Institute Of Cancerologie Gustave Roussy Cancer Campus Grcc

Villejuif, France

Institute Of Cancerologie Gustave Roussy Cancer Campus Grcc

Villejuif, France
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Fend L.,Transgene S.A. | Fend L.,Institute Of Cancerologie Gustave Roussy Cancer Campus Grcc | Yamazaki T.,Institute Of Cancerologie Gustave Roussy Cancer Campus Grcc | Yamazaki T.,French Institute of Health and Medical Research | And 22 more authors.
Cancer Research | Year: 2017

Athough the clinical efficacy of oncolytic viruses has been demonstrated for local treatment, the ability to induce immune-mediated regression of distant metastases is still poorly documented. We report here that the engineered oncolytic vaccinia virus VVWR-TK-RR--Fcu1 can induce immunogenic cell death and generate a systemic immune response. Effects on tumor growth and survival was largely driven by CD8+ T cells, and immune cell infiltrate in the tumor could be reprogrammed toward a higher ratio of effector T cells to regulatory CD4+ T cells. The key role of type 1 IFN pathway in oncolytic virotherapy was also highlighted, as we observed a strong abscopal response in Ifnar-/- tumors. In this model, single administration of virus directly into the tumors on one flank led to regression in the contralateral flank. Moreover, these effects were further enhanced when oncolytic treatment was combined with immunogenic chemotherapy or with immune checkpoint blockade. Taken together, our results suggest how to safely improve the efficacy of local oncolytic virotherapy in patients whose tumors are characterized by dysregulated IFNa signaling. © 2017 American Association for Cancer Research.


Zitvogel L.,Institute Of Cancerologie Gustave Roussy Cancer Campus Grcc | Zitvogel L.,French Institute of Health and Medical Research | Zitvogel L.,University of Paris Saclay | Daillere R.,Institute Of Cancerologie Gustave Roussy Cancer Campus Grcc | And 12 more authors.
Nature Reviews Microbiology | Year: 2017

The human gut microbiome modulates many host processes, including metabolism, inflammation, and immune and cellular responses. It is becoming increasingly apparent that the microbiome can also influence the development of cancer. In preclinical models, the host response to cancer treatment has been improved by modulating the gut microbiome; this is known to have an altered composition in many diseases, including cancer. In addition, cancer treatment with microbial agents or their products has the potential to shrink tumours. However, the microbiome could also negatively influence cancer prognosis through the production of potentially oncogenic toxins and metabolites by bacteria. Thus, future antineoplastic treatments could combine the modulation of the microbiome and its products with immunotherapeutics and more conventional approaches that directly target malignant cells. © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.


Vetizou M.,Institute Of Cancerologie Gustave Roussy Cancer Campus Grcc | Vetizou M.,French Institute of Health and Medical Research | Vetizou M.,University Paris - Sud | Pitt J.M.,Institute Of Cancerologie Gustave Roussy Cancer Campus Grcc | And 65 more authors.
Science | Year: 2015

Antibodies targeting CTLA-4 have been successfully used as cancer immunotherapy. We find that the antitumor effects of CTLA-4 blockade depend on distinct Bacteroides species. In mice and patients,Tcell responses specific for B. thetaiotaomicron or B. fragilis were associated with the efficacy of CTLA-4 blockade. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA blockade. This defect was overcome by gavage with B. fragilis, by immunization with B. fragilis polysaccharides, or by adoptive transfer of B. fragilis-specific T cells. Fecal microbial transplantation from humans to mice confirmed that treatment of melanoma patients with antibodies against CTLA-4 favored the outgrowth of B. fragilis with anticancer properties. This study reveals a key role for Bacteroidales in the immunostimulatory effects of CTLA-4 blockade.


Semeraro M.,Institute Of Cancerologie Gustave Roussy Cancer Campus Grcc | Semeraro M.,French Institute of Health and Medical Research | Semeraro M.,University Paris - Sud | Rusakiewicz S.,Institute Of Cancerologie Gustave Roussy Cancer Campus Grcc | And 47 more authors.
Science Translational Medicine | Year: 2015

The immunosurveillance mechanisms governing high-risk neuroblastoma (HR-NB), a major pediatric malignancy, have been elusive. We identify a potential role for natural killer (NK) cells, in particular the interaction between the NK receptor NKp30 and its ligand, B7-H6, in the metastatic progression and survival of HR-NB after myeloablative multimodal chemotherapy and stem cell transplantation. NB cells expressing the NKp30 ligand B7-H6 stimulated NK cells in an NKp30-dependent manner. Serum concentration of soluble B7-H6 correlated with the down-regulation of NKp30, bone marrow metastases, and chemoresistance, and soluble B7-H6 contained in the serum of HR-NB patients inhibited NK cell functions in vitro. The expression of distinct NKp30 isoforms affecting the polarization of NK cell functions correlated with 10-year event-free survival in three independent cohorts of HR-NB in remission from metastases after induction chemotherapy (n = 196, P < 0.001), adding prognostic value to known risk factors such as N-Myc amplification and age >18 months. We conclude that the interaction between NKp30 and B7-H6 may contribute to the fate of NB patients and that both the expression of NKp30 isoforms on circulating NK cells and the concentration of soluble B7-H6 in the serum may be clinically useful as biomarkers for risk stratification.


