Publications by authors named "François Ghiringhelli"

281 Publications

Follicular helper-T cells restore CD8-dependent antitumor immunity and anti-PD-L1/PD-1 efficacy.

J Immunother Cancer 2021 Jun;9(6)

Centre de Recherche INSERM LNC-UMR1231, Dijon, France.

Background: T follicular helper cells (Tfh) are essential to shape B cell response during germinal center formation. Tfh accumulation has been reported in various human cancers, with positive or negative prognostic roles. However, the mechanisms explaining the accumulation of Tfh and their role in cancer remain obscure.

Methods: In vitro differentiated and mouse cell sorted Tfh phenotype was evaluated by flow cytometry and quantitative PCR (qPCR). Antitumor effect of Tfh was evaluated by adoptive transfer in different tumor-bearing mice models. The involvement of immune cells, cytokines and chemokines was evaluated, using depleting antibodies. Chemokines and cytokines expression and production were evaluated by qPCR and ELISA. In human, the impact of immune cells and chemokines on survival was evaluated by analyzing transcriptomic data from public databases and from our own patient cohorts.

Results: In this study, we show that Tfh exert an antitumor immune effect in a CD8-dependent manner. Tfh produce interleukin-21, which sustains proliferation, viability, cytokine production and cytotoxic functions of exhausted T cells. The presence of Tfh is required for efficacy of antiprogrammed cell death ligand-1 therapy. Tfh accumulate in the tumor bed and draining lymph nodes in different mouse cancer models. This recruitment is due to the capacity of transforming growth factor β to drive Chemokine (C-X-C motif) Ligand 13 expression, a chemoattractant of Tfh, by intratumor CD8 T cells. Accumulation of Tfh and exhausted CD8 T cells predicts cancer outcome in various cancer types. In patients treated with anti-programmed cell death-1 mAb, accumulation of Tfh and CD8 at the tumor site is associated with outcome.

Conclusion: This study provides evidence that CD8/Tfh crosstalk is important in shaping antitumor immune response generated by immunotherapy.
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http://dx.doi.org/10.1136/jitc-2020-002157DOI Listing
June 2021

ILC2s in cancer: context matters.

Nat Immunol 2021 Jun 7. Epub 2021 Jun 7.

UMR INSERM, 1231, Dijon, France.

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http://dx.doi.org/10.1038/s41590-021-00945-xDOI Listing
June 2021

Evaluation of tumor immune contexture among intrinsic molecular subtypes helps to predict outcome in early breast cancer.

J Immunother Cancer 2021 Jun;9(6)

Transfer Biology Cancer Platform, Centre Georges-Francois Leclerc, Dijon, France

Background: The prognosis of early breast cancer is linked to clinic-pathological stage and the molecular characteristics of intrinsic tumor cells. In some patients, the amount and quality of tumor-infiltrating immune cells appear to affect long term outcome. We aimed to propose a new tool to estimate immune infiltrate, and link these factors to patient prognosis according to breast cancer molecular subtypes.

Methods: We performed in silico analyses in more than 2800 early breast cancer transcriptomes with corresponding clinical annotations. We first developed a new gene expression deconvolution algorithm that accurately estimates the quantity of immune cell populations (tumor immune contexture, TIC) in tumors. Then, we studied associations between these immune profiles and relapse-free and overall survival among the different intrinsic molecular subtypes of breast cancer defined by PAM50 classification.

Results: TIC estimates the abundance of 15 immune cell subsets. Both myeloid and lymphoid subpopulations show different spread among intrinsic molecular breast cancer subtypes. A high abundance of myeloid cells was associated with poor outcome, while lymphoid cells were associated with favorable prognosis. Unsupervised clustering describing the 15 immune cell subsets revealed four subgroups of breast tumors associated with distinct patient survival, but independent from PAM50. Adding this information to clinical stage and PAM50 strongly improves the prediction of relapse or death.

Conclusions: Our findings make it possible to refine the survival stratification of early patients with breast cancer by incorporating TIC in addition to PAM50 and clinical tumor burden in a prognostic model validated in training and validation cohorts.
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http://dx.doi.org/10.1136/jitc-2020-002036DOI Listing
June 2021

Vascular Endothelial Growth Factor, a Key Modulator of the Anti-Tumor Immune Response.

Int J Mol Sci 2021 May 4;22(9). Epub 2021 May 4.

Faculté des Sciences de Santé, Université Bourgogne Franche-Comté, 21000 Dijon, France.

During tumor growth, angiogenesis is required to ensure oxygen and nutrient transport to the tumor. Vascular endothelial growth factor (VEGF) is the major inducer of angiogenesis and appears to be a key modulator of the anti-tumor immune response. Indeed, VEGF modulates innate and adaptive immune responses through direct interactions and indirectly by modulating protein expressions on endothelial cells or vascular permeability. The inhibition of the VEGF signaling pathway is clinically approved for the treatment of several cancers. Therapies targeting VEGF can modulate the tumor vasculature and the immune response. In this review, we discuss the roles of VEGF in the anti-tumor immune response. In addition, we summarize therapeutic strategies based on its inhibition, and their clinical approval.
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http://dx.doi.org/10.3390/ijms22094871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124522PMC
May 2021

Targeting BRAF and RAS in Colorectal Cancer.

Cancers (Basel) 2021 May 3;13(9). Epub 2021 May 3.

University of Burgundy-Franche Comté, Maison de l'université Esplanade Erasme, 21000 Dijon, France.

Colorectal cancer (CRC) is still one of the most frequent forms of cancer in the world in terms of incidence. Around 40% of CRC patients carry a mutation of the Kirsten rat sarcoma (KRAS) gene, while 10% have a mutation in the B-Raf proto-oncogene serine/threonine kinase (BRAF) gene. These mutations are responsible for dysregulation of the mitogen-associated protein kinase (MAPK) pathway, leading to the proliferation, differentiation, angiogenesis, and resistance to apoptosis of cells. Activation of the MAPK pathway results in adaptive therapeutic resistance, rendering EGFR inhibitors ineffective. This review aims to highlight the recent findings that have improved our understanding of KRAS and BRAF mutations in colorectal cancer and to describe new targeted therapies, used alone or in combination.
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http://dx.doi.org/10.3390/cancers13092201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124706PMC
May 2021

FOLFIRINOX-R study design: a phase I/II trial of FOLFIRINOX plus regorafenib as first line therapy in patients with unresectable RAS-mutated metastatic colorectal cancer.

