In house or mutual R&D research programmes

AACR Atlanta 2019

Poster selection – Oncodesign

 

We are very proud to let you discover our latest breakthroughs & expertise through this series of 5 posters selected & presented during last AACR in Atlanta.

 

If you want to discuss with our experts, please fix a meeting now!

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1- Induction of immunogenic cell death and enhancement of dendritic cell function: Development of an in vitro, ex vivo ICD platform for the identification of novel ICD inducers

Authors: Akanksha Gangar, Didier Grillot, Raphaelle Guillard-Huet, Jean-François Mirjolet, Fabrice Viviani.
Oncodesign, Dijon, France

Immunological cell death (ICD) is a form of cancer cell death induced by radiotherapy, photodynamic therapy and a few chemotherapeutic agents such as Doxorubicin, Mitoxantrone, and Oxaliplatin.  Unlike apoptosis or necrosis, ICD can induce an effective immune response directed against the tumor whereby both dendritic cells and T lymphocytes are mediators of this response. Dying cancer cells recruit and activate immune cells by releasing damage-associated molecular patterns (DAMPS) that help and promote the immune response to antigenic tumor neo-epitopes. Three key DAMPS are associated with the ICD process: calreticulin exposition on the cell surface, ATP secretion and high-mobility group box 1 (HMGB1) release. 

Using our in-house developed screening strategy facilitated by an automated in vitro platform with four assays, we have identified and characterized six cell lines (human breast MDA-MB-436 and MDA-MB-231, human osteosarcoma U-2 OS, murine pancreas Pan02, murine colon CT26, murine liver Hepa 1-6) for the three key DAMPs and cell viability. Furthermore, the screening of Oncodesign’s Nanocyclix® library using the ICD bona fide cell lines described above resulted in the identification of ODS2006336, a potential in vitro ICD inducer.

As dendritic cells (DCs) play a key role in the recognition of DAMPs associated with ICD and the subsequent uptake and presentation of tumor antigens, we examined the phagocytosis of ICD inducer-treated tumor cells by DCs. ICD inducer-treated CT26 cells when cultured with spleen-derived DCs were efficiently phagocytosed by DCs. An increase in IL-1b  secretion in the co-culture supernatant was observed. IL-1b plays an important role in anti-tumor T cell priming. In addition, pro-inflammatory cytokines IL-6 and TNFa that promote T cell differentiation and NK cell activation were also detected. Increased secretion of IL-12 by activated DCs can also enhance NK cell functionality. Thus, ICD activates both innate and adaptive arms of the immune system. With respect to cancer immunotherapy, the ICD process elicits enhanced adjuvanticity and antigenicity from dying cancer cells and consequently, promotes the development of clinically desired antitumor immunity.

In essence, we describe a novel strategy for the identification of ICD inducers within large chemical libraries followed by a streamlined ex-vivo co-culture assay to demonstrate enhanced DC function.

AACR Poster Request Form

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Since you are a valuable customer or prospect, we want to make sure that you can choose to stay connected with Oncodesign. Oncodesign collectgs your data to provide you with information regarding our offering and news.
In accordance with the law "Informatique et Libertés", you can exercise your right of access to the data concerning you and have them rectified by contacting odsmarketing@oncodesign.com.
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Oncodesign is registered with CNIL under number 2102182.
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In accordance with the law "Informatique et Libertés", you can exercise your right of access to the data concerning you and have them rectified by contacting odsmarketing@oncodesign.com.
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Oncodesign is registered with CNIL under number 2102182.
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Since you are a valuable customer or prospect, we want to make sure that you can choose to stay connected with Oncodesign. Oncodesign collectgs your data to provide you with information regarding our offering and news.
In accordance with the law "Informatique et Libertés", you can exercise your right of access to the data concerning you and have them rectified by contacting odsmarketing@oncodesign.com.
Your Email address has not been and will not be given to third parties. 

