Study and development of new anti-cancer therapeutic strategies based on immunomodulation and dendritic cells – IMOCA

IMOCA includes 80% of the fundamental research of its coordinator S. Amigorena, plus a portfolio of research projects with strong application potential shared with Sanofi. The themes chosen at the beginning for this collaboration were: 1) the design of syngeneic and / or allogeneic mouse models adapted to the preclinical study of immunotherapies, 2) the better understanding of cross-presentation by the dendritic cells in order to design activators of the anti-tumor immune responses.
The close interactions between the two structures, academic and industrial, favor the formation of «post-docs« and «PhDs« with a double culture, able to engage more easily into complex positions in the field of applied research in immuno-oncology.

The scientific program of IMOCA evolved during the first 18 months of the project and now comprises 7 projects:
• A cross-section project on the molecular mechanisms of immunity and immunomodulation. This project (P1) aims at understanding the fundamental mechanisms of cross-presentation of tumor antigens to CD8 + T cells and to define new strategies to induce anti-tumor immune responses.
• Three areas of study for the development of new therapies:
o P 2: Development of new humanized mouse models to evaluate the activity of innovative immunotherapies.
o P 3: Exploration of the role of the various known activators of dendritic cells in the polarization of a subtype of T cells.
o P 4: Development of new tools to increase the effectiveness of antigen cross- presentation.
o P 5: Training and dissemination actions to increase the impact of the project and communicate on the results of the Chair.
o P 6: Study of some invariant T lymphocytes as targets in inflammatory diseases.
o P 7: Development of in vitro functional tests to study the activity of mono and multi-specific anti-«checkpoints« antibodies.

The IMOCA Chair responds perfectly to the expectations of its partners. Through frequent meetings of its program directors and project managers, research has progressed at a sustained pace. Exchanges of protocols, expertise and staff have taken place between the two partner institutions, Institut Curie (IC) and Sanofi. A post-doc from IMOCA was hired as a researcher at Sanofi in 2017. These close relationships, coupled with a precise project follow-up, yielded results that were presented at congresses and will soon be published in pair reviewed scientific journals. The budgets obtained through ANR and Sanofi funding have made possible to recruitment of post-docs, bio-info, PhD Cifre who develop a double academic and industrial culture. They participate in discovering and validating new hypotheses in the field of immuno-oncology both through their fundamental research within the team of S. Amigorena and by their more applied research within the teams of O. Lantz, E. Piaggio and V. Soumelis on themes of interest for both partners. Their findings will lead to patent filings or publications that will certainly have socio-economic benefits and will have positive consequences for human health.

In November 2016, the Institut Curie created, following the dynamics of success associated to immunotherapies, the scientific achievements of the researchers of the Inserm unit «Immunité et Cancer» (U932) and the creation of the IMOCA industrial chair: the Centre for Cancer Immunotherapies (IT), which includes IC's early clinical trial in IT and all unit personnel involved in translational research, including the one’s of IMOCA, on the same floor of the Hospital.

The current major issue at a time when immunotherapy treatments are developing in cancer and inflammatory diseases is to identify the mechanisms of action of immunotherapies and to find new biomarkers of response or resistance in order to better treat patients. The new objectives defined by the IMOCA Joint Steering Committee (JSC) go in this direction and are aligned with the initial objectives of this project, but also take into account the evolution of Sanofi's strategy and of the projects team leaders of the U932. IMOCA's most promising results will be patented, published and used by Sanofi for drug development.
The IMOCA Industrial Chair embodies a unique model of public-private collaboration in the field of immunomodulation, in which the cultures of basic research and the development of new therapies will act in synergy. It will be a valuable tool to promote the rational design and development of innovative therapies, and to train highly qualified personnel adapted to both professional environments.

Posters :
1. Development of novel anti-tumor immunotherapies using optimized experimental mouse model, JSM, Institut Curie, Paris
Authors:  P. De La Rochère1, et al. (Congress of the French Society of Immunology, SFI, Paris; 28-30/11/16. And Keystone congress. Cancer immunology and immunotherapy taking a place in mainstream oncology, Canada. 19/3/2017)  

Seminars:
1. Development of novel humanized mice models for the study of cancer immunotherapy.
C. Sedlik (World Preclinical congress- Europe. Preclinical models for cancer immunotherapy and combinations Lisbone, 14/11/2017)

2. Development of mice models for the study of cancer immunotherapy. P. De La Rochère (EuroPDX Workshop, Weggis, Switzerland, 3-5/10/16)

3. Development of mice models for the study of cancer immunotherapy. P. De La Rochère (Tumor model summit, Basel, Switzerland, 12-13/05/16)

4. Development of novel humanized mice models for the study of cancer immunotherapy”. E. Piaggio (Tumour Models London Summit 2015 – 3rd December 2015, London.)