BMC Cancer 2021 May 17;21(1):564. Epub 2021 May 17.

IRCM, Inserm, Université Montpellier, ICM, Montpellier, France.

Background: The chemotherapy triplet FOLFOXIRI combined to the anti-VEGF antibody bevacizumab is an option in selected patients with metastatic colorectal cancer. In this setting, RAS-mutated metastatic colorectal cancer do not benefit the same from treatment than RAS-wildtype metastatic colorectal cancer do. Together with its antiangiogenic properties, the tyrosine-kinase inhibitor regorafenib has also anti-proliferative activities whatever the RAS status is. The present trial aims at studying the safety and the efficacy of regorafenib in combination with FOLFIRINOX - a chemotherapy triplet using a different dosing schedule than FOLFOXIRI - in patients with RAS-mutated metastatic colorectal cancer.

Methods: FOLFIRINOX-R is a prospective, multicentric, non-randomised, dose-finding phase 1-2 trial. The primary endpoints are the determination of the maximum tolerated dose, the recommended phase 2 dose, and the proportion of patients achieving disease control at 48-weeks. Phase 1 follows a 3 + 3 design (12 to 24 patients to be included). Sixty nine patients will be necessary in phase 2, including 5% non-evaluable ones, with the following assumptions, one-stage Fleming design, α = 5%, β = 20%, p0 = 35% and p1 = 50%. Key eligibility criteria include Eastern Cooperative Oncology Group Performance Status of ≤1 and RAS-mutated metastatic colorectal cancer not amenable to surgery with curative intent and not previously treated for metastatic disease. FOLFIRINOX (oxaliplatin 85 mg/m, folinic acid 400 mg/m, irinotecan 150-180 mg/m, 5-fluorouracil: 400 mg/m then 2400 mg/m over 46 h) is administered every 14 days. Regorafenib (80 to 160 mg, as per dose-level) is administered orally, once daily on days 4 to 10 of each cycle.

Discussion: FOLFIRINOX-R is the first phase I/II study to evaluate the safety and efficacy of regorafenib in combination with FOLFIRINOX as frontline therapy for patients with RAS-mutated metastatic colorectal cancer.

Trial Registration: EudraCT: 2018-003541-42 ; ClinicalTrials.gov: NCT03828799 .
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http://dx.doi.org/10.1186/s12885-021-08312-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130420PMC
May 2021

Performance of Next Generation Sequencing for the Detection of Microsatellite Instability in Colorectal Cancer with Deficient DNA Mismatch Repair.

Gastroenterology 2021 May 13. Epub 2021 May 13.

Sorbonne Université, INSERM, Unité Mixte de Recherche Scientifique 938 and SIRIC CURAMUS, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012 Paris, France; Sorbonne Université, Genetics Department, AP-HP.Sorbonne Université, hospital Pitié-Salpêtrière, F-75012 Paris, France. Electronic address:

Background & Aims: Next generation sequencing (NGS) was recently approved by the FDA to detect microsatellite instability (MSI) arising from defective mismatch repair (dMMR) in patients with metastatic colorectal cancer (mCRC) prior to treatment with immune checkpoint inhibitors (ICI). In this study, we aimed to evaluate and improve the performance of NGS to identify MSI in CRC, especially dMMR mCRC treated with ICI.

Methods: CRC samples used in this post-hoc study were reassessed centrally for MSI and dMMR status using the reference methods of pentaplex PCR and immunohistochemistry (IHC). Whole exome (WES) was used to evaluate MSISensor, the FDA-approved and NGS-based method for assessment of MSI. This was performed in (i) a prospective, multicenter cohort (C1) of 102 mCRC patients (25 dMMR/MSI, 24 treated with ICI) from clinical trials NCT02840604 and NCT033501260, (ii) an independent retrospective, multicenter cohort of 113 patients (C2, 25 mCRC, 88 non-mCRC, all dMMR/MSI untreated with ICI), (iii) and a publicly available series of 118 CRC patients from the TCGA (C3, 51 dMMR/MSI). A new NGS-based algorithm, namely MSICare, was developed. Its performance for assessment of MSI was compared to MSISensor in C1, C2 and C3 at the exome-level or after downsampling sequencing data to the MSK-Impact gene panel. MSICare was validated in an additional retrospective, multicenter cohort (C4) of 152 new CRC patients (137 dMMR/MSI) enriched in MSH6 and PMS2 deficient tumors (35 dMSH6, 9 dPMS2) following targeted sequencing of samples with an optimized set of microsatellite markers (MSIDIAG).

Results: At the exome-level, MSISensor was highly specific but failed to diagnose MSI in 16% of MSI/dMMR mCRC from C1 (4/25; sensitivity 84%, 95%CI: 63.9%-95.5%), 32% of mCRC (8/25; sensitivity 68%, 95%CI: 46.5%-85.1%) and 9.1% of nmCRC from C2 (8/88; sensitivity 90.9%, 95%CI: 82.9%-96%), and 9.8% of CRC from C3 (5/51; sensitivity 90.2%, 95%CI: 78.6%-96.7%). Misdiagnosis included 4 mCRCs treated with ICI of which 3 showed an overall response rate without progression at this date. At the exome-level, reevaluation of the MSI genomic signal using MSICare detected 100% of cases with true MSI status amongst C1 and C2. Further validation of MSICare was obtained in CRC tumors from C3, with 96.1% concordance for MSI status. Whereas misdiagnosis with MSISensor even increased when analyzing downsampled WES data from C1 and C2 with microsatellite markers restricted to the MSK-Impact gene panel (sensitivity 72.5%, 95%CI: 64.2-79.7%), particularly in MSH6 deficient setting, MSICare sensitivity and specificity remained optimal (100%). Similar results were obtained with MSICare following targeted NGS of tumors from C4 with the optimized microsatellite panel MSIDIAG (sensitivity 99.3%, 95%CI: 96%-100%; specificity 100%).

