Translational Immunotherapy

Publications

Year of publication 2014

Louis Pérol, Gaëlle H Martin, Sébastien Maury, José L Cohen, Eliane Piaggio (2014 Sep 17)

Potential limitations of IL-2 administration for the treatment of experimental acute graft-versus-host disease.

Immunology letters : 173-84 : DOI : 10.1016/j.imlet.2014.10.027 Learn more
Summary

Low-dose IL-2 administration can control autoimmunity by specifically activating CD4(+) Foxp3(+) regulatory T cells (Tregs). Here, we studied IL-2-based immunotherapy in experimental graft-versus-host disease (GVHD). IL-2 administration to donor mice induced a dose-dependent expansion of Tregs in the graft but was insufficient to control GVHD. IL-2 administration to allogeneic-grafted recipient mice activated T-conventional cells (Tcons) and did not prevent GVHD. This loss of IL-2 selectivity toward Tregs was explained by an IL-2-induced increase in the IL-2 receptor α-chain expression on Tcons. Finally, in xeno-GVHD generated by human PBMCs transplanted into immunodeficient mice, low-dose IL-2 increased Treg frequencies but did neither control pro-inflammatory cytokine production by pathogenic Tcons, nor prevented GVHD. Furthermore, combination of low-dose IL-2 with rapamycin was ineffective in this model. Our results indicate that limitations on the use of IL-2 during acute GVHD are likely due to the massive activation of the allogeneic T cells unique to this setting.

Fold up
Guillaume Churlaud, Veronica Jimenez, Jesus Ruberte, Martin Amadoudji Zin, Gwladys Fourcade, Gaelle Gottrand, Estefania Casana, Benedicte Lambrecht, Bertrand Bellier, Eliane Piaggio, Fatima Bosch, David Klatzmann (2014 Mar 1)

Sustained stimulation and expansion of Tregs by IL2 control autoimmunity without impairing immune responses to infection, vaccination and cancer.

Clinical immunology (Orlando, Fla.) : 114-26 : DOI : 10.1016/j.clim.2014.02.003 Learn more
Summary

Interleukin 2 (IL2) is the key cytokine supporting survival and function of regulatory T cells (Tregs). We recently reported that low-dose IL2 safely expands/stimulates Tregs and improves autoimmune conditions in humans. Further development of IL2 in autoimmune diseases will require chronic IL2 administration, which could affect beneficial effector immune responses regulated by Tregs. We used recombinant adeno-associated viral vector (rAAV)-mediated gene transfer to continuously release IL2 in mice and assessed its long-term effects on immune responses. A single rAAV-IL2 injection enabled sustained stimulation and expansion of Tregs without inducing Teff activation and prevented diabetes in NOD mice. After several weeks of IL2 production, mice responded normally to a viral challenge and to vaccination, and had pregnancies with offspring that developed normally. They showed no change in the occurrence and growth of chemically-induced tumors. Altogether, chronic low-dose IL2 treatment does not affect beneficial effector immune responses at doses that prevent autoimmune diabetes.

Fold up

Year of publication 2013

Lydie Wintz, Alran Séverine, Fabien Reyal (2013 Jul 25)

[Interactive information tools for women facing a mastectomy].

Soins; la revue de référence infirmière : 37-40 Learn more
Summary

Around 20 to 30% of women treated for breast cancer undergo a mastectomy in France. Of these patients, 70% do not have reconstructive surgery. It would seem that information surrounding reconstructive procedures is insufficient. Tools created in partnership with caregivers and patients are necessary to help women understand the choices they have.

Fold up
François-Clément Bidard, Lisa Belin, Suzette Delaloge, Florence Lerebours, Charlotte Ngo, Fabien Reyal, Séverine Alran, Sylvie Giacchetti, Michel Marty, Ronald Lebofsky, Jean-Yves Pierga (2013 Jun 14)

Time-Dependent Prognostic Impact of Circulating Tumor Cells Detection in Non-Metastatic Breast Cancer: 70-Month Analysis of the REMAGUS02 Study.

