Explore our posters & talk on oncology

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Please see the list of posters & talk, below, which provide a hint of our deep expertise in Oncology!

“Development of a high throughput in vitro screening platform to identify novel inducers of immunological cell death”

Time: April 15, 2018, 1:00 PM - 5:00 PM

Authors: Didier Grillot, Akanksha Gangar, Raphaelle Guillard-Huet, Eric Boursier, Florent Potvain, Guillaume Serin, Jean-François Mirjolet.

Abstract:

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. In order to identify new therapeutic agents that promote ICD in malignant cells, we developed a screening strategy facilitated by an automated in vitro platform with four assays on three different tumor cell lines (human osteosarcoma U-2 OS, human breast MDA-MB-231 and murine liver Hepa 1-6). ICD inducers Doxorubicin and Mitoxantrone used as positive controls increased ATP secretion by 2 to 10-fold at a non-cytotoxic dose after 72 hours incubation on the three cell lines. Both compounds also increased calreticulin exposition by 2 to 4-fold (determined by immunofluorescence using the Operetta High-Content Imaging System) and HMGB1 release by two-fold on the three cell lines. Here we will present recent data from the screening of Oncodesign’s Nanocyclix® library using this platform to identify novel ICD inducers.

“Modulating T cell immunity in tumors by targeting PD-L1 and neoantigens using a live attenuated oral Salmonella platform”

Time: April 15, 2018, 1:00 PM - 5:00 PM

Authors: Sébastien Wieckowski, Lilli Podola, Heiko Smetak, Anne-Lucie Nugues, Philippe Slos, Amine Adda Berkane, Ming Wei, Klaus Breiner, Albrecht Meichle, Philipp Beckhove, Marc Mansour, Heinz Lubenau. 

Abstract:

Significant progresses have been achieved recently in cancer vaccines that aim at engaging or reengaging tumor directed T cells, in particular   in the rapidly growing field of personalized immunotherapy. Yet novel immunization solutions to produce effective tumor-associated (neo)antigens T cell responses while simultaneously overcoming the immunosuppressive tumor microenvironment are urgently needed. We     are developing a unique and versatile oral T-cell vaccination platform based on the FDA-approved live-attenuated Salmonella Typhi strain Ty21a vaccine Vivotif®, capable of delivering tumor-associated antigens encoded in DNA expression construct to the gut-associated lymphoid tissue, breaking immune tolerance and inducing anti-tumor immunity. This study summarizes the immunogenicity and antileukemia efficacy of VXM10 vaccines based on the live-attenuated Salmonella Typhimurium strain SL7207, transformed with a eukaryotic expression plasmid encoding the murine programmed death-ligand 1 (PD-L1) protein. It also describes for the first time the systemic immunogenicity of Salmonella based polyepitope oral vaccines, supporting the design of Salmonella based neoantigen vaccines. The antileukemia activity of VXM10 was evaluated in the FBL-3 disseminated model of leukemia, in which the tumor cells express high levels of PD-L1. Oral administration of VXM10 produced a strong anti-tumor effect in the FBL-3 leukemia model, with 100% of surviving animals 80 days after leukemia challenge in the highest dose groups. In contrast, administration of the empty vector control did not show any anti-cancer effect. Moreover, 100% of long-term surviving mice resisted re-challenge with FBL-3 cells, demonstrating that vaccination with VXM10 generated a potent memory T cell response against the leukemia. Importantly, full leukemia control was achieved in both prophylactic and therapeutic settings. The anti-tumor effect observed in these experiments was as strong as in previous experiments using a Salmonella Typhimurium transformed with a plasmid encoding Wilm's tumor 1 (WT1). The anti-tumor efficacy was accompanied by an increased systemic antibody response, and the activation of T cells directed against PD-L1 epitopes. Finally, different polyepitope vaccines encoding model epitopes from VEGFR2, Mesothelin, WT1, CEA, and Ovalbumin, induced a significant systemic immunogenicity for up to 6 out of 9 epitopes, 10 days after vaccination of healthy C57BL/6 mice via the oral route, as measured in the spleen by flow cytometry using peptide-MHC class I pentamers. These studies demonstrate that the Salmonella Ty21a platform can be used to generate anti PD-L1 antibody and T cell responses, as well as CD8-positive T cell responses against a majority of MHC class I epitopes of a polyepitope construct. We are now designing a clinical neo-antigen based vaccine that employs the concepts presented.