Conclusions: In contrast to MSISensor, the new MSICare test we propose performs at least as efficiently as the reference method, MSI PCR, to detect MSI in CRC regardless of the defective MMR protein under both WES and targeted NGS conditions. We suggest MSICare may become rapidly a reference method for NGS-based testing of MSI in CRC, especially in mCRC where accurate MSI status is required before the prescription of ICI.
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http://dx.doi.org/10.1053/j.gastro.2021.05.007DOI Listing
May 2021

Intestinal microbiota influences clinical outcome and side effects of early breast cancer treatment.

Cell Death Differ 2021 May 7. Epub 2021 May 7.

Gustave Roussy Cancer Center, Villejuif, France.

The prognosis of early breast cancer (BC) relies on cell autonomous and immune parameters. The impact of the intestinal microbiome on clinical outcome has not yet been evaluated. Shotgun metagenomics was used to determine the composition of the fecal microbiota in 121 specimens from 76 early BC patients, 45 of whom were paired before and after chemotherapy. These patients were enrolled in the CANTO prospective study designed to record the side effects associated with the clinical management of BC. We analyzed associations between baseline or post-chemotherapy fecal microbiota and plasma metabolomics with BC prognosis, as well as with therapy-induced side effects. We examined the clinical relevance of these findings in immunocompetent mice colonized with BC patient microbiota that were subsequently challenged with histo-compatible mouse BC and chemotherapy. We conclude that specific gut commensals that are overabundant in BC patients compared with healthy individuals negatively impact BC prognosis, are modulated by chemotherapy, and may influence weight gain and neurological side effects of BC therapies. These findings obtained in adjuvant and neoadjuvant settings warrant prospective validation.
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http://dx.doi.org/10.1038/s41418-021-00784-1DOI Listing
May 2021

Using Exome Sequencing to Improve Prediction of FOLFIRINOX First Efficacy for Pancreatic Adenocarcinoma.

Cancers (Basel) 2021 Apr 13;13(8). Epub 2021 Apr 13.

Platform of Transfer in Biological Oncology, Georges François Leclerc Cancer Center-Unicancer, 1 rue du Professeur Marion, 21000 Dijon, France.

Purpose: The first line treatment of advanced pancreatic ductal adenocarcinoma cancer (PDAC) comprises a FOLFIRINOX regimen for most patients with good performance status. However, no biomarker to predict efficacy is currently available. We investigated whether exome sequencing could be used to predict progression-free and overall survival in patients undergoing FOLFIRINOX for PDAC.

Methods: In this single-center observational study, we included 78 patients with advanced PDAC who underwent somatic and germline exome analyses during first line therapy with FOLFIRINOX or gemcitabine. Exome-derived variables associated with outcome were then used in Cox regression models to generate a composite biomarker.

Results: Performance status, tumor stage, liver metastasis, and lung metastasis were retained to generate a prognostic clinical score associated with overall and progression-free survival. Clonality, ploidy, and copy number variant (CNV) signatures 1 and 5, as well as gene variants in the calcium, non-homologous end-joining (NHEJ), and spliceosome pathways, were retained to generate a genomic prognostic score. The addition of genomic score improved the prediction of prognosis compared to the clinical score alone.

Conclusions: This study underlines that structural and pathway genomic features could be used to predict FOLFIRINOX survival in patients with advanced PDAC.
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http://dx.doi.org/10.3390/cancers13081851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070262PMC
April 2021

Hype and hope of hepatic arterial infusion for colorectal cancer.

Hepatobiliary Surg Nutr 2021 Apr;10(2):235-237

Centre de Recherche INSERM LNC-UMR1231, Dijon, France.

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http://dx.doi.org/10.21037/hbsn-20-756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050592PMC
April 2021

Development of a novel highly anti-proliferative family of gold complexes: Au(i)-phosphonium-phosphines.

Dalton Trans 2021 Apr 22;50(14):4880-4889. Epub 2021 Mar 22.

ICMUB UMR6302, CNRS, Univ. Bourgogne Franche-Comté, F-21000 Dijon, France.

A family of gold(i)-phosphonium-phosphine complexes was synthesized thanks to an efficient 5-step strategy, which involves a phospha-Fries rearrangement. It enables the facile variation of the phosphonium moiety. All the complexes along with a synthetic intermediate were fully characterized (a crystal structure was obtained for two of them). The antiproliferative properties of the six novel complexes were evaluated on three human cancer cell lines (A549, MDA-MB-231, and SW480) and compared to those of three benchmark anticancer drugs used in clinics (oxaliplatin, 5-fluorouracil, and paclitaxel) and to a phosphonium-free gold(i) complex [Au(PPh)Br]. All the gold(i) complexes, containing a phosphonium, displayed strong anti-proliferative properties. They were more efficient than oxaliplatin and 5-fluorouracil, and one of the complexes was even more efficient than paclitaxel.
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http://dx.doi.org/10.1039/d0dt03708gDOI Listing
April 2021

Seroprevalence of SARS-CoV-2 among the staff and patients of a French cancer centre after first lockdown: The canSEROcov study.

Eur J Cancer 2021 05 27;148:359-370. Epub 2021 Feb 27.

Methodology and Biostatistics Unit, Centre Georges François Leclerc, Dijon, France.

Background: In view of the potential gravity of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection for patients with cancer, epidemiological data are vital to assess virus circulation among patients and staff of cancer centres. We performed a prospective study to investigate seroprevalence of SARS-CoV-2 antibodies among staff and patients with cancer at a large cancer centre, at the end of the period of first national lockdown in France and to determine factors associated with the risk of SARS-CoV-2 infection.

Methods: After the first lockdown, all medical and non-medical staff, as well as all patients attending the medical oncology department were invited to undergo serological testing for SARS-CoV-2 between 11 May and 30 June 2020. All participants were also invited to complete a questionnaire collecting data about their living and working conditions, and for patients, medical management during lockdown.

