Program 2

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Immunosurveillance and escape mechanisms

Immunosurveillance and escape mechanisms

The researchers of this Program seek to understand the contribution of chronic viral infection, inflammation and immunity in the process of cellular transformation and tumor progression. This project aims to understand the processes of tumor and virus immuno-surveillance and escape mechanisms and the contribution of abnormal host response to tumor or virus benefit. Within this overall aim, each team brings to this Program complementary expertises and approaches.

As for the other projects of LYric, this Program benefit from the involvement of basic researchers and clinicians, which ensures both cognitive and clinical research and close links with clinical departments of the Centre Léon Bérard and the university hospital (Hospices Civils de Lyon). This translational research aims to develop innovative therapeutic strategies, based on experimental and clinical investigations. From basic research programs on the role of innate sensors and innate immune cells in initiation of adaptive immunity and evasion mechanisms, the teams will establish novel concepts in human clinic through cohort studies. In particular they aimed at demonstrating the importance of the anti-tumor immune arm in the therapeutic response and in the control of tumor stem cells. These programs will lead to the identification and validation of therapeutic strategies, targets and drugs to restore anti-tumor immunity that will be pursued through first in man clinical trial. In particular in link with program 1, the teams are involved in the development of therapies directed against cellular oncogene and viral targets, in combination with strategies based on immune reactivation against viruses and cancers in the objective to induce long lasting anti-tumor (viral) immunity preventing tumor relapse. The teams also aim to identify and validate clinically relevant prognostic and predictive parameters in the cancer models of the LYRIC including those associated with chronic viral infections.

As for the two other programs of the LYRIC, the major objective of this theme, dedicated to the analysis of host response against tumors is to accelerate the transfer from basic research to clinic, but also to exploit the data generated during clinical trials to feed the fundamental research programs. It emcompass 3 major objectives:

  • Identify targets to restore anti-tumor immunity
  • Develop a therapeutic mAb against validated Lyric target

Initiate clinical trials to restore immune dysfunction and induced anti-tumor immune memory

1- BASIC RESEARCH COMPONENT

Understand how inflammation and immune response can control or promote tumor development, in the context of viral or non viral induced tumors: Identify the molecular mechanisms by which tumor cells and virus alter the numbers, phenotype and function of immune cells in vitro, in preclinical models and in vivo in man. Understand how innate sensors contribute to immunosurveillance or to inflammation and tumor development.

2- TRANSLATIONAL RESEARCH COMPONENT
Investigation of immune alteration in cohorts of patients and contribution to progression and of the relevance of anti-tumor (anti-viral) immunity in therapeutic responses: The teams benefit from CLB platform: “Innovation in Immunotherapy & Immunomonitoring Platform (PI3)” dedicated to translational research allowing i) efficient transfer from scientific concepts to innovative clinical trials and ii) monitoring of the immune response of cancer patients to bring validation in clinic of innovative concepts. The program also involved tight interactions with the Lyon Sud Immunomonitoring platform directed by J Bienvenu, and the emerging C3D platform aiming at drug discovery.

3- CLINICAL RESEARCH COMPONENT OF THE WP3
Early clinical trial based on immune restoration: Develop and implement prospective clinical trials evaluating immune restoration strategies. The goal is to accelerate the development of clinical trials aiming to restore the immunological alterations observed in cancer patients and induce long lasting anti-tumor immunity leading to dormant disseminated tumor stem cells eradication and preventing tumor recurrence.

Schéma 1 : Overall objective of WP3

LYRIC-PROG2-anglais

 

Progress through 2012

1- BASIC RESEARCH COMPONENT
Among ongoing basic programs on tumor immunosurveillance initially identified with Lyric, 3 emerging projects have or will directly benefit from the Lyric WP3 support :

  • Emerging program 1: Investigate the impact of therapeutic antibody in inducing CD8 anti-tumor immunity against endogenous TAA and the importance of antibody mediated target cross-linking through FcR on accessory cells in therapeutic efficacy (C Dumontet started in January 2012) Learn more
  • Emerging program 2: Analyze of tumoral and cellular immune responses in paraneoplasic syndromes: a successful anti-tumor immune response. Thanks to cohorts accrued through the European Network of J Honnorat group (Didelot et al. 2009) and associated CRB in Lyon, we will be in a unique position to analyse the immunological parameters of these patients. (J Honnorat started in January 2013) Learn more
  • Emerging program 3: Contribution of viral immune escape to tumor development. HBV or HCV proteins induce carcinogenesis in animal model and in vitro. Whether the immune escape mechanism developed by the virus to maintain persistence contribute to tumor development will be analyzed (Lucifora et al. 2010). (F Zoulim/D Durantel to be started in January 2014)

2- TRANSLATIONAL RESEARCH COMPONENT

2 Major structuring actions have been initiating through the present year of the Lyric program: i) Assemble elements to succeed in developing a therapeutic mAb against a Lyric target; ii) Immunomonitoring platforms: Development of tools & monitoring of patients.

Transversal action 1: Assemble elements to succeed in developing a therapeutic mAb against a Lyric target

The objective of this action is to discover and develop therapeutic antibodies directed against targets validated with Program 1 or Program 2 of Lyric. These will be done through partnership with biotechs, and the emerging platform C3D aiming at drug discovery and supported by the SLC fundation.

During the past year we have: i) evaluated >10 targets that were proposed by Lyric teams, ii) identified a partner to develop therapeutic mAbs, iii) select a first target, iv) allocate resources to initiate the program, and v) respond to several national and international calls to increase the resource on this specific program to transform it in success.