MORAB-202 A FOLATE RECEPTOR ALPHA-TARGETED ANTIBODY-DRUG CONJUGATE SHOWS A HIGHLY POTENT ACTIVITY AGAINST A PANEL OF FRΑ-EXPRESSING TUMORS

Time: April 16, 2018, 8:00 AM - 12:00 PM

Authors: C. MIGNARDa, C. DURIXa, K. RYBINSKIb, X. CHENGb, K.FURUUCHIb, E. ALBONEb, T.UENAKAb,c M. HILLAIRET de BOISFERON
a - Oncodesign ; b - MORPHOTEK Inc ; c - Eisai Co.

Abstract:

Folate receptor alpha (FRA) is a membrane protein with high affinity for binding and transporting folate into cells. Overexpression of FRA may confer a growth advantage to tumors by increasing folate uptake and affecting cell proliferation via alternative cell signaling pathways (1). FRA levels have been found to be elevated in tumors of epithelial origin compared to normal tissue as cancers of the breast (including TNBC (2)), colon, lungs and ovary (3).

In this study, we report the development of MORAb-202, an anti-FRA antibody-drug conjugate (ADC), consisting of a FRA-binding antibody (MORAb-003, farletuzumab) with a cathepsin-cleavable form of eribulin (eribulin mesylate, marketed as Halaven®), a highly potent anti-mitotic agent that induces cell-cycle arrest and cell death by targeting microtubules.*

We first study expression of FRA on a large panel of tumors patient-derived xenograft (PDX) and Cancer Cell Line-derived Xenograft (CDX). Then, we performed in vitro and in vivo anti-proliferation assays and compare antitumor activity of MORAb-202 with free eribulin accordingly to the FRA expression level. FRA expression was found to be determinant in the sensitivity of tumor cells to the cytotoxic effect of the ADC. Moreover, in case of high expression of FRA, MORAb-202 showed a higher antitumor activity compared with free eribulin.

These results suggest that FRA expression could be used as a response-predictive biomarker for this targeted therapy. The ability to identify and treat patients with an effective therapy based on the known expression of the tumor marker is a key point in predictive medicine progress. These findings support the clinical development of MORAb-202 ADC as a novel targeted therapy for patients with FRA-expressing tumors.

The ADC described in this abstract is investigational, as efficacy and safety have not been established.  There is no guarantee that this ADC will be available commercially.

1-Siu MK et al., PLoS One. 2012;7(11)
2-Nacela BM. et al., PLoS One. 2015, 10(3)
3-Cheung A. et al., Oncotarget. 2016 7(32), 52553-52574
4-Arrowsmith J. & Miller P. 2011–2012. Nat. Rev. Drug Discov. 12, 569 (2013).
5-Paul S.M. et al. Nat. Rev. Drug Discov. 9, 203–214 (2010).
6-Hidalgo, M. et al. Cancer Discov. 4, 998–1013 (2014).

“Single mouse preclinical trial: A tool for translational research”

Time: April 16, 2018, 1:00 PM - 5:00 PM

Authors: Caroline Mignard. Marc Hillairet de Boisferon, Francis Bichat , Damien France,  Olivier Duchamp.

Abstract:

Roughly, 85% of preclinical agents entering oncology clinical trials fail to demonstrate sufficient safety or efficacy to gain regulatory approval. Hence, there is a need for experimental systems which better mimic the inter-patient response heterogeneity observed in the clinic. Patient-derived tumor xenograft (PDX) mouse models have emerged as a relevant oncology research tool to study tumor evolution, drug response, biomarkers, resistance phenomenon and adjusting chemotherapeutic approaches for individual patients.

We will here expose the effectiveness of the single mouse preclinical trial paradigm for evaluating drug response, as mono or combo therapy using our well-characterized PDX collection. Based on the “1 PDX tumor/1 mouse/1 treatment” experimental design, a cohort of colorectal, breast, pancreas, lungs PDX models (minimum 20 of each) was used to explore response to Standard Of Care (SOC) and combo therapy used in clinic. We compared single-animal response data with treatment group data taken from historical experiments. We demonstrated that about >80% of the individual response matched the treatment group data, supporting the idea of using one single animal to predict the drug response.