Findings: A total of 1,674 subjects (663 staff members, 1011 patients) were included. Seroprevalence was low in both staff (1.8%) and patients (1.7%), despite more features of high risk for severe forms among patients. None of the risk factors tested in our analysis (working or living conditions, comorbidities, management characteristics during lockdown) was found to be statistically associated with seroprevalence in either staff or patients. There was no significant difference in the proportion of symptomatic and asymptomatic subjects between staff and patients. Only fever, loss of smell, and loss of taste were significantly more frequent among seropositive patients, in both staff and patients.

Interpretation: We report very low seroprevalence of antibodies against SARS-CoV-2 in the staff (caregiving and non-caregiving) and patients of a large cancer care centre in which strict hygiene, personal protection, and social distancing measures were implemented.
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http://dx.doi.org/10.1016/j.ejca.2021.02.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914029PMC
May 2021

Percutaneous Implantation of a Microcatheter-Port System for Hepatic Arterial Infusion Chemotherapy of Unresectable Liver Tumors: Technical Feasibility, Functionality, and Complications.

Diagnostics (Basel) 2021 Feb 26;11(3). Epub 2021 Feb 26.

Department of Vascular and Interventional Radiology, Image-Guided Therapy Center, François-Mitterrand University Hospital, 14 Rue Paul Gaffarel, BP 77908, 21079 Dijon, France.

To evaluate the feasibility and safety of percutaneously implanted arterial port catheter systems for hepatic arterial infusion of chemotherapy (HAI) in patients with unresectable liver malignancies. From October 2010 to August 2018, arterial port catheters for HAI were percutaneously implanted in 43 patients with unresectable liver malignancies. Three different catheter placement techniques were compared: a conventional end-hole catheter placed in the common hepatic artery (technique 1, = 16), a side-hole catheter with the tip fixed in the gastroduodenal artery (technique 2, = 18), and a long-tapered side-hole catheter with the tip inserted distally in a segmental hepatic artery (technique 3, = 6). Catheter implantation was successful in 40 (93%) of the 43 patients. Complications related to catheter placement were observed in 10 (23%) patients; 5 (83%) of the 6 major complications were resolved, as well as all 4 minor complications. Catheter migration and occlusion occurred in 9 (22.5%) patients. Catheter migration was more frequent with technique 1 ( = 6) than with technique 2 ( = 1), although the difference was not significant ( = 0.066). Percutaneous arterial port catheter implantation for HAI is highly feasible and carries a low risk of complications.
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http://dx.doi.org/10.3390/diagnostics11030399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996956PMC
February 2021

Transarterial Radioembolization of Hepatocellular Carcinoma, Liver-Dominant Hepatic Colorectal Cancer Metastases, and Cholangiocarcinoma Using Yttrium90 Microspheres: Eight-Year Single-Center Real-Life Experience.

Diagnostics (Basel) 2021 Jan 14;11(1). Epub 2021 Jan 14.

Department of Vascular and Interventional Radiology, Image-Guided Therapy Center, François-Mitterrand University Hospital, 14 Rue Paul Gaffarel, BP 77908, 21079 Dijon, France.

Liver tumors are common and may be unamenable to surgery or ablative treatments. Consequently, other treatments have been devised. To assess the safety and efficacy of transarterial radioembolization (TARE) with Yttrium-90 for hepatocellular carcinoma (HCC), liver-dominant hepatic colorectal cancer metastases (mCRC), and cholangiocarcinoma (CCA), performed according to current recommendations, we conducted a single-center retrospective study in 70 patients treated with TARE (HCC, = 44; mCRC, = 20; CCA, = 6). Safety and toxicity were assessed using the National Cancer Institute Common Terminology Criteria. Treatment response was evaluated every 3 months on imaging studies using Response Evaluation Criteria in Solid Tumors (RECIST) or mRECIST criteria. Overall survival and progression-free survival were estimated using the Kaplan-Meier method. The median delivered dose was 1.6 GBq, with SIR-Spheres or TheraSphere microspheres. TARE-related grade 3 adverse events affected 17.1% of patients. Median follow-up was 32.1 months. Median progression-free survival was 5.6 months and median overall time from TARE to death was 16.1 months and was significantly shorter in men. Progression-free survival was significantly longer in women (HR, 0.49; 95%CI, 0.26-0.90; = 0.031). Risk of death or progression increased with the number of systemic chemotherapy lines. TARE can be safe and effective in patients with intermediate- or advanced-stage HCC, CCA, or mCRC refractory or intolerant to appropriate treatments.
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http://dx.doi.org/10.3390/diagnostics11010122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828820PMC
January 2021

The Tumor Microenvironment Impairs Th1 IFNγ Secretion through Alternative Splicing Modifications of Pre-mRNA.

Cancer Immunol Res 2021 Mar 8;9(3):324-336. Epub 2021 Jan 8.

CRI INSERM UMR1231 "Lipids, Nutrition and Cancer," Team "CAdIR," Dijon, Burgundy, France.

It is clearly established that the immune system can affect cancer response to therapy. However, the influence of the tumor microenvironment (TME) on immune cells is not completely understood. In this respect, alternative splicing is increasingly described to affect the immune system. Here, we showed that the TME, via a TGFβ-dependent mechanism, increased alternative splicing events and induced the expression of an alternative isoform of the IRF1 transcription factor (IRF1Δ7) in Th1 cells. We found that the SFPQ splicing factor (splicing factor, proline- and glutamine-rich) was responsible for the IRF1Δ7 production. We also showed, in both mice and humans, that the IRF1 alternative isoform altered the full-length IRF1 transcriptional activity on the promoter, resulting in decreased IFNγ secretion in Th1 cells. Thus, the IRF1Δ7 isoform was increased in the TME, and inhibiting IRF1Δ7 expression could potentiate Th1 antitumor responses.
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http://dx.doi.org/10.1158/2326-6066.CIR-19-0679DOI Listing
March 2021

Immunodynamics of explanted human tumors for immuno-oncology.

EMBO Mol Med 2021 Jan 29;13(1):e12850. Epub 2020 Dec 29.

Institut Gustave Roussy, Villejuif, France.

