Fondation ARC pour la Recherche sur le Cancer

Natural killer (NK) cells are cytotoxic and cytokine-producing innate lymphocytes with established roles in antiviral and antitumor immunity. In recent years, the biology of NK cells has been exploited in innovative cancer immunotherapies, leading to clinical advances including allogeneic NK cell infusions, chimeric antigen receptor NK cells, and NK cell engager technologies. These studies pave the way to explore how advances in NK cell-based immunotherapies could be leveraged outside of oncology to selectively target pathogenic cells and restore tissue homeostasis in viral infections, neurodegenerative disorders, autoimmunity, and transplantation medicine.

<div>AbstractPurpose:<p>TNF blockers can be used to manage gastrointestinal inflammatory side effects following nivolumab and/or ipilimumab treatment in patients with advanced melanoma. Our preclinical data showed that anti-TNF could promote the efficacy of immune checkpoint inhibitors.</p>Patients and Methods:<p>TICIMEL (NTC03293784) is an open-label, two-arm phase Ib clinical trial. Fourteen patients with advanced and/or metastatic melanoma (stage IIIc/IV) were enrolled. Patients were treated with nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) combined to infliximab (5 mg/kg, <i>N</i> = 6) or certolizumab (400/200 mg, <i>N</i> = 8). The primary endpoint was safety and the secondary endpoint was antitumor activity. Adverse events (AEs) were graded according to the NCI Common Terminology Criteria for Adverse Events and response was assessed following RECIST 1.1.</p>Results:<p>Only one dose-limiting toxicity was observed in the infliximab cohort. The two different combinations were found to be safe. We observed lower treatment-related AEs with infliximab as compared with certolizumab. In the certolizumab cohort, one patient was not evaluable for response. In this cohort, four of eight patients exhibited hepatobiliary disorders and seven of seven evaluable patients achieved objective response including four complete responses (CRs) and three partial responses (PRs). In the infliximab cohort, we observed one CR, two PRs, and three progressive diseases. Signs of activation and maturation of systemic T-cell responses were seen in patients from both cohorts.</p>Conclusions:<p>Our results show that both combinations are safe in human and provide clinical and biological activities. The high response rate in the certolizumab-treated patient cohort deserves further investigations.</p></div>

A comprehensive translational cancer research approach focused on personalized and precision medicine, and covering the entire cancer research-care-prevention continuum has the potential to achieve in 2030 a 10-year cancer-specific survival for 75% of patients diagnosed in European Union (EU) member states with a well-developed healthcare system. Concerted actions across this continuum that spans from basic and preclinical research through clinical and prevention research to outcomes research, along with the establishment of interconnected high-quality infrastructures for translational research, clinical and prevention trials and outcomes research, will ensure that science-driven and social innovations benefit patients and individuals at risk across the EU. European infrastructures involving comprehensive cancer centres (CCCs) and CCC-like entities will provide researchers with access to the required critical mass of patients, biological materials and technological resources and can bridge research with healthcare systems. Here, we prioritize research areas to ensure a balanced research portfolio and provide recommendations for achieving key targets. Meeting these targets will require harmonization of EU and national priorities and policies, improved research coordination at the national, regional and EU level and increasingly efficient and flexible funding mechanisms. Long-term support by the EU and commitment of Member States to specialized schemes are also needed for the establishment and sustainability of trans-border infrastructures and networks. In addition to effectively engaging policymakers, all relevant stakeholders within the entire continuum should consensually inform policy through evidence-based advice.