International journal of breast cancer : 130470 : DOI : 10.1155/2013/130470 Learn more
Summary

Introduction. In non-metastatic breast cancer patients, the REMAGUS02 neoadjuvant study was the first to report a significant impact of circulating tumor cells (CTCs) detection by the CellSearch system on the distant metastasis-free survival (DMFS) and overall survival (OS) endpoints. However, these results were only reported after a short follow-up. Here, we present the updated data, with a longer follow-up. Material and Methods. CTC count was performed before and after neoadjuvant chemotherapy in 118 patients and correlated to survival. Results. CTC count results were available before and/or after neoadjuvant chemotherapy in 115 patients. After a median follow-up of 70 months, detection of ≥1 CTC/7.5 mL before chemotherapy (N = 95) was significantly associated with DMFS (P = 0.04) and OS (P = 0.03), whereas postchemotherapy CTC detection (N = 85) had no significant impact. In multivariable analysis, prechemotherapy CTC and triple negative phenotype were the two independent prognostic factors for survival. We observed that the CTC impact is most significant during the first three years of follow-up. Discussion. We confirm that the detection of CTC is independently associated with a significantly worse outcome, but mainly during the first 3-4 years of follow-up. No prognostic impact is seen in patients who are still relapse-free at this moment.

Fold up
Audrey Baeyens, Louis Pérol, Gwladys Fourcade, Nicolas Cagnard, Wassila Carpentier, Janine Woytschak, Onur Boyman, Agnès Hartemann, Eliane Piaggio (2013 May 13)

Limitations of IL-2 and rapamycin in immunotherapy of type 1 diabetes.

Diabetes : 3120-31 : DOI : 10.2337/db13-0214 Learn more
Summary

Administration of low-dose interleukin-2 (IL-2) alone or combined with rapamycin (RAPA) prevents hyperglycemia in NOD mice. Also, low-dose IL-2 cures recent-onset type 1 diabetes (T1D) in NOD mice, partially by boosting pancreatic regulatory T cells (Treg cells). These approaches are currently being evaluated in humans. Our objective was to study the effect of higher IL-2 doses (250,000-500,000 IU daily) as well as low-dose IL-2 (25,000 IU daily) and RAPA (1 mg/kg daily) (RAPA/IL-2) combination. We show that, despite further boosting of Treg cells, high doses of IL-2 rapidly precipitated T1D in prediabetic female and male mice and increased myeloid cells in the pancreas. Also, we observed that RAPA counteracted IL-2 effects on Treg cells, failed to control IL-2-boosted NK cells, and broke IL-2-induced tolerance in a reversible way. Notably, the RAPA/IL-2 combination failure to cure T1D was associated with an unexpected deleterious effect on glucose homeostasis at multiple levels, including β-cell division, glucose tolerance, and liver glucose metabolism. Our data help to understand the therapeutic limitations of IL-2 alone or RAPA/IL-2 combination and could lead to the design of improved therapies for T1D.

Fold up
Peter Mallon, Jean-Guillaume Feron, Benoit Couturaud, Alfred Fitoussi, Perig Lemasurier, Thierry Guihard, Isabelle Cothier-Savay, Fabien Reyal (2013 May 1)

The role of nipple-sparing mastectomy in breast cancer: a comprehensive review of the literature.

Plastic and reconstructive surgery : 969-84 : DOI : 10.1097/PRS.0b013e3182865a3c Learn more
Summary

The role of nipple-sparing mastectomy for breast cancer is controversial, as there is concern regarding its oncologic safety and complication rate. The authors reviewed the literature to quantify the incidence of occult nipple malignancy in breast cancer, identify the factors influencing occult nipple malignancy, quantify locoregional recurrence rates, and quantify nipple-sparing mastectomy complication rates.

Fold up
Fabien Reyal, Jean-Guillaume Feron, Solene Leman Detour, Anne Gaelle Pourcelot, Morgane Valentin, Anne-Cecile Phillippe, Yaelle Levy-Zauberman, Antoine Agman, Sindy Monier, Anne Blondel, Isabelle Cothier-Savey, Thierry Guihard, Perig Le Masurier, Alfred Fitoussi, Benoit Couturaud (2013 Apr 2)

The impact of poly implant prothèse fraud on breast cancer patients: a report by the institut curie.

