Cancer immunotherapy has been described as "The Breakthrough of 2013", switching cancer treatment from targeting the tumor to targeting the immune system.
The blockade of immune checkpoints with antibodies (Ab) anti-CTLA-4, anti-PD1 and anti-PD-L1, has given impressive clinical results and manageable toxicity profiles.
Checkpoint inhibitors were first shown as being therapeutically efficient in metastatic melanoma, renal cell carcinoma and lung cancer where they obtained the first marketing authorizations. The number of cancers responding to these therapies has continued to increase (breast, ovary, ENT and pediatric).
In addition, researchers and doctors are exploring numerous avenues to better understand resistance mechanisms to these new therapies and optimize them according to the genetic, immunological and tumor profiles of the different patients.
Main Research Programs
Immunotherapy studies based on the analysis of human tumor-draining lymph nodes (LNs).
We are performing a holistic comparison of the immune profile of invaded versus non-invaded LNs. Our aim is to identify immunomodulatory mechanisms associated to the presence of the invading tumor in the LNs, and to discover biomarkers that could guide the design of patient-tailored immune therapies.
Techniques: phenotypic and functional analysis of tumor, fibroblasts, B and T, DCs and NK cells by multi-parametric flow cytometry, ELISPOT, LUMINEX, RNAseq.
We have established national and international collaborations with groups expert in each of the subpopulation studied. We have created a lymph node collection for research purposes.
Particular emphasis was placed on the study of tumor neoepitopes identified by comparing the tumor transcriptome and the exome of neuroblastoma and breast cancer patients. A prediction of mutated tumor neoepitopes can be presented on the surface of class I and II histocompatibility molecules (MHC-I and MHC-II) will be performed using algorithms available in the public domain. The synthesis of corresponding peptides will allow us to look for the presence of lymphocytes T CD8+ or CD4+, which are specific to these tumoral neoepitopes, in the blood, tumor infiltrate or the lymph nodes draining the patient tumor. The existence of this kind of tumor-specific lymphocyte and the evaluation of their activation level permit us to envisage the use of personalized anti-cancer vaccines
Translation of IL-2/antI-IL-2 Ab complexes immunotherapy to the clinics
The FDA has already approved high-dose IL-2 therapy for metastatic melanoma and renal carcinoma treatment.
However, high-dose of IL-2 administration is highly toxic and has low efficacy. In this project, we want to use IL-2/anti-IL-2 antibodies targeting CD8 and NK cells as a monotherapy or in association with other immunotherapies in different tumor mouse models with the objective of developing this in the clinic.
Study immunotherapies in optimized in vivo models for cancer
To improve our understanding of anti-checkpoint action mechanisms and to construct mouse models which can predict the clinical response we are developing humanized mouse models. These immunodeficient mice are reconstituted with human immune cells and can be transplanted with tumors from the patients called xenografts.
This is a collaborative project with the Laboratory of Preclinical Investigation, LIP.
The final aim is improving the therapeutic index of immunotherapies and defining rationalized drug combinations with immune checkpoints and proprietary molecules developed by collaborators, including novel immunomodulatory approaches generated at our unit.
Also, using this model we are evaluating the role of microbiota on the response to anti-PD-1 Ab treatment.
Eliane Piaggio, PhD, DR2 INSERM, Director
Delphine Loirat, MD, PhD, Medical Oncologist
- Christine Sedlik, PhD, IR, IC
- Julie Helft, PhD, Researcher
- Nicolas Nunez, PhD, Post-doc
- Laeticia Niborski, PhD, Post-doc
- Rodrigo Ramos, PhD, Post-doc
- Pamela Caudana, Doctorant
- Philippe De La Rochère, Doctorant
- Sophie Viel, AI, INSERM
- Anais Pinto, IE
- Marine Dubois, IE
- Wilfrid Richer, Bioinformatician
- Loss of immune tolerance to IL-2 in type 1 diabetes. Louis Pérol, John M. Lindner , Pamela Caudana, Nicolas Nunez, Audrey Baeyens, Andrea Valle, Christine Sedlik, Delphine Loirat, Olivier Boyer, Alain Créange, José Laurent Cohen, Ute Christine Rogner, Jun Yamanouchi, Martine Marchant, Xavier Charles Leber, Meike Scharenberg, Marie-Claude Gagnerault, Roberto Mallone, Manuela Battaglia, Pere Santamaria, Agnès Hartemann, Elisabetta Traggiai, Eliane Piaggio. Nat Commun. 2016 Oct 6;7:13027.
- Heparan sulfates targeting increases MHC class I- and MHC class II-restricted antigen presentation and CD8+ T-cell response. Knittel D, Gadzinski A, Hua S, Denizeau J, Savatier A, de la Rochère P, Boulain JC, Amigorena S, Piaggio E, Sedlik C, Léonetti M. Vaccine. 2016 May 4. pii: S0264-410X(16)30238-9.
- Regulatory T cells delay disease progression in Alzheimer-like pathology Cira Dansokho, Dylla Ait Ahmed, Saba Aid, Cécile Toly-Ndour, Thomas Chaigneau, Vanessa Calle, Nicolas Cagnard, Martin Holzenberger, Eliane Piaggio, Pierre Aucouturier, Guillaume Dorothée. Brain. 2016 Apr. 139(Pt 4):1237-51.