International audience

Background: NSCLC is the leading cause of cancer death. Recently, much progress has been made to identify and target specific oncogenic drivers such as EGFR mutations and ALK translocations. Unfortunately, the majority of NSCLCs do not have a single driver, but instead harbor complex systems of molecular alterations. The advent of immunooncology has opened newer avenues for treating these patients, but still, many tumors are resistant. Therefore, selection of precise therapies targeting the appropriate pathways in these tumors is an important area of research. In previously published work, the Worldwide Innovative Network (WIN) Consortium has developed the Simplified Interventional Mapping System (SIMS) algorithm to match patients to a targeted drug triplet. The SIMS algorithm is based on the hypothesis that the use of both genomic as well as transcriptomic data is important in selecting an ideal tri-therapy regimen. Since the transcriptome varies widely between different types of normal tissue, the relative level of transcription of any given gene in a tumor must be normalized against the expected level of transcription of that gene in the analogous normal tissue. The SPRING trial is the first trial assessing a rational, SIMS-based tri-therapy regimen in advanced NSCLC. The drugs utilized for SPRING–avelumab (anti-PDL1), axitinib (VEGFR inhibitor) and palbociclib (CDK4/6 inhibitor)–were chosen because the SIMS genomic/transcriptomic analysis demonstrated that ~10% of NSCLCs have a combination of these targets.Methods: Patients with locally advanced or metastatic NSCLC without EGFR or ALK alterations are being enrolled and treated with avelumab, palbociclib, and axitinib after informed consent. During phase I, any prior treatment is allowed. SPRING will assess the safety of the tri-therapy combination and determine the recommended phase II dose (RP2D) (3+3 dose escalation). Once the RP2D is found, the study will proceed directly to the phase II portion, which will permit only previously untreated patients in the metastatic setting. A biopsy of both tumor and normal tissue (by endobronchial mucosal biopsy) is obtained on all patients, both of which are analysed in a central genomics and transcriptomics platform. The SIMS algorithm is being validated retrospectively by determining the degree of genomic and transcriptomic matching and correlating with outcome.Results: The phase I study is open in USA, Israel, Spain and Luxembourg and has enrolled 12 patients to date and has progressed to cohort 3. The phase II portion is expected to open later in 2019. This research is supported by the EMD Serono/Pfizer alliance and ARC Foundation for cancer research.Citation Format: Benjamin Solomon, Enriqueta Felip, Jair Bar, Guy Berchem, Lyudmila Bazhenova, Pierre Saintigny, Nicolas Girard, Raed Sulaiman, Catherine Bresson, Fanny Wunder, J Jack Lee, Jacques Raynaud, Eitan Rubin, Brandon Young, Vladimir Lazar, Amir Onn, Brian Leyland Jones, Razelle Kurzrock. Survival Prolongation by Rationale INnovative Genomics (SPRING): An international WIN Consortium Phase I/II proof-of-concept study to explore the safety and efficacy of a tri-therapy approach using avelumab, palbociclib and axitinib in advanced/metastatic non-small cell lung cancer (NSCLC) with integrated genomic and transcriptomic correlates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT223.

To investigate the associations between head and neck cancer (HNC) risk and occupations. We harmonized data on occupations in a pooled analysis of 8839 HNC cases and 13,730 controls in International Head and Neck Cancer Epidemiology (INHANCE) consortium. Logistic regression was used to estimate odds ratios (ORs) for associations of occupations and HNC risk. Population attributable fraction (PAF) for occupations was calculated using the formula PEC × (OR - 1)/OR. Trend of increasing HNC risk was found with increasing duration of employment for many occupations, including cooks (OR = 1.36; 95% confidence interval [CI] 1.09 to 1.68), cleaners (OR = 1.38; 95% CI 1.13 to 1.69), painters (OR = 1.82; 95% CI 1.42 to 2.35). The PAF for a priori occupations was 14.5% (95% CI 7.1% to 21.9%) for HNC. We found associations between certain occupations and HNC risks, including for subsites, with a duration-response relationship.

Aneuploidy, an abnormal chromosome number, has been linked to aging and age-associated diseases, but the underlying molecular mechanisms remain unknown. Here we show, through direct live-cell imaging of young, middle-aged, and old-aged primary human dermal fibroblasts, that aneuploidy increases with aging due to general dysfunction of the mitotic machinery. Increased chromosome mis-segregation in elderly mitotic cells correlates with an early senescence-associated secretory phenotype (SASP) and repression of Forkhead box M1 (FoxM1), the transcription factor that drives G2/M gene expression. FoxM1 induction in elderly and Hutchison–Gilford progeria syndrome fibroblasts prevents aneuploidy and, importantly, ameliorates cellular aging phenotypes. Moreover, we show that senescent fibroblasts isolated from elderly donors’ cultures are often aneuploid, and that aneuploidy is a key trigger into full senescence phenotypes. Based on this feedback loop between cellular aging and aneuploidy, we propose modulation of mitotic efficiency through FoxM1 as a potential strategy against aging and progeria syndromes.

For over a century, researchers have been comparing embryogenesis and regeneration hoping that lessons learned from embryonic development will unlock hidden regenerative potential. This problem has historically been a difficult one to investigate because the best regenerative model systems are poor embryonic models and vice versa. Recently, however, there has been renewed interest in this question, as emerging models have allowed researchers to investigate these processes in the same organism. This interest has been further fueled by the advent of high-throughput transcriptomic analyses that provide virtual mountains of data. Here, we present Nematostella vectensis Embryogenesis and Regeneration Transcriptomics (NvERTx), a platform for comparing gene expression during embryogenesis and regeneration. NvERTx consists of close to 50 transcriptomic data sets spanning embryogenesis and regeneration in Nematostella These data were used to perform a robust de novo transcriptome assembly, with which users can search, conduct BLAST analyses, and plot the expression of multiple genes during these two developmental processes. The site is also home to the results of gene clustering analyses, to further mine the data and identify groups of co-expressed genes. The site can be accessed at http://nvertx.kahikai.org.