Plastic and reconstructive surgery : 690-5 : DOI : 10.1097/PRS.0b013e3182827605 Learn more
Summary

In March of 2010, French authorities suspended the use of breast implants made by the company Poly Implant Prothèse. Institut Curie is a large cancer center, and Poly Implant Prothèse was one major silicone-filled breast implant brand used. This report describes the impact of the fraudulent implants worldwide and more specifically on patient care at the authors’ unit. From 2002 to 2009, the median number of Poly Implant Prothèse implants removed per year was 32. Since the first alert in March of 2010, 252 of these breast implants were removed in 2010 and 2011. The breast implants removed were mainly reported as normal, with a rupture rate of less than 5 percent before 2008. However, the annual rupture rate has increased from 2008 to 2011 (8, 14, 20, and 23 percent, respectively). The Institut Curie, in conjunction with breast cancer patients, has organized a management plan to deal with this major industrial fraud. Its surveillance program of breast cancer patients facilitated the management of patients during this difficult time.

Fold up
Fabien Reyal, David Hajage, Alexia Savignoni, Jean-Guillaume Feron, Marc Andrew Bollet, Youlia Kirova, Alain Fourquet, Jean-Yves Pierga, Paul Cottu, Veronique Dieras, Virginie Fourchotte, Fatima Laki, Severine Alran, Bernard Asselain, Anne Vincent-Salomon, Brigitte Sigal-Zafrani, Xavier Sastre-Garau (2013 Mar 26)

Long-term prognostic performance of Ki67 rate in early stage, pT1-pT2, pN0, invasive breast carcinoma.

PloS one : e55901 : DOI : 10.1371/journal.pone.0055901 Learn more
Summary

Molecular signatures may become of use in clinical practice to assess the prognosis of breast cancers. However, although international consensus conferences sustain the use of these new markers in the near future, concerns remain about their degree of discordance and cost-effectiveness in different international settings. The present study aims to validate Ki67 as prognostic factor in a large cohort of early-stage (pT1-pT2, pN0) breast cancer patients.

Fold up

Year of publication 2012

Fabien Reyal, Catherine Belichard, Roman Rouzier, Emmanuel de Gournay, Claire Senechal, Francois-Clement Bidard, Jean-Yves Pierga, Paul Cottu, Florence Lerebours, Youlia Kirova, Jean-Guillaume Feron, Virginie Fourchotte, Anne Vincent-Salomon, Jean-Marc Guinebretiere, Brigitte Sigal-Zafrani, Xavier Sastre-Garau, Yann De Rycke, Charles Coutant (2012 Oct 12)

Non-sentinel lymph node metastasis prediction in breast cancer with metastatic sentinel lymph node: impact of molecular subtypes classification.

PloS one : e47390 : DOI : 10.1371/journal.pone.0047390 Learn more
Summary

To decipher the interaction between the molecular subtype classification and the probability of a non-sentinel node metastasis in breast cancer patients with a metastatic sentinel lymph-node, we applied two validated predictors (Tenon Score and MSKCC Nomogram) on two large independent datasets.

Fold up
Virginie Marchand, Antoine Angelergues, Vanessa Gobaux, David Hajage, Youlia M Kirova, François Campana, Rémi Dendale, Fabien Reyal, Jean-Yves Pierga, Alain Fourquet, Marc A Bollet (2012 Jun 19)

Prospective and comparative evaluation of the toxicity of adjuvant concurrent chemoradiotherapy after neoadjuvant chemotherapy for breast cancer.

American journal of clinical oncology : 425-9 : DOI : 10.1097/COC.0b013e31825466a6 Learn more
Summary

The lack of pathologic breast cancer response to neoadjuvant chemotherapy (NCT), a negative prognostic factor, has prompted the addition of chemotherapy to adjuvant radiotherapy. This study aims to investigate prospectively the toxicities of adjuvant concurrent chemoradiotherapy versus radiotherapy alone.

Fold up
Carole Massabeau, Nathalie Fournier-Bidoz, Georges Wakil, Pablo Castro Pena, Romain Viard, Sofia Zefkili, Fabien Reyal, François Campana, Alain Fourquet, Youlia M Kirova (2012 Apr 27)

Implant breast reconstruction followed by radiotherapy: can helical tomotherapy become a standard irradiation treatment?

