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Toward enhancing activities of European institutions in the FDUSCC-IM cancer research joint institute in China

Final Report Summary - IMMUNOCAN (Toward enhancing activities of European institutions in the FDUSCC-IM cancer research joint institute in China)

Executive Summary:
The joint institute Fudan University Shanghai Cancer Centre – Institut Mérieux laboratory (FDUSCC-IM), created in May 2010, is conducting ambitious scientific research projects on oncology in China. Its 2 founding partners, Fudan University (China) and Transgene (part of Institut Mérieux, France) wish to increase their translational medical research cooperation with European countries and initiated the IMMUNOCAN collaboration with the support of the European Commission.
In a first step, this collaboration has been enlarged to an active and productive scientific partnership with Danish, Italian and German teams, with the following objectives:
(i) Increase the EU-China knowledge exchanges in the field of cancer prognosis – by organizing in China summer schools, seminars and international conferences, as well as by hosting PhDs and post PhD research fellows in the joint institute,
(ii) Enhance the research capacity and the technological transfer to the joint institute – by providing adequate human resources and equipment to conduct beyond the state-of-the-art oncology research,
(iii) Promote a reference Euro-Asian centre on Chinese cancer prognosis – by spreading the knowledge and by raising awareness in China and European Union.

Research activities has been held for four years in China in collaboration with the European partners, in order to enhance current research activities of the joint institute and to create durable links between Chinese and European teams. The area of research focused on immune phenotype as personalized medical biomarker for prognosis of Chinese cancer patients, and has been extended to new types of cancer and biomarkers (especially for lung, colorectal and breast cancers). The patient recruitment has been completed for the four cohorts and survival data collection is ongoing. Pending the results from the statistical analyses, these prognosis studies will help to guide clinical decision-making by facilitating the selection of appropriate treatment options.

Ultimately, this FP7 INCOLAB has been an opportunity to build a Euro-Asian reference centre for medical and scientific research on cancer and to extend the already existing cooperation between the FDUSCC-IM laboratory and Europe by considering the opening of the joint institute to additional European member. This has been successfully performed with the inclusion of IRCAN (Nice, France) as a new partner for the future and the renewal of mutual interests to pursue Sino-European research collaboration in immuno-oncology.

Project Context and Objectives:
Cancer is a leading cause of death worldwide: according to the World Health Organization, it accounted for 7.9 million deaths in 2007; lung, gastric, liver, colorectal and breast cancers being the most frequent types. In a context where novel diagnosis and care strategies are strongly needed, immunotherapy is a promising tool to treat cancer patients in addition to chemotherapy. FuDan University Shanghai Cancer Center (previously called “FuDan University Cancer Hospital”) and bioMérieux (representative of Institut Merieux) have signed a Term Sheet for a tumor biomarker research partnership on August 18th 2006. A 3 year period joint laboratory collaboration agreement has been executed on March 28th, 2007, and ended on March 27th 2010. FuDan University Shanghai Cancer Center and INSTITUT MERIEUX agreed to amend and extend the original research partnership term for another 5 year period, effective from March 28th 2010. INSTITUT MERIEUX signed this amended and restated agreement for all the affiliate corporations, like bioMérieux and Transgene. The signature ceremony has been taken place on May 13th 2010. The joint institute FuDan University Shanghai Cancer Center – Institut Mérieux laboratory (FDUSCC-IM), created in May 2010, is conducting ambitious scientific research projects on oncology in China. This joint laboratory was created to promote interactions with hospital physicians and place public health as well as medicine at the heart of research activities. A dedicated research team and a laboratory are currently running at the FuDan University Shanghai Cancer Center to develop new biomarkers for early diagnosis and management of colorectal, lung and breast cancer.

The Joint Institute counts five projects. Two of them concern breast cancer research, among which one project is linked to a blood test for early detection, and the other for prediction of response to neo adjuvant chemotherapy. The two other projects on which the institute is concentrating are related to colorectal cancer research. As the first project on breast cancer, this first one is also concerning the blood test for early detection. The second project associated to rectal cancer research also concerns the response to neoadjuvant radiochemotherapy. The fifth project undertaken by the Joint Institute is the one on evaluate CancerTYPE ID (CTID) molecular assay on the Chinese population. Researchers implicated in the Joint Institute published, among others, three articles linked to these projects:
1. Using peripheral blood mRNA signature to distinguish between breast cancer and benign breast disease in non-conclusive mammography patients. Benlong Yang et al. Cancer Biology & Therapy 2010
2. Decrease in natural killer cell associated gene expression as a major characteristic of the immune status in the bloodstream of colorectal cancer patients. Ye Xu et al. Cancer Biology & Therapy 2011
3. Estrogen receptor-related genes as an important panel of predictorsfor breast cancer response to neoadjuvant chemotherapy. Yizuo Chen et al. Cancer Letters 2011