Decision making in immuno-oncology is pivotal to adapt therapy to the tumor microenvironment (TME) of the patient among the numerous options of monoclonal antibodies or small molecules. Predicting the best combinatorial regimen remains an unmet medical need. Here, we report a multiplex functional and dynamic immuno-assay based on the capacity of the TME to respond to ex vivo stimulation with twelve immunomodulators including immune checkpoint inhibitors (ICI) in 43 human primary tumors. This "in sitro" (in situ/in vitro) assay has the potential to predict unresponsiveness to anti-PD-1 mAbs, and to detect the most appropriate and personalized combinatorial regimen. Prospective clinical trials are awaited to validate this in sitro assay.
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http://dx.doi.org/10.15252/emmm.202012850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799366PMC
January 2021

Pooled analysis of 115 patients from updated data of Epitopes-HPV01 and Epitopes-HPV02 studies in first-line advanced anal squamous cell carcinoma.

Ther Adv Med Oncol 2020 4;12:1758835920975356. Epub 2020 Dec 4.

Centre Hospitalier Universitaire de Besançon, Besançon, France.

Aims: The addition of docetaxel to cisplatin and 5-fluorouracil (DCF) has shown promising efficacy in advanced squamous cell carcinoma of the anus (SCCA). Preliminary results of Epitopes-HPV01 study showed a high rate of long-lasting complete response to DCF. The prospective, multicenter, Epitopes-HPV02 trial then confirmed the high efficacy of the modified DCF (mDCF) regimen in terms of complete response rate and long-term survival in metastatic or non-resectable locally advanced recurrent SCCA. Here, we present updated results of the Epitopes-HPV01 and Epitopes-HPV02 studies.

Patients & Methods: Epitopes-HPV01 is a prospective study performed by the regional cancer network of Franche-Comté, France. Epitopes-HPV02 is a phase II study supported by two French collaborative oncological groups, performed in 25 centers. Both studies included patients with metastatic, or with unresectable local recurrent SCCA, treated with DCF regimen.

Results: In Epitopes-HPV01, 51 patients were enrolled between September 2012 and January 2019, and 49 patients were included for analysis; while 69 patients were included between September 2014 and December 2016 in Epitopes-HPV02, and 66 patients for analysis. Pooled analysis of 115 patients showed a median progression-free survival of 12.2 months [95% confidence interval (CI) 10.6-16.1] [11.0 months (9.3-16.0) in -HPV02, and 15.6 months (11.2-34.5) in -HPV01, ( = 0.06)]. The median overall survival was 39.2 months (26.0-109.1) [36.3 in -HPV02 (25.2-NR), and 61.1 months (21.4-120.0) in -HPV01 ( = 0.62)]. Objective response rate was 87.7% (90.9% in -HPV02 and 83.3% in -HPV01) with 40.3% of complete response (45.5% in -HPV02 and 33.3% in -HPV01). No differences were observed between standard DCF ( = 54) and mDCF ( = 58) in terms of OS ( = 0.57) and PFS ( = 0.99). 5-years PFS and OS rates were 24.5% and 44.4%, respectively, in the whole population. No treatment-related death was observed.

Conclusion: Updated results of Epitopes-HPV01 and 02 studies, as well as the pooled analysis, confirm mDCF as a standard treatment in patients with advanced SCCA.
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http://dx.doi.org/10.1177/1758835920975356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720302PMC
December 2020

Can the hyperthermia-mediated heat shock factor/heat shock protein 70 pathway dampen the cytokine storm during SARS-CoV-2 infection?

Br J Pharmacol 2020 Dec 11. Epub 2020 Dec 11.

INSERM LNC UMR1231, University of Bourgogne Franche-Comté, Centre Georges François Leclerc, Dijon, France.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major global public health problem. Infection by this virus involves many pathophysiological processes, such as a "cytokine storm," that is, very aggressive inflammatory response that offers new perspectives for the management and treatment of patients. Here, we analyse relevant mechanism involved in the hyperthermia-mediated heat shock factors (HSFs)/heat shock proteins (HSP)70 pathway which may provide a possible treatment tool.
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http://dx.doi.org/10.1111/bph.15343DOI Listing
December 2020

Ileal immune tonus is a prognosis marker of proximal colon cancer in mice and patients.

Cell Death Differ 2021 May 1;28(5):1532-1547. Epub 2020 Dec 1.

Gustave Roussy Cancer Campus (GRCC), Villejuif, France.

Ileal epithelial cell apoptosis and the local microbiota modulate the effects of oxaliplatin against proximal colon cancer by modulating tumor immunosurveillance. Here, we identified an ileal immune profile associated with the prognosis of colon cancer and responses to chemotherapy. The whole immune ileal transcriptome was upregulated in poor-prognosis patients with proximal colon cancer, while the colonic immunity of healthy and neoplastic areas was downregulated (except for the Th17 fingerprint) in such patients. Similar observations were made across experimental models of implanted and spontaneous murine colon cancer, showing a relationship between carcinogenesis and ileal inflammation. Conversely, oxaliplatin-based chemotherapy could restore a favorable, attenuated ileal immune fingerprint in responders. These results suggest that chemotherapy inversely shapes the immune profile of the ileum-tumor axis, influencing clinical outcome.
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http://dx.doi.org/10.1038/s41418-020-00684-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167112PMC
May 2021

Understanding Inflammasomes and PD-1/PD-L1 Crosstalk to Improve Cancer Treatment Efficiency.

Cancers (Basel) 2020 Nov 27;12(12). Epub 2020 Nov 27.

Platform of Transfer in Cancer Biology, Centre Georges François Leclerc, INSERM LNC UMR1231, University of Bourgogne Franche-Comté, F-21000 Dijon, France.