Semeraro M.,Institute Of Cancerologie Gustave Roussy Cancer Campus Grcc | Semeraro M.,French Institute of Health and Medical Research | Semeraro M.,University Paris - Sud | Rusakiewicz S.,Institute Of Cancerologie Gustave Roussy Cancer Campus Grcc | And 10 more authors.
OncoImmunology | Year: 2015

Until recently, the pathophysiological impact of natural killer (NK) lymphocytes has been largely elusive. Capitalizing on our previous discovery that NK cells mediate immunosurveillance against gastrointestinal stromal tumors (GISTs), we have now investigated the potential influence of immunostimulatory and immunosuppressive isoforms of the NK receptor NKp30 on the fate of infants with neuroblastoma. In three independent cohorts of high-risk neuroblastoma, we observed a similar prognostic impact of the ratio of immunostimulatory vs. immunosuppressive NKp30 isoforms. Patients with high-risk neuroblastoma that are in remission after induction chemotherapy have a higher risk of relapse if their circulating and bone marrow NK cells express the preponderantly immunosuppressive NKp30 C isoform, as determined by a robust RT-PCR-based assay. We also found that neuroblastoma cells express the NKp30 ligand B7-H6, which can be shed from the tumor cells. Elevated soluble B7-H6 levels contained in patient sera inhibited NK functions in vitro and correlated with downregulation of NK-p30 on NK cells, as well as with bone marrow metastasis and chemoresistance. Altogether, these results support the contention that NK cells play a decisive role in the immunosurveillance of neuroblastoma. In light of these results, efforts should be undertaken to investigate NK cell functions in all major cancer types, with the obvious expectation of identifying additional NK cell-related prognostic or predictive biomarkers and improving NK cell based immunotherapeutic strategies against cancer. © 2015, Taylor & Francis Group, LLC.


Pitt J.M.,Institute Of Cancerologie Gustave Roussy Cancer Campus Grcc | Pitt J.M.,French Institute of Health and Medical Research | Pitt J.M.,University Paris - Sud | Vetizou M.,Institute Of Cancerologie Gustave Roussy Cancer Campus Grcc | And 15 more authors.
Cancer Research | Year: 2016

The equilibrium linking the intestinal microbiota, the intestinal epithelium, and the host immune system establishes host health and homeostasis, with perturbations of this balance resulting in chronic inflammatory and autoimmune immunopathologies. The mutualistic symbiosis between gut microbiota and host immunity raises the possibility that dysbiosis of the intestinal content also influences the outcome of cancer immunotherapy. Here, we present our recent findings that specific gut-resident bacteria determine the immunotherapeutic responses associated with CTLA-4 checkpoint blockade. This new evidence hints that interindividual differences in the microbiome may account for the significant heterogeneity in therapeutic and immunopathologic responses to immune checkpoint therapies. We discuss how this new understanding could improve the therapeutic coverage of immune checkpoint inhibitors, and potentially limit their immune-mediated toxicity, through the use of adjunctive "oncomicrobiotics" that indirectly promote beneficial immune responses through optimizing the gut microbiome. Cancer Res; 76(16); 4602-7. © 2016 American Association for Cancer Research.


PubMed | New York University, University Paul Sabatier, Service de microbiologie, University Paris - Sud and 9 more.
Type: Journal Article | Journal: Science (New York, N.Y.) | Year: 2015

Antibodies targeting CTLA-4 have been successfully used as cancer immunotherapy. We find that the antitumor effects of CTLA-4 blockade depend on distinct Bacteroides species. In mice and patients, T cell responses specific for B. thetaiotaomicron or B. fragilis were associated with the efficacy of CTLA-4 blockade. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA blockade. This defect was overcome by gavage with B. fragilis, by immunization with B. fragilis polysaccharides, or by adoptive transfer of B. fragilis-specific T cells. Fecal microbial transplantation from humans to mice confirmed that treatment of melanoma patients with antibodies against CTLA-4 favored the outgrowth of B. fragilis with anticancer properties. This study reveals a key role for Bacteroidales in the immunostimulatory effects of CTLA-4 blockade.


PubMed | Monash University, Paris-Sorbonne University, University of Kiel, Institut Universitaire de France and 12 more.
Type: Journal Article | Journal: Immunity | Year: 2016

The efficacy of the anti-cancer immunomodulatory agent cyclophosphamide (CTX) relies on intestinal bacteria. How and which relevant bacterial species are involved in tumor immunosurveillance, and their mechanism of action are unclear. Here, we identified two bacterial species, Enterococcus hirae and Barnesiella intestinihominis that are involved during CTX therapy. Whereas E.hirae translocated from the small intestine to secondary lymphoid organs and increased the intratumoral CD8/Treg ratio, B.intestinihominis accumulated in the colon and promoted the infiltration of IFN--producing T cells in cancer lesions. The immune sensor, NOD2, limited CTX-induced cancer immunosurveillance and the bioactivity of these microbes. Finally, E.hirae and B.intestinihominis specific-memory Th1 cell immune responses selectively predicted longer progression-free survival in advanced lung and ovarian cancer patients treated with chemo-immunotherapy. Altogether, E.hirae and B.intestinihominis represent valuable oncomicrobiotics ameliorating the efficacy of the most common alkylating immunomodulatory compound.

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