The joint institute’s founding partners, the Chinese FuDan University Shanghai Cancer Center (FDUSCC #2) providing the public funds part and the French Institut Mérieux (TRANSGENE #1) providing the private funds part wish to increase their transnational medical research cooperation with European countries. Durable collaborations in research are necessarily fostered by conducting joint research activities. In that perspective, the IMMUNOCAN project has been built to jointly promote the investigation results obtained through mutual research projects and activities. This strategy will simultaneously allow to:

• Strengthen existing partnerships within IMMUNOCAN.
• Prepare and motivate new European collaborators to enter into the FDUSCC-IM joint institute.
• Conduct beyond the-state-of-the-art research work and obtain promising results in order to be recognized worldwide.
In a first step, collaboration between TRANSGENE #1 and FDUSCC #2 has enlarged to an active partnership with Italian (Fondazione IRCCS #3), Danish (UCPH #4) and German (MHH #5) research teams. This group of five partners consists of the operational nucleus of IMMUNOCAN until 2015 when new partners joined.

The group had the following objectives:
(1) Increase knowledge exchanges between Europe and China in the field of cancer prognosis, by organizing summer schools, seminars and an international conference in China, as well as hosting PhDs and post-doctorate research fellows in the joint institute.

(2) Enhance the research capacity and the competence transfer to the joint institute, by providing adequate human resources and equipment to conduct beyond the state-of-the-art oncology research.

(3) Identify novel biomarkers enabling to predict the response to standard-of-care treatment in cancer patients. These prognosis studies will help guiding clinical decision-making by facilitating the selection of appropriate treatment options.

(4) Promote a leading Euro-Asian research centre on cancer prognosis, by spreading knowledge and raising awareness in China and European Union.

In order to accomplish the above objectives, leading European scientists in the field of cancer research from Italy, Germany and Denmark accepted to join the IMMUNOCAN project. All teams have several years of valuable experience and a high level of expertise in their respective fields as well as great peer recognition. In addition, they have demonstrated their will to develop cooperation both in China and with other European research teams by being part of IMMUNOCAN from the elaboration of the program.

Research activities have been held for four years in Shanghai with the contribution of the new European partners, in order to enhance current research activities of the joint institute and create durable links between Chinese and European teams. Research efforts have been focused on immune phenotype as personalized medical biomarker for prognosis of Chinese cancer patients, and have been extended to new types of cancer and biomarkers.

The optimal setting-up of the joint institute at the heart of a renowned university and hospital in Shanghai gave access to infrastructures adapted to all the dimensions of this project:

• University infrastructures for welcoming students and young researchers.
• Proximity with the first oncology hospital centre in Shanghai and one of the 3 most important in China, treating annually 22,500 in-patients and 592,000 out-patients. This cancer centre, among the most famous ones in Asia, offers access to high level clinical teams and a lot of patients, facilitating the clinical studies set-up.

Ultimately, this FP7- INCOLAB call for projects has been an opportunity to build a Euro-Asian leading centre for medical and scientific research on cancer and extend the already existing cooperation between the FDUSCC-IM laboratory and Europe by furthering the opening of the joint institute to additional European members.

Project Results:
Scientific results
A delay of patient’s recruitment of approximatively 11 months was observed during the program. So data completion and analyses is not completed at the end of the program, but the consortium was extended until September 2017 to analyze data and prepare publications (signature process on-going).

1) Comparison Healthy Vs Breast cancer
Levels of circulating factors (panel of 27 cytoikines and TGFβ) were compared between 151 Breast Cancer patients and 25 healthy women donors. In addition, cancer biomarkers such as CA15.3 and CA125 and parameters related to hematology (leukocytes, red blood cells, monocytes, neutrophils, eosinophils, basophils etc...) were compared between the two groups.
The parameters significantly different between healthy donors and breast cancer patients are:
- Cytokines: Eotaxin, FGF basic, GM-CSF, IFNγ, IL-10, IL-13, IL-1ra, IL-2, IL-4, IL-8, IL-9, IP-10, MCP-1 and TNFα.
- Hematology parameters: Basophils, Eosinophils, Lymphocytes, Neutrophils and Neutrophils on Lymphocytes ratio.
- Other : CA125 concentration, TGF-β1 and TGF-β2
Except for IL-10, IL-13, IL-2, IL-8 and IL-9, concentrations of most chemokines and cytokines are higher in healthy donors than in BC patients, illustrating the dogma that cancer patient immune status is usually less active. In line with this observation, blood counts of lymphocytes, eosinophils, basophils are in the normal ranges, but are higher in healthy donors as compared with cancer patients. Interestingly, both neutrophil-related chemokine IL-8 and neutrophil blood counts are more elevated in cancer patients. This might be explained by that some inflammatory mediators play a role in cancer initiation and tumor progression.