Inflammasomes and immune checkpoints have been shown to participate in carcinogenesis, cancer growth and response to treatment. Thus, targeting cytokines resulting from inflammasome activation, such as interleukin (IL)-1β, has emerged as a new tool in the therapeutic arsenal. Moreover, the use of checkpoint inhibitors such as anti-PD-1 or anti-PD-L1 has revolutionized the treatment of some cancer patients. However, inflammasome activation and consecutive cytokine release only occurs in some chemotherapeutic treatments and immune checkpoint inhibitors only work for a restricted number of patients, thus limiting the use of therapies targeting these pathways. Expanding knowledge about the inefficiency of these therapies recently brought forward the hypothesis of targeting both pathways. In this review, we provide an overview of the crosstalk between inflammasomes and programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) that might explain how these two pathways are mutually dependent, and perhaps why targeting only one of them leads to inefficiency of cancer treatment in some patients.
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http://dx.doi.org/10.3390/cancers12123550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761387PMC
November 2020

Influence of primary tumor location and resection on survival in metastatic colorectal cancer.

World J Gastrointest Oncol 2020 Nov;12(11):1296-1310

Department of Medical Oncology, Centre Georges-François Leclerc, Dijon 21000, France.

Background: Patients with right sided colorectal cancer are known to have a poorer prognosis than patients with left sided colorectal cancer, whatever the cancer stage. To this day, primary tumor resection (PTR) is still controversial in a metastatic, non resectable setting.

Aim: To explore the survival impact of PTR in patients with metastatic colorectal cancer (mCRC) depending on PTL.

Methods: We retrospectively collected data from all consecutive patients treated for mCRC at the Centre Georges Francois Leclerc Hospital. Univariate and multivariate Cox proportional hazard regression models were used to assess the influence of PTR on survival. We then evaluated the association between PTL and overall survival among patients who previously underwent or did not undergo PTR. A propensity score was performed to match cohorts.

Results: Four hundred and sixty-six patients were included. A total of 153 (32.8%) patients had unresected synchronous mCRC and 313 (67.2%) patients had resected synchronous mCRC. The number of patients with right colic cancer, left colic cancer and rectal cancer was respectively 174 (37.3%), 203 (43.6%) and 89 (19.1%). In the multivariate analysis only PTL, PTR, resection of hepatic and or pulmonary metastases and the use of oxaliplatin, EGFR inhibitors or bevacizumab throughout treatment were associated to higher overall survival rates. Survival evaluation depending on PTR and PTL found that PTR improved the prognosis of both left and right sided mCRC. Results were confirmed by using a weighted propensity score.

Conclusion: In mCRC, PTR seems to confer a higher survival rate to patients whatever the PTL.
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http://dx.doi.org/10.4251/wjgo.v12.i11.1296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667454PMC
November 2020

Association of 5-FU Therapeutic Drug Monitoring to DPD Phenotype Assessment May Reduce 5-FU Under-Exposure.

Pharmaceuticals (Basel) 2020 Nov 23;13(11). Epub 2020 Nov 23.

Centre Georges-François Leclerc, 21000 Dijon, France.

In order to limit 5-fluorouracil (5-FU) toxicity, some health agencies recommend evaluating dihydropyrimidine dehydrogenase (DPD) deficiency before any 5-FU treatment introduction. In our study, we investigated relationships between 5-FU clearance and markers of DPD activity such as uracilemia (U), dihydrouracilemia (UH)/U ratio, or genotype of the gene encoding DPD (). All patients with gastrointestinal cancers who received 5-FU-based regimens form March 2018 to June 2020 were included in our study. They routinely benefited of a pre-therapeutic genotyping and phenotyping. During 5-FU infusion, blood samples were collected to measure 5-FU steady-state concentration in order to adapt 5-FU doses at the following cycles. A total of 169 patients were included. Median age was 68 (40-88) years and main primary tumor sites were colorectal (40.8%) and pancreas (31.4%), metastatic in 76.3%. 5-FU was given as part of FOLFIRINOX (44.4%), simplified FOLFOX-6 (26.6%), or docetaxel/FOLFOX-4 (10.6%). Regarding DPD activity, median U and UH/U were, respectively, 10.8 ng/mL and 10.1, and almost 15% harbored a heterozygous mutation. On the range of measured U and UH/U, no correlation was observed with 5-FU clearance. Moreover, in patients with U < 16 ng/mL, 5-FU exposure was higher than in other patients, and most of them benefited of dose increase following 5-FU therapeutic drug monitoring (TDM). If recent guidelines recommend decreasing 5-FU dose in patients harboring U ≥ 16 ng/mL, our study highlights that those patients are at risk of under-exposure and that 5-FU TDM should be conducted in order to avoid loss of efficacy.
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http://dx.doi.org/10.3390/ph13110416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700344PMC
November 2020

Angiotensin-converting enzyme (ACE) inhibitor prescription affects non-small-cell lung cancer (NSCLC) patients response to PD-1/PD-L1 immune checkpoint blockers.

Oncoimmunology 2020 10 27;9(1):1836766. Epub 2020 Oct 27.

Department of Medical Oncology, GF Leclerc Centre, Dijon, France.

Angiotensin-converting enzyme (ACE) inhibitors are frequently used to treat hypertension and congestive heart failure. Preclinical data show that ACE plays a role on both innate and adaptive immune responses. Since interactions between ACE inhibitors and immune checkpoint inhibitors (ICIs) have not been reported, the aim of this study is to investigate the influence of ACE inhibitors on non-small cell lung cancer (NSCLC) patients treated with programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitors. We conducted a retrospective cohort analysis of NSCLC patients treated with PD-1/PD-L1 inhibitors. Clinical and co-medication data as well as tumor biopsies were collected. Groups were defined according to patients' co-medications at the time of ICI initiation. Among the 178 patients included, 22 (13.1%) received ACE inhibitors. While baseline characteristics were similar in both groups, ACE inhibitors group had a shorter median PFS (Progression-Free Survival) compared to the control group: 1.97 vs. 2.56 months, = .01 (HR = 1.8 CI95% 1.1-2.8). Using CIBERSORT, RNA sequencing suggested that tumors from the ACE inhibitors group had less M1 macrophages, activated mast cells, NK cells and memory activated T cells, thus suggesting an immunosuppressed state. , the ACE inhibitor, captopril, induced M2 marker at the cell surface of monocytes engaged into M1 differentiation. Thus, ACE inhibitors prescription concomitant to PD-1/PD-L1 inhibitors treatment seems to be associated with impaired outcome and with a tumor immunosuppressed state in patients with advanced NSCLC. These results should be validated in larger prospective cohorts.
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http://dx.doi.org/10.1080/2162402X.2020.1836766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595630PMC
October 2020

Immunological features of coronavirus disease 2019 in patients with cancer.