5. Development of novel humanized mice models for the study of cancer immunotherapy”. E. Piaggio (Pre-clinical Models in Immuno-oncology 2016 – 24th February, Copenhagen)

Publications :
1. Aryl Hydrocarbon Receptor controls monocyte differentiation into dendritic cells versus macrophages. C. Goudot et al. accepted in Immunity. 2017.

2. Human inflammatory dendritic cells. T-L. Tang-Huau et al. Invited review. Seminars in Cell and Developmental Biology (in press) 2017.

3. Alloatti A, Rookhuizen DC, Joannas L, Carpier JM, Iborra S, Magalhaes JG, Yatim N, Kozik P, Sancho D, Albert ML, Amigorena S. Critical role for Sec22b-dependent antigen cross-presentation in antitumor immunity. J Exp Med. 2017  Aug 7;214(8):2231-2241.

Cours : LabEx-IMOCA: 13-15 Mars 2017, à l’Institut Curie, à Paris, 60 participants internationaux. Conférence donnée par B. Pasquier (Sanofi) : « Checkpoints for cancer Immunotherapy «

Cancer therapy is currently undergoing a true “revolution”, switching cancer treatment strategies from “targeting the tumour” to “targeting the immune system”. The blockade of immune checkpoints with antibodies (Abs) anti-CTLA-4, anti-PD1 or anti-PD-L1, has given impressive clinical results together with manageable safety profiles. Reports of therapeutic efficacy with checkpoint inhibitors include metastatic melanoma, renal cell carcinoma and other tumours. Even if response rates are exceptionally high for metastatic patients that have previously received other lines of treatment, improving it and extending the indications represent major goals in the future years.
Cancer indications, in which checkpoint Abs showed clinical efficiency so far, are cancer types that bear elevated numbers of somatic mutations, suggesting that checkpoint Abs somehow “unravel” existing anti-tumour responses, most likely to mutated tumour antigens. Increasing anti-tumour immune responses should therefore synergize with checkpoint Abs.
Indeed, checkpoint Ab treatments were shown in mouse models to reverse restrains imposed by tumours to the immune system. Tumour-induced suppressive signals to the immune system are, at least in part, mediated through a dedicated population of “suppressor” lymphocytes, called regulatory T cells (Treg). However, Tregs are not the only suppressive cells in tumours. Myeloid cells, stromal cells and other lymphoid cells may also be suppressive. On the other hand, dendritic cells (DCs) play a central role in the initiation of immune responses. They are the only cells that effectively induce effector CD8+ T cell responses to tumours through a process commonly referred as “cross presentation”. But DCs can also participate to immunosuppression under the influence of the tumour environment. DC’s and other cell type’s surface proteins that mediate Treg activation or suppress CD8+ T cell functions therefore represent promising targets for immunomodulation.
In this context, this Industrial Chair project entitled “Study and development of new anti-cancer therapeutic strategies based on immunomodulation and dendritic cells” or IMOCA, is dedicated to the understanding of cancer immunity and the development of new strategies for cancer therapy. IMOCA’s scientific program includes five main complementary axes:
•One axis on translational study of the molecular mechanisms of immunity and immunomodulation. This first work package consists in understanding the fundamental mechanisms of cross presentation of tumour antigens to CD8+ T cells and defines new strategies to induce or increase anti-tumour immune responses.
•Three axes for the development of new therapies:
o Work Package 2: Development of new humanized mouse models to evaluate the activity of innovative immunotherapies and analyse the mechanism of action of immunomodulatory Abs.
o Work Package 3: Exploration of the Axl role in the induction of Th17 cells in cancer and development of original tools to target Axl for cancer immunotherapy.
o Work Package 4: Development of new tools to increase the efficiency of cross presentation aiming to determine new combination therapies with immunomodulatory Abs.
•One axis dedicated to training and dissemination to reinforce IMOCA’s impact and communicate on the industrial Chair model and results.
This Chair will represent a unique mix academic-industrial structure where the cultures of fundamental research and drug development will meet and synergize. IMOCA will be an invaluable tool for promoting rational design and development of innovative therapy, and training of highly specialized staff having a mixed culture.