Medical dosimetry : official journal of the American Association of Medical Dosimetrists : 425-31 : DOI : 10.1016/j.meddos.2012.03.006 Learn more
Summary

To evaluate the benefits and limitations of helical tomotherapy (HT) for loco-regional irradiation of patients after a mastectomy and immediate implant-based reconstruction. Ten breast cancer patients with retropectoral implants were randomly selected for this comparative study. Planning target volumes (PTVs) 1 (the volume between the skin and the implant, plus margin) and 2 (supraclavicular, infraclavicular, and internal mammary nodes, plus margin) were 50 Gy in 25 fractions using a standard technique and HT. The extracted dosimetric data were compared using a 2-tailed Wilcoxon matched-pair signed-rank test. Doses for PTV1 and PTV2 were significantly higher with HT (V95 of 98.91 and 97.91%, respectively) compared with the standard technique (77.46 and 72.91%, respectively). Similarly, the indexes of homogeneity were significantly greater with HT (p = 0.002). HT reduced ipsilateral lung volume that received ≥20 Gy (16.7 vs. 35%), and bilateral lungs (p = 0.01) and neighboring organs received doses that remained well below tolerance levels. The heart volume, which received 25 Gy, was negligible with both techniques. HT can achieve full target coverage while decreasing high doses to the heart and ipsilateral lung. However, the low doses to normal tissue volumes need to be reduced in future studies.

Fold up
Fabien Reyal, Marc A Bollet, Martial Caly, David Gentien, Sabrina Carpentier, Hélène Peyro-Saint-Paul, Jean-Yves Pierga, Paul Cottu, Véronique Dieras, Brigitte Sigal-Zafrani, Anne Vincent-Salomon, Xavier Sastre-Garau (2012 Apr 25)

Respective prognostic value of genomic grade and histological proliferation markers in early stage (pN0) breast carcinoma.

PloS one : e35184 : DOI : 10.1371/journal.pone.0035184 Learn more
Summary

Genomic grade (GG) is a 97-gene signature which improves the accuracy and prognostic value of histological grade (HG) in invasive breast carcinoma. Since most of the genes included in the GG are involved in cell proliferation, we performed a retrospective study to compare the prognostic value of GG, Mitotic Index and Ki67 score.

Fold up

Year of publication 2011

David Hajage, Yann de Rycke, Marc Bollet, Alexia Savignoni, Martial Caly, Jean-Yves Pierga, Hugo M Horlings, Marc J Van de Vijver, Anne Vincent-Salomon, Brigitte Sigal-Zafrani, Claire Senechal, Bernard Asselain, Xavier Sastre, Fabien Reyal (2011 Nov 17)

External validation of Adjuvant! Online breast cancer prognosis tool. Prioritising recommendations for improvement.

PloS one : e27446 : DOI : 10.1371/journal.pone.0027446 Learn more
Summary

Adjuvant! Online is a web-based application designed to provide 10 years survival probability of patients with breast cancer. Several predictors have not been assessed in the original Adjuvant! Online study. We provide the validation of Adjuvant! Online algorithm on two breast cancer datasets, and we determined whether the accuracy of Adjuvant! Online is improved with other well-known prognostic factors.

Fold up
Marc A Bollet, Lisa Belin, Fabien Reyal, François Campana, Rémi Dendale, Youlia M Kirova, Fabienne Thibault, Véronique Diéras, Brigitte Sigal-Zafrani, Alain Fourquet (2011 Sep 13)

Preoperative radio-chemotherapy in early breast cancer patients: long-term results of a phase II trial.

Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology : 82-8 : DOI : 10.1016/j.radonc.2011.08.017 Learn more
Summary

This phase II trial aimed to investigate the efficacy of concurrent radio- (RT) and chemotherapy (CT) in the preoperative setting for operable, non-metastatic breast cancer (BC) not amenable to initial breast-conserving surgery (BCS).

Fold up
Fabien Reyal, Roman Rouzier, Berenice Depont-Hazelzet, Marc A Bollet, Jean-Yves Pierga, Severine Alran, Remy J Salmon, Virginie Fourchotte, Anne Vincent-Salomon, Xavier Sastre-Garau, Martine Antoine, Serge Uzan, Brigitte Sigal-Zafrani, Yann De Rycke (2011 Jun 10)

The molecular subtype classification is a determinant of sentinel node positivity in early breast carcinoma.

PloS one : e20297 : DOI : 10.1371/journal.pone.0020297 Learn more
Summary

Several authors have underscored a strong relation between the molecular subtypes and the axillary status of breast cancer patients. The aim of our work was to decipher the interaction between this classification and the probability of a positive sentinel node biopsy.

Fold up