Oncodesign is registered with CNIL under number 2102182.
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We care about your privacy.
Since you are a valuable customer or prospect, we want to make sure that you can choose to stay connected with Oncodesign. Oncodesign collectgs your data to provide you with information regarding our offering and news.
In accordance with the law "Informatique et Libertés", you can exercise your right of access to the data concerning you and have them rectified by contacting odsmarketing@oncodesign.com.
Your Email address has not been and will not be given to third parties. 

Oncodesign is registered with CNIL under number 2102182.
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your address is not a proper one. Please check.

We care about your privacy.
Since you are a valuable customer or prospect, we want to make sure that you can choose to stay connected with Oncodesign. Oncodesign collectgs your data to provide you with information regarding our offering and news.
In accordance with the law "Informatique et Libertés", you can exercise your right of access to the data concerning you and have them rectified by contacting odsmarketing@oncodesign.com.
Your Email address has not been and will not be given to third parties. 

Oncodesign is registered with CNIL under number 2102182.
Invalid Input

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your address is not a proper one. Please check.

Please send the following poster(s):

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We care about your privacy.
Since you are a valuable customer or prospect, we want to make sure that you can choose to stay connected with Oncodesign. Oncodesign collectgs your data to provide you with information regarding our offering and news.
In accordance with the law "Informatique et Libertés", you can exercise your right of access to the data concerning you and have them rectified by contacting odsmarketing@oncodesign.com.
Your Email address has not been and will not be given to third parties. 

Oncodesign is registered with CNIL under number 2102182.
Invalid Input

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your address is not a proper one. Please check.

We care about your privacy.
Since you are a valuable customer or prospect, we want to make sure that you can choose to stay connected with Oncodesign. Oncodesign collectgs your data to provide you with information regarding our offering and news.
In accordance with the law "Informatique et Libertés", you can exercise your right of access to the data concerning you and have them rectified by contacting odsmarketing@oncodesign.com.
Your Email address has not been and will not be given to third parties. 

Oncodesign is registered with CNIL under number 2102182.
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Invalid Input

your address is not a proper one. Please check.

Please send the following poster(s):

Invalid Input

We care about your privacy.
Since you are a valuable customer or prospect, we want to make sure that you can choose to stay connected with Oncodesign. Oncodesign collectgs your data to provide you with information regarding our offering and news.
In accordance with the law "Informatique et Libertés", you can exercise your right of access to the data concerning you and have them rectified by contacting odsmarketing@oncodesign.com.
Your Email address has not been and will not be given to third parties. 

Oncodesign is registered with CNIL under number 2102182.

2- Customized methodology to investigate immuno-oncology drugs using humanized mouse models

Authors: Jean-François Mirjolet, Josselin Caradec, Olivier Duchamp, Francis Bichat, Damien France, Caroline Mignard, Fabrice Viviani.

Oncodesign, Dijon, France

Immunotherapy is one of the most exiting recent breakthroughs in the field of cancer treatment. Different approaches are developed such as cancer vaccines, adoptive cellular immunotherapy or immune checkpoint blockade, and a number have been regulatory approved or are currently investigated in clinic.

Effective immunity against cancer involves complex interaction between the tumor, the host and the environment. The assessment of cancer immunotherapy approaches in preclinical settings requires the use of appropriate animal models that sufficiently reflect the physiological situation in humans and that must be chosen carefully to address specific mechanisms of action.

In light of evaluating the therapeutic potential of different immunomodulatory agents in mice xenografted with cancer cell lines or patient-derived xenografts, we developed multiple humanization strategies on different immuno-deficient mouse strains. Either human PBMCs, Hematopoietic Stem Cells (HSCs), or specific human immune cells such as Dendritic Cells (DCs), T cells, subset of T cells (e.g. gamma9 delta2 T cells) and NK cells were used, but also the combinations of immune subpopulations such as the co-transfer of autologous T cells and DCs.

We will highlight some results of our therapeutic efficacy investigation and evaluation of novel immuno-oncology therapies eg. adoptive cell therapy, bispecific T-cell engager antibody, and vaccine immunomodulatory agents in such humanized mouse models, assessing survival, tumor growth and effects on tumors and immune cells by flow cytometry and immunohistochemistry analyses.

All these different humanized models can permit to evidence significant antitumor efficacy of immunomodulatory agents in vivo and might help improve the success rate in clinical trials.

3- Biomarker identification using xenograft mouse model based clinical trial simulation and Artificial Intelligence data analytics

Authors: Afshar M1, Bichat F2, Duchamp O2, Etcheto A1,  France D2,  Kindermans M1, Mignard C2, Parmentier F1, Ratsima H2

1- Ariana Pharmaceuticals, Paris, France
2- Oncodesign, Dijon, France

The growing number of anti-cancer drugs available at different stages of clinical development combined with the broadening potential use of combination therapy further complexifies the early identification of companion markers, markers of synergy as well as novel indications for existing and new drug combinations. Well characterized patient derived xenograft mouse models (PDX), combined with Artificial Intelligence tools that can integrate and analyze the broad range of generated data can help address this challenge. PDX experiments can providing an opportunity to simulate a clinical assessment using multiple mice models.

In this study, we developed a PDX platform combined with the KEM® Artificial Intelligence data analytics, that is based on Formal Concept Analysis, to simulate a clinical trial and identify biomarkers of response. The platform was tested on colon cancer patient derived PDX.  Respectively mRECIST response and survival of respectively 21 and 26 PDXs against Oxalipaltin combined with 5-Fluorouracil and folinic acid (Folfox) was experimentally assessed against a placebo, simulating a clinical trial–like setting with 2 arms. Biomarkers of response (mRECIST) and survival were identified using KEM®, combined with statistical modelling (Cox survival-modelling).  24 candidate biomarker genes were identified including PGAP3, ERBB2, NOTCH2, WDR70, and ZNF227. Alone or combined, these biomarkers are significantly linked to an increase or decrease of the survival PDX (p ranging from 2.2e-10 to 0.048, odd-ratio ranging from 0.12 to 10.00), with the potential to be used as inclusion or exclusion biomarkers. 

This work demonstrates the ability of a combined PDX / Artificial Intelligence platform to simulate clinical trials and identify biomarkers of drug efficacy and synergy, thus fostering the design of precision medicine clinical trials.

4- Immune Checkpoint Blockade and Autoimmune Diseases: Development of a mouse model of colitis induced by anti-CTLA-4

Authors: Edwige Nicodeme, Florence Blandel, Valerie Boullay, Yannick Saintillan, Gael Krysa, Anne-Benedicte Boullay, Jean-Jacques Tousaint, Robin Artus, Laure Levenez, Jeremy Odillard, Ingrid Jacquet, Fabrice Viviani

Oncodesign, Dijon, France

Immunotherapies prime or activate patient’s immune system to fight disease and has recently been a source of registered and promising new cancer treatments with major beneficial clinical outcomes in several cancers. However, by increasing the activity of the immune system, therapies as such targeting the immune checkpoint blockade can have profound inflammatory side effects, termed immune-related adverse events, with particular organs affected such as gastrointestinal tract, endocrine glands, skin and liver. In patients treated with the anti-CTLA-4 antibody, Ipilimumab, the overall incidence of diarrhea and colitis has been reported as 32.8%. This side effect is also observed in patients treated with anti-PD-1 therapy.

The reproduction of such aspects of immune checkpoint inhibitors side effects in preclinical animal models would serve to dig into deciphering mechanisms involved, but also to evaluate combination therapies and modalities to reduce and manage such incidence with potential beneficial translation in clinical practice.

We thus first ought to establish a checkpoint blockade-related autoimmune mouse model of colitis, using female C57BL/6 mice which were tested to determine their response to orally administered dextran sulfate sodium (DSS) combined to multiple injections of anti–CTLA-4 antibody or an isotype control antibody. After administration of DSS in drinking water for 7 days, mice that received an anti–CTLA-4 antibody showed no difference in body weight loss and Disease Activity Index (composite of body weight loss, stool consistency and presence of blood in stools), when compared to mice that received DSS plus the isotype control antibody. Histological sections analysis from the colons of mice culled at Day 10 confirmed that the combined treatment did not change the colitis score.

However, when looking at later time points corresponding to the usual recovery phase of colitis, the effect of anti-CTLA4 treatment was clearly revealed by a sustained body weight loss and the persistence of a high Disease Activity Index, while the isotype control-treated animals slowly returned to baseline values similar to untreated animals. At sacrifice on Day 19, these in life findings were confirmed by a decrease in colon length (- 0.94 cm), an increase in colon weight (+ 231 mg) and a high mucus colon production in the anti-CTLA4-treated group versus the isotype control-treated group. Histological analysis of colons, and a more in depth characterization of the immune infiltrates will be presented.

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5- Preclinical assessment of external or targeted radiotherapy in combination with immunotherapies and co-development of companion imaging diagnostic

Authors: Olivier Raguin1,4, Céline Mirjolet2,4, Claire Bernhard3, Peggy Provent1,4, Bertrand Collin2,3,4, Franck Denat3, Fabrice Viviani1,4, Alexandre Cochet2,4, Cyril Berthet1,4

1- Oncodesign, 20 rue Jean Mazen, BP 27627, 21076 Dijon
2- Centre Georges François Leclerc, 1 rue Professeur Marion, BP 77980, 21079 Dijon, France
3- ICMUB UMR 6302, CNRS, Université de Bourgogne Franche-Comté, 9 avenue Alain Savary, 21000 Dijon, France
4- Pharmimage, 64 rue de Sully, 21000 Dijon, France

Immunotherapies have proven to be highly efficient for cancer treatments and combination with either internal vectorized or external radiotherapies can enhance this efficacy through notably increasing tumor immune infiltrate. The clinical evaluation of such combination therapies requires expertise and exquisite processes in multiple fields, immunotherapy, radiotherapy and nuclear medicine. Similarly, this applies into preclinical settings for assessing proof of concept of novel combinations.

Herein, we will present our preclinical evaluation process to combine external or internal (i.e. lutetium‑177 radiolabeled molecule) radiotherapy with immunotherapies that include radiochemistry, target expression in tissue by autoradiography, in vitro binding evaluation, in vivo tolerance and activity based on single or fractionated treatment doses.

The targeted radiotherapy (TRT) is a systemic target-based approach combining a high-affinity receptor-binding ligand radiolabeled with a high-energy beta-emitting radionuclide whereas external 3D image guided radiotherapy targets the shape of the tumors very precisely. Combination studies with immunotherapies in preclinical setting require the selection of appropriate and relevant syngenic or humanized mouse models, driven by target expression, radioresistance (i.e hypoxia), and tumor immune infiltrate (lymphocyte CD8, macrophages…). In addition, the therapeutic evaluation should take into consideration the tolerance related to ionizing radiations, the scheduling of treatment (cumulated dose, fractionation), antitumor immune response and monitoring of immune checkpoint target expression.

As nuclear imaging is a powerful tool to monitor and predict in vivo target expression and treatment efficacy, TRT is systematically developed in parallel of a PET or SPECT companion diagnostic to visualize and quantify the target expression prior to the treatment with a therapeutic radiolabeled drug. It necessitates the development of radiolabeling processes for either therapeutic or diagnostic purposes and is then performed concomitantly using appropriate bioconjugation strategies suited for theranostic pairs of radionuclides.

We will present our recent results that highlight the importance to optimize the external radiotherapy schedule to improve the efficacy and synergistic effect of the association radiotherapy/immunotherapy such as anti-PDL1. Similarly, it is of high interest to combine 177Lu-labeled molecule with immune checkpoint inhibitors in various solid tumors. Transversal skills are mandatory to perform such models and experiments, all being conducted in a dedicated facility for external 3D image guided radiotherapy (SARRP), radiochemistry (hot cells, 177Lu, 68Ga, 64Cu, 89Zr, 111In) and pharmaco-imaging (PET, SPECT, MRI, CT, and optical).