Eur J Cancer 2020 11 7;139:70-80. Epub 2020 Sep 7.

Cancer Biology Transfer Platform, Centre Georges-François Leclerc, F-21000, Dijon, France; Centre de Recherche INSERM LNC-UMR1231, F-21000, Dijon, France; Department of Medical Oncology, Centre Georges-François Leclerc, F-21000, Dijon, France; University of Burgundy Franche-Comté, F-21000, Dijon, France; Genetic and Immunology Medical Institute, Dijon, France. Electronic address:

Background: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, has caused a major pandemic. Patients with cancer are at higher risk of severe COVID-19. We aimed to describe and compare the immunological features of cancer patients hospitalised for COVID-19 or other concomitant, cancer-related illness.

Methods: In this prospective study, the clinical and immunological characteristics of 11 cancer patients with COVID-19 and 11 non-COVID-19 cancer patients hospitalised in the same unit at the same period for other medical issues were analysed. We also used 10 healthy volunteers as controls. Peripheral immune parameters were analysed using multiparametric flow cytometry.

Results: The median age of COVID-19-positive cancer patients was 71.1 years, and 66.4 years for controls. Compared with non-COVID-19 cancer patients, COVID-19-positive cancer patients had more extensive lymphopenia and hypoalbuminemia, with higher levels of C-reactive protein. In COVID-19 patients, elevated procalcitonin was associated with a higher risk of death. By phenotypic analysis, COVID-19-positive patients presented CD3 lymphopenia, with inversion of the CD4/CD8 ratio and modification of monocyte activation, with accumulation of mMDSC (monocytic Myeloid-Derived Suppressor Cells) -like cells and a decrease in activated monocytes. Analysis of the T-cell compartment revealed a T-dependent inflammatory response with accumulation of Th17 cells and cytotoxic CD8 T cells producing TNFα, a decrease in HLA-DR (Human Leukocyte Antigen - DR isotype)-positive CD8 T cells and Treg/CD8 ratio.

Conclusion: SARS-CoV-2 infection in cancer patients is associated with CD4 T-cell lymphopenia with induction of an inflammatory T-cell response, accumulation of IFNγ TNFα CD8 T and Th17 cells, and a concomitant modification of monocyte activation status.
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http://dx.doi.org/10.1016/j.ejca.2020.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476569PMC
November 2020

Immunogenic Cell Death and Elimination of Immunosuppressive Cells: A Double-Edged Sword of Chemotherapy.

Cancers (Basel) 2020 Sep 16;12(9). Epub 2020 Sep 16.

Department of Medical Oncology, Center GF Leclerc, 21000 Dijon, France.

Chemotherapy is initially used to kill proliferative cells. In the current area of emerging immunotherapy, chemotherapies have shown their ability to modulate the tumor micro environment and immune response. We focus here on two main effects: first, immunogenic cell death, defined as a form of regulated cell death (RCD) that is sufficient to activate an adaptive immune response in immunocompetent hosts; and second, the depletion of suppressive cells, known to play a major role in immune escape and resistance to immunotherapy. In this review, we present a review of different classically used chemotherapies focusing on this double effect on immunity. These immunological effects of chemotherapy could be exploited to promote efficacy of immunotherapy. Broadening our understanding will make it possible to provide rationales for the combination of chemoimmunotherapy in early clinical trials.
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http://dx.doi.org/10.3390/cancers12092637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565832PMC
September 2020

Radiotherapy Scheme Effect on PD-L1 Expression for Locally Advanced Rectal Cancer.

Cells 2020 09 10;9(9). Epub 2020 Sep 10.

Department of Radiation Oncology, Unicancer-Georges-Francois Leclerc Cancer Center, 21079 Dijon, France.

In locally advanced rectal cancer, radiotherapy (RT) followed by surgery have improved locoregional control, but distant recurrences remain frequent. Although checkpoint inhibitors have demonstrated objective response in several cancers, the clinical benefit of PD-1/PD-L1 blockade remains uncertain in rectal cancer. We collected data from biopsies and surgical specimens in 74 patients. The main objective was to evaluate the impact of neoadjuvant RT and fractionation on PD-L1 expression. Secondary objectives were to study the relation between PD-L1 expression and tumor regression grade (TRG), progression-free survival (PFS), overall survival (OS), and CD8 TILs infiltration. Median rates of cells expressing PD-L1 pre- and post-RT were 0.15 (range, 0-17) and 0.5 (range, 0-27.5), respectively ( = 0.0005). There was no effect of RT fractionation on PD-L1+ cell rates. We found no relation between CD8+ TILs infiltration and PD-L1 expression and no difference between high-PD-L1 or low-PD-L1 expression and TRG. High-to-high PD-L1 expression profile had none significant higher OS and PFS compared to all other groups ( = 0.06). Median OS and PFS were higher in biopsies with >0.08 PD-L1+ cells. High-to-high PD-L1 profile and ypT0-2 were significantly associated with higher OS and PFS. This study did not show the differential induction of PD-L1 expression according to fractionation.
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http://dx.doi.org/10.3390/cells9092071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563314PMC
September 2020

Tumor Infiltrating Lymphocytes Signature as a New Pan-Cancer Predictive Biomarker of Anti PD-1/PD-L1 Efficacy.

Cancers (Basel) 2020 Aug 26;12(9). Epub 2020 Aug 26.

Cancer Biology Transfer Platform, Georges-François Leclerc Cancer Center, 1 rue du Professeur Marion, F-21000 Dijon, France.