The selected target represents an immune check point and its blockade through the use of neutralizing mAbs represents a highly attractive, potent and safe strategy for the development of a highly potent and innovative immunotherapy. Such mAbs may reverse tumor-induced immuno-suppression and prevent metastasis in numerous cancers, improving the patients’ life expectancy and quality of life. 3 Lyric teams are deeply involved in this lyric project: T Renno/S Lebecque, C Dumontet, C Caux.

Transversal action 2:  Immunomonitoring platforms: Development of tools & monitoring of patients

Immunoring-platform-PROG2-anglais

 

The platform PI3 from CLB and the Lyon-Sud Immunomonitoring platforms work as a single platform with Lyric.

Several tools and assays have been developed set-up in this platform:

  • Lymphopenia and TCR diversity in patients with advanced cancers (collaboration ImmunID)
  • Analysis of all immune cell subsets frequency and phenotype through multi-parametric flow cytometry
  • Analysis of innate and adaptive immune cells functional competence in whole blood of patients using innovative assays based on multi-parametric flow cytometry coupled to intracytoplasmic cytokine detection, following activation.
  • Analysis of T cell specific anti-cancer immunity in breast cancer patients. Tools are presently under development in this objective.
  • CD8 T cell memory assays: Multiparametric flow cytometry assay in blood for qualitative evluation of CD8 T cell memory (ongoing, J Marvel, Lyon Sud)
  • Determination of cytokine in plasma of patients before /during therapy. This assay mainly used multiplex bead based assay (Luminex), as well as elisa for selected cytokines not available in Bead multiplex.

3- CLINICAL RESEARCH COMPONENT OF THE WP3
Early clinical trial based on immune restoration: Develop and implement prospective multi-centric clinical trials evaluating immune restoration strategies. The goal is to accelerate the development of clinical trials aiming to restore the immunological alterations observed in cancer patients and induce long lasting anti-tumor immunity leading to dormant disseminated tumor stem cells eradication and preventing tumor recurrence.

Immunosurveillance and escape mechanisms

The researchers of this Program seek to understand the contribution of chronic viral infection, inflammation and immunity in the process of cellular transformation and tumor progression. This project aims to understand why our immune system is not able to struggle against tumor cells proliferation.

As for the other projects of LYric, this program benefit from the involvement of basic researchers and clinicians, which ensures both cognitive and clinical research and close links with clinical departments of the Centre Léon Bérard and the university hospital (Hospices Civils de Lyon).

The research projects of this program will lead to the identification and validation of therapeutic strategies, targets and drugs to restore anti-tumor immunity that will be pursued through first in man clinical trial. In particular in link with program 1, the teams are involved in the development of therapies directed against cellular oncogene and viral targets.

This program encompass 3 major objectives:

  • Identify targets to restore anti-tumor immunity
  • Develop a therapeutic mAb against validated Lyric target
  • Initiate clinical trials to restore immune dysfunction and induced anti-tumor immune memory 

 1- BASIC RESEARCH COMPONENT

Understand how inflammation and immune response can control or promote tumor development :

  • Identify the molecular mechanisms by which tumor cells and virus can alter immune responses, in preclinical models and in vivo in man.
  • Understand how innate sensors contribute to immunosurveillance or to inflammation and tumor development.

2- TRANSLATIONAL RESEARCH COMPONENT
The translational research projects follow immune alterations in cohorts of patients, thanks to tumor analysis and patients’ blood analysis. The translational projects benefits from the technological platforms like the CLBInnovation in Immunotherapy & Immunomonitoring Platform (PI3)”, the Lyon Sud Immunomonitoring platform or the emerging C3D platform aiming at drug discovery.

3- CLINICAL RESEARCH COMPONENT OF THE WP3
Early clinical trials are based on immune restoration: Develop and implement clinical trials evaluating immune restoration strategies. The goal is to accelerate the development of clinical trials aiming to restore the immunological alterations observed in cancer patients and induce long lasting anti-tumor immunity leading to dormant disseminated tumor stem cells eradication and preventing tumor recurrence.

Schéma 1 : Overall Objective of WP3

LYRIC-PROG2-anglais

Clinical Studies

ProfiLER (Lyric 1)

Etude prospective de caractérisation moléculaire et immunitaire des tumeurs des patients opérés ou biopsiés au Centre Léon Bérard : corrélation avec les données cliniques et de suivi (JY Blay, Lyric) (n=2000)

Molecular and immune caracterization of LYric patient tumors

MOST (Lyric 2)

Etude multicentrique de phase II, randomisée, évaluant le bénéfice clinique d’un traitement de maintenance par une thérapie ciblée adaptée aux altérations moléculaires identifiées tous types de tumeurs solides en rechute ou réfractaires après une 1ere ligne de chimiothérapie en phase avancée. (JY Blay, Lyric) (n=500)

Treatment adaptation to molecular alteration

Immuno-Greffe (Lyric 3)

Immune reconstitution following Blood Hematopoietic Stem Cell transplantation in AML (J Bienvenu/T Walzer/M Michallet, Lyric), Lyon Sud (n=40)

Immune reconstitution following Hematopoietic Stem Cell transplantation in AML

Effector-mAbs (Lyric 4)

Evaluation of  functional competence of effector cells contributing to therapeutic activity of mAbs (J Valladeau/T Walzer, Lyric), Lyon Sud