2) Medical need
Neoadjuvant chemotherapy is the standard treatment for patients with locally breast cancer. The goal is to shrink the tumor in order to make easier the surgery. Achieving a pathological complete response (pCR), is the ultimate goal of successful neoadjuvant treatment. pCR is determined by the pathological examination of surgery specimen and is characterized by the absence of residual tumor in breast and axillary lymph node absence. pCR, is an important predictor of long-term survival in patients, and mainly in breast tumors negative for hormone receptors (HR-) which includes HER2+ and TNBC subtypes. In addition, in these latter groups which are known to be more aggressive, pCR rates are higher as compared with HR+ subtypes (Luminal A/B). For these two reasons we decided to evaluate the capacity of the circulating factors to predict pCR in HR- patients.
Amongst the 151 breast cancer patients included, 68 patients are HR-. 54.4% (37/68) are HER2+ and received trastuzumab, whereas 46.6% (31/68) are TNBC. pCR rates in HER2+ and in TNBC are 54.1% and 35.5% respectively.

3) Comparison between the molecular subsets HER2+ and TNBC
Distinct immune profiles are observed between HER2+ and TNBC patients for the following parameters:
- Cytokines: Eotaxin, G-CSF, GM-CSF, IFNγ, IL-13, IL-17, IL-1b, IL-1ra, IL-4, IL-5, IL-7, IL-8, IP-10, MIP-1α, TNF-α
- Hematology: Neutrophils, Lymphocytes
- Other : TARC
Except TARC/CCL17 and GM-CSF, all the immune parameters significantly different between the two groups are increased in TNBC subtype, suggesting a more pro-inflammatory profile of these patients as shown by the increased level of neutrophils, IL-8, IL-1β, IFNγ, IL-6 and TNF.
Regarding the concentration of cancer biomarkers, several cancer biomarkers notably including CA15-3 are increased in TNBC patients , what is expected since pCR rate is lower in this group (35.5%) as compared with HER2+ (54.1%).

4) Parameters associated with pCR in HR-, HER2+ and TNBC
In both groups, HR- and HER2+, concentrations of Eotaxin-1 and thrombocyte absolute numbers are significantly different between pCR and No-pCR patients. Whereas Eotaxin-1 concentration is decreased in pCR patients, thrombocyte counts are diminished in no-pCR patients. In HER2+, in addition to Eotaxin-1 concentration, eosinophil blood counts is also decreased in pCR patients.
Concentrations of cancer biomarkers including, EpCAM (in HR- and TNBC), L1CAM (in HER2+) are elevated in No-pCR patients.
In TNBC subtype, IL-7 and IL-8 concentrations are higher in pCR patients than in No-pCR.
Erythrocyte count and Hemoglobin concentration are elevated in no-pCR group in TNBC.


Technologic results

Carbohydrates are important in all the main events of cancer progression; tumor proliferation, invasion, metastasis and angiogenesis. Furthermore, all cancers exhibit abnormal expression of carbohydrates either attached on cell surfaces or on circulating factors. We here describe the development of an assay targeting such aberrant glycosylations.
MUC1 (CA15-3) and MUC16 (CA125) are mucin type glyco-proteins, which may be circulating in blood or associated with the cell membrane. These mucins are major carriers of O-linked glycans and thus also of the cancer related carbohydrate antigens Neu5Ac-α2, 6-GalNAc-β1-Ser/Thr (STn) and GalNAc-β1-Ser/Thr (Tn).
We recently implemented a method procedure in the Luminex platform using lectins that allowed us to detect STn/Tn and poly-LacNAc. This detection strategy builds on the work related to antibody microarrays by Chen et al. 2013 demonstrating its relevance in differential diagnosis of ovarian cancer.
This technology was used to evaluate the predictive and prognostic value of the glycan biomarker assay in four Chinese cancer cohorts: Non Small Cells Lung Cancer (NSCLC), Gastric Cancer (GC), Breast Cancer (BC) and Colorectal Cancer (CRC).
A significant difference in the CA15-3STn/Tn readout for pCR vs non-pCR TNBC patients was observed. For this particular type of breast cancer, a clear correlation between pCR and OS has been reported and thus CA15-3STn/Tn shows great potential as a prognostic biomarker. The mean signal readouts (fluorescence intensity units, FI) were 46 and 27 for the two responder groups, respectively.
Survival analysis of CRC revealed CA125 concentration to be related to PFS and CA15-3 poly-LacNAc to be related to OS. With the clinical outcome approach