANTIC study

Marina Chiara Garassino, Byoung-Chul Cho, Joo-Hang Kim

Introduction : In the phase II ATLANTIC study, durvalumab provided durable responses with acceptable tolerability in heavily pretreated patients with advanced NSCLC, across three independent patient cohorts defined by EGFR/ ALK status and tumour PD-L1 expression. Preliminary overall survival (OS) data were encouraging. We now report final OS and updated safety data. Methods : Patients with advanced NSCLC with disease progression following ?2 previous systemic regimens received durvalumab [...]

Menée à partir de données portant sur 2 287 patientes atteintes d’un cancer du sein précoce, cette étude rétrospective compare l’efficacité, du point de vue de la survie sans maladie, et en fonction de l’indice de masse corporelle, d’une chimiothérapie adjuvante à base de docétaxel et d’une chimiothérapie utilisant un autre agent

Differential Benefit of Adjuvant Docetaxel-Based Chemotherapy in Patients With Early Breast Cancer According to Baseline Body Mass Index

Christine Desmedt, Marco Fornili, Florian Clatot (et al.)

PURPOSE : Lipophilic drugs, such as taxanes, have a high affinity for adipose tissue and a resulting higher volume of distribution. Here, we reanalyzed clinical trial data to investigate whether the efficacy of docetaxel-based chemotherapy differs from non-docetaxel–based chemotherapy in patients with breast cancer according to their baseline body mass index (BMI). PATIENTS AND METHODS : We retrospectively analyzed data from all of the patients in the adjuvant BIG 2-98 trial (ClinicalTrials.gov [...]

Mené sur 2 002 patientes atteintes atteintes d'un cancer du sein HER2+ de stade métastatique et présentant des métastatases cérébrales, cet essai de phase IIIb évalue l'efficacité, du point de vue du taux de réponse globale, de la survie sans progression et de la survie globale, et la toxicité du trastuzumab emtansine

Trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer and brain metastases: exploratory final analysis of cohort 1 from KAMILLA, a single-arm phase IIIb clinical trial

Montemurro, F. ; Delaloge, S. ; Barrios, C. H. ; Wuerstlein, R. ; Anton, A. ; Brain, E. ; Hatschek, T. ; Kelly, C. M. ; Peña-Murillo, C. ; Yilmaz, M. ; Donica, M. ; Ellis, P.

Background : Patients with brain metastases (BM) from human epidermal growth factor receptor 2 (HER2)-positive breast cancer represent a difficult-to-treat population. Trastuzumab emtansine (T-DM1) has shown potential activity in this subset of patients in small clinical series. Patients and Methods : KAMILLA is an ongoing, phase IIIb study of T-DM1 in patients with HER2-positive locally advanced/metastatic breast cancer (MBC) with prior HER2-targeted therapy and chemotherapy. Patients received [...]

Cette étude compare les caractéristiques mutationnelles, épigénomiques et transcriptomiques de plusieurs centaines de lignées cellulaires avec celles des types ou sous-types tumoraux dont elles sont supposées provenir, puis dresse un catalogue de 366 lignées cellulaires dont les profils transcriptomique et épigénomique ressemblent fortement au type tumoral d'origine

Matching cell lines with cancer type and subtype of origin via mutational, epigenomic, and transcriptomic patterns

Salvadores, Marina ; Fuster-Tormo, Francisco ; Supek, Fran

Cell lines are commonly used as cancer models. The tissue of origin provides context for understanding biological mechanisms and predicting therapy response. We therefore systematically examined whether cancer cell lines exhibit features matching the presumed cancer type of origin. Gene expression and DNA methylation classifiers trained on ~9000 tumors identified 35 (of 614 examined) cell lines that better matched a different tissue or cell type than the one originally assigned. Mutational [...]

Menée à partir de données canadiennes portant sur 1 096 patients atteints d'un mélanome et présentant des métastases cérébrales traitées entre 2007 et 2016 (âge moyen : 61,7 ans ; 751 hommes), cette étude analyse l'association entre l'évolution des techniques de radiothérapie et des traitements systémiques et la survie des patients

Association of Innovations in Radiotherapy and Systemic Treatments With Clinical Outcomes in Patients With Melanoma Brain Metastasis From 2007 to 2016

Brastianos, Harry C. ; Nguyen, Paul ; Sahgal, Arjun ; Eisenhauer, Elizabeth A. ; Baetz, Tara ; Hanna, Timothy P.

Importance : Treatments for melanoma brain metastasis changed between 2007 and 2016 with the advent of new radiotherapy techniques, targeted therapeutic agents, and immunotherapy. Changes in clinical outcomes over time have not been systematically investigated in large population-based studies. Objective : To investigate the association of innovations in radiotherapy techniques and systemic therapies with clinical outcomes among patients with melanoma brain metastasis. Design, Setting and [...]