Tumor immune infiltrates are associated with tumor prognosis in many cancer types. However, their capacity to predict the efficacy of checkpoint inhibitors is poorly documented. We generate three signatures that evaluate in different ways these infiltrates: lymphoid- and myeloid-alone signatures, and a combined signature of both named the TIL (tumor-infiltrating lymphocyte) transcriptomic signature. We evaluate these signatures in The Cancer Genome Atlas Program (TCGA) Pan-Cancer cohort and four cohorts comprising patients with melanoma, lung, and head and neck cancer treated with anti-PD-1 or anti-CTLA-4 therapies. We observe using TCGA Pan-Cancer cohort that this TIL or lymphoid-alone signature accurately estimates prognosis in most cancer types and outperforms histological TIL evaluation or myeloid signature alone. Both TIL and lymphoid signatures are correlated with response rate to immunotherapy. Combining lymphoid signature or TIL with tumor mutational burden generates a score that is highly efficient in predicting response to immunotherapy. In different series of patients treated with checkpoint inhibitors for non-small cell lung cancer, head and neck cancer, and melanoma, we observed that TIL or lymphoid signature were associated with outcome. These data demonstrate that a simple TIL or lymphoid signature could be used as a Pan-Cancer prognostic and predictive biomarker to estimate patient survival under checkpoint inhibitors.
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http://dx.doi.org/10.3390/cancers12092418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564481PMC
August 2020

Cross-reactivity between tumor MHC class I-restricted antigens and an enterococcal bacteriophage.

Science 2020 08;369(6506):936-942

Department of Physics of Complex Systems, ELTE Eötvös Loránd University, Budapest, Hungary.

Intestinal microbiota have been proposed to induce commensal-specific memory T cells that cross-react with tumor-associated antigens. We identified major histocompatibility complex (MHC) class I-binding epitopes in the tail length tape measure protein (TMP) of a prophage found in the genome of the bacteriophage Mice bearing harboring this prophage mounted a TMP-specific H-2K-restricted CD8 T lymphocyte response upon immunotherapy with cyclophosphamide or anti-PD-1 antibodies. Administration of bacterial strains engineered to express the TMP epitope improved immunotherapy in mice. In renal and lung cancer patients, the presence of the enterococcal prophage in stools and expression of a TMP-cross-reactive antigen by tumors correlated with long-term benefit of PD-1 blockade therapy. In melanoma patients, T cell clones recognizing naturally processed cancer antigens that are cross-reactive with microbial peptides were detected.
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http://dx.doi.org/10.1126/science.aax0701DOI Listing
August 2020

Precision medicine phase II study evaluating the efficacy of a double immunotherapy by durvalumab and tremelimumab combined with olaparib in patients with solid cancers and carriers of homologous recombination repair genes mutation in response or stable after olaparib treatment.

BMC Cancer 2020 Aug 10;20(1):748. Epub 2020 Aug 10.

Department of Medical Oncology, Center GF Leclerc, 1 rue du Professeur Marion, 21000, Dijon, France.

Background: Tumors with deficient homologous repair are sensitive to PARP inhibitors such as olaparib which is known to have immunogenic properties. Durvalumab (D) is a human monoclonal antibody (mAb) which inhibits binding of programmed cell death ligand 1 (PD-L1) to its receptor. Tremelimumab (T) is a mAb directed against the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). This study is designed to evaluate the efficacy of combination of olaparib, durvalumab and tremelimumab in patients with a solid tumors with a mutation in homologous gene repair.

Methods: This phase II study will assess the efficacy and safety of olaparib/D/T association in patients (n = 213) with several types of solid cancers (breast cancer, ovarian cancer, pancreatic cancer, endometrial cancer, prostate cancer and others) with at least one mutation in homologous repair genes (BRCA1, BRCA2, PALB2, ATM, FANCA, FANCB, FANCC, FANCE, FANCF, CHEK2, RAD51, BARD1, MRE11, RAD50, NBS1, HDAC2), LKB1/STK11, INPP4B, STAG2, ERG, CHEK1, BLM, LIG4, ATR, ATRX, CDK12). Good performance status patients and corresponding to specific inclusion criteria of each cohort will be eligible. STEP1: Patients will receive olaparib 300 mg BID. In absence of progression after 6 weeks of olaparib, they will follow STEP 2 with olaparib and immunotherapy by durvalumab (1500 mg Q4W) + tremelimumab (75 mg IV Q4W) during 4 months and will further pursue durvalumab alone until disease progression, death, intolerable toxicity, or patient/investigator decision to stop (for a maximum duration of 24 months, and 36 months for ovarian cohort). Primary endpoint is safety and efficacy according to progression-free survival (PFS) of olaparib + immunotherapy (durvalumab + tremelimumab) during 4 months followed by durvalumab alone as maintenance in patients with solid cancers and in response or stable, after prior molecular target therapy by olaparib; secondary endpoints include overall survival (OS), disease control rate (DCR), response rate after 6 weeks of olaparib, safety of olaparib/durvalumab/tremelimumab association. Blood, plasma and tumor tissue will be collected for potential prognostic and predictive biomarkers.

Discussion: This study is the first trial to test the combination of olaparib and double immunotherapy based on molecular screening.

Trial Registration: NCT04169841 , date of registration November 20, 2019.
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http://dx.doi.org/10.1186/s12885-020-07253-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418426PMC
August 2020

Interleukin-1β and Cancer.

Cancers (Basel) 2020 Jul 4;12(7). Epub 2020 Jul 4.

Platform of Transfer in Cancer Biology, Centre Georges François Leclerc, INSERM LNC UMR1231, University of Bourgogne Franche-Comté, F-21000 Dijon, France.

Within a tumor, IL-1β is produced and secreted by various cell types, such as immune cells, fibroblasts, or cancer cells. The IL1B gene is induced after "priming" of the cells and a second signal is required to allow IL-1β maturation by inflammasome-activated caspase-1. IL-1β is then released and leads to transcription of target genes through its ligation with IL-1R1 on target cells. IL-1β expression and maturation are guided by gene polymorphisms and by the cellular context. In cancer, IL-1β has pleiotropic effects on immune cells, angiogenesis, cancer cell proliferation, migration, and metastasis. Moreover, anti-cancer treatments are able to promote IL-1β production by cancer or immune cells, with opposite effects on cancer progression. This raises the question of whether or not to use IL-1β inhibitors in cancer treatment.
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http://dx.doi.org/10.3390/cancers12071791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408158PMC
July 2020