The response of each PDX to treatment was correlated to their histological and genetic profiles.

This approach represents a new experimental design to address the tumor biology of cancer patients, and investigate targeted therapies in relevant mouse models, which could improve our ability to predict clinical trial responses, stratify patients for clinical trial, identify drug resistance mechanism, responsive sub-populations as well as biomarker.

By combining genomic profiling data and drug screening data, and clinical data from patients, SMPT process is a helpful tool for precision cancer medicine and individualized drug selection.

“Humanized mouse models for evaluation of cancer therapies”

Time: April 18, 2018, 8:00 AM - 12:00 PM

Authors: Jean-François Mirjolet, Josselin Caradec, Olivier Duchamp, Francis Bichat, Caroline Mignard

Abstract: 

Mice with a humanized immune system, so called “humanized” mouse models, can be used to study the complex interactions between the human immune system and tumor cells. In order to assess compounds efficiency in immune-oncology, the in vivo model should recapitulate the biological characteristics of the human tumor and the related immune microenvironment.

The choice of mouse strain is the first critical factor as genetically engineered mouse strains differentially express cytokines and growth factors. Then the choice of human antigen/target to be assessed drives the choice of the tumor models and the immune population to be transferred into mice.

We developed on different immunodeficient mouse strains multiple humanization strategies using 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. We also developed mouse humanization models using combinations of immune subpopulations such as co-transfer of autologous T cells and DCs.

Humanized models were then used for in vivo proof of concept studies with mice xenografted with cell lines (human disseminated lymphoma, orthotopic/subcutaneous solid tumors) or patient-derived xenografts. Tumor-bearing humanized mice were treated with cancer therapeutics such as bispecific antibodies, ADCC-inducing antibodies, Treg targeting antibodies, TLR agonists, vaccines and adoptive T cells transfer therapeutic antibodies. Therapeutics efficiency was assessed by following up mice survival and tumor growth. The impact of therapeutics on tumors and immune cells was also assessed  by flow cytometry and immunohistochemistry analyses.

In case of disseminated lymphoma and ovarian human tumor in mice reconstituted with human PBMCs,  significant antitumor activity of bispecific antibodies were evidenced by an increase in survival, decrease in specific biomarkers (CA125 for ovary) and decrease of residual disease. 

“Advantages in using orthotopic syngeneic tumor models to evaluate immune-based approaches for cancer treatment”

Time: April 17, 2018, 4:35 PM - 4:50 PM

Authors: Sylvie Maubant , Philippe Slos, Marc Hillairet de Boisferon, Francis Bichat, Jean-François Mirjolet

Abstract:

Immune checkpoint modulators are now accepted as the fourth pillar of cancer care for both solid tumors and hematological malignancies. In addition to CTLA-4, PD-1 or PD-L1 targeting antibodies, novel immune-oncology targets are currently tested in patients but also new strategies such as bispecific T cell engagers or cell therapies including CAR-T cells. Some of them have been already approved.

Prediction of preclinical models is still a long-standing debate, even more when considering modulators of the immune system. Despite significant progresses made in humanized mouse model field during the last decade, having a complete and stable immune system comprising both lymphoid and myeloid subpopulation is not yet possible. Syngeneic tumors thus remain the model of choice to interrogate and better understand the mechanisms of action of new compounds targeting immune cell interactions.

In order to improve prediction and relevance of these syngeneic models, orthotopic (OT) models were developed in parallel of standard subcutaneous (SC) models. Here, comparison of regular SC versus OT engraftments are provided. Various models, such as EMT-6 (breast), MBT-2 (bladder) as well as RenCa (kidney) will be described in addition to other OT models like Hepa1-6 (liver) or PAN-02 (pancreas) models. In addition to growth characteristics using imaging for OT models, antitumor efficacy of CTLA-4 and PD-1 targeting antibodies will be detailed for both SC and OT models. One of the most interesting model is MBT-2 (bladder) for which response to CTLA-4 targeting antibody is changing depending engraftment site: significant increase in survival was evidenced for the OT model (treated to control ratio (T/C) of 285%) and only moderate efficacy was observed for the SC model (T/C = 66%). For the PD‑1 targeting antibody, OT injection seemed to be the preferential site to observe increased efficacy. Attempting to correlate immune profile and response to treatment, differences in immune infiltrate between OT and SC tumors will also be presented.