- Effective anti-tumor therapy based on a novel antibody drug-conjugate targeting the Tn carbohydrate antigen. Christine Sedlik, Adèle Heitzmann, Sophie Viel, Rafik Ait Sarkouh, Cornélie Batisse, Frédéric Schmidt, Philippe De La Rochere, Nathalie Amzallag, Eduardo Osinaga, Pablo Oppezzo, Otto Pritsch, Xavier Sastre-Garau, Pascale Hubert, Sebastian Amigorena and Eliane Piaggio. Oncoimmunology. 2016 Apr 22;5(7):e1171434.
- New Molecular and Cellular Mechanisms of Tolerance: Tolerogenic Actions of IL-2. Pérol L, Piaggio E. Methods Mol Biol. 2016;1371:11-28.
- Inhibition of the JAK/STAT Signaling Pathway in Regulatory T Cells Reveals a Very Dynamic Regulation of Foxp3 Expression. Goldstein JD, Burlion A, Zaragoza B, Sendeyo K, Polansky JK, Huehn J, Piaggio E, Salomon BL, Marodon G. PLoS One. 2016 Apr 14;11(4):e0153682.
- Effector T Cells Boost Regulatory T Cell Expansion by IL-2, TNF, OX40, and Plasmacytoid Dendritic Cells Depending on the Immune Context. Baeyens A, Saadoun D, Billiard F, Rouers A, Grégoire S, Zaragoza B, Grinberg-Bleyer Y, Marodon G, Piaggio E, Salomon BL. J Immunol. 2015 Mar 1;194(5):2117-27.
- Heterogeneous CD3 Expression Levels in Differing T Cell Subsets Correlate with the In Vivo Anti-CD3–Mediated T Cell Modulation. Andrea Valle, Giulia Barbagiovanni,Tatiana Jofra, Angela Stabilini, Louis Perol, Audrey Baeyens, Santosh Anand, Nicolas Cagnard, Nicola Gagliani, Eliane Piaggio, and Manuela Battaglia. J Immunol. 2015 Mar 1;194(5):2117-27.
- Immunoendocrine dysbalance during uncontrolled T. cruzi infection is associated with the acquisition of a Th-1-like phenotype by Foxp3+ T cells. González FB, Villar SR, Fernández Bussy R, Martin GH, Pérol L, Manarin R, Spinelli SV, Pilon C, Cohen JL, Bottasso OA, Piaggio E*, Pérez AR*. (*: co-senior authors). Brain Behav Immun. 2015 Mar;45:219-32.
- Potential limitations of IL-2 administration for the treatment of experimental acute graft-versus-host disease. Perol L., Martin G., Maury S., Cohen JL, Piaggio E. Immunology letters. 2014 Dec;162(2 Pt B):173-84.
- Different immunogenicity but similar antitumor efficacy of two DNA vaccines coding for an antigen secreted in different membrane vesicle-associated forms. Sedlik C, Vigneron J, Torrieri-Dramard L, Pitoiset F, Denizeau J, Chesneau C, de la Rochere P, Lantz O, Thery C, Bellier B. J Extracell Vesicles. J Extracell Vesicles. 2014 Aug 27;3.
- Limitations of IL-2 and rapamycin in immunotherapy of type 1 diabetes. Baeyens A, Pérol L, Fourcade G, Cagnard N, Carpentier W, Woytschak J, Boyman O, Hartemann A, Piaggio E. Diabetes. 2013 Sep;62(9):3120-31.
- Role of cytokines in thymus- versus peripherally derived- regulatory T cell differentiation and function. Jérémie D. Goldstein, Louis Pérol, Bruno Zaragoza, Audrey Baeyens, Gilles Marodon and Eliane Piaggio. Front Immunol. 2013 Jun 19;4:155.
- Immune reconstitution is preserved in hematopoietic stem cell transplant co-administered with regulatory T cells for GVHD prevention. Aline Gaidot, Dan Avi Landau, Gaëlle Hélène Martin, Olivia Bonduelle, Yenkel Grinberg-Bleyer, Diana Matheoud, Sylvie Grégoire, Claude Baillou, Béhazine Combadière, Eliane Piaggio*, José Laurent Cohen*. (*: co-senior authors). Blood. 2011 Mar 10;117(10):2975-83.
- IL-2 reverses established type 1 diabetes in NOD mice by a local effect on pancreatic regulatory T cells. Grinberg-Bleyer Y, Baeyens A, You S, Elhage R, Fourcade G, Gregoire S, Cagnard N, Carpentier W, Tang Q, Bluestone J, Chatenoud L, Klatzmann D, Salomon BL, Piaggio E. J Exp Med. 2010 Aug 30;207(9):1871-8.
- Pathogenic T cells have a paradoxical protective effect in murine autoimmune diabetes by boosting Tregs. Grinberg-Bleyer Y, Saadoun D, Baeyens A, Billiard F, Goldstein JD, Grégoire S, Martin GH, Elhage R, Derian N, Carpentier W, Marodon G, Klatzmann D, Piaggio E*, Salomon BL*. J Clin Invest. 2010 Dec 1;120(12):4558-68. (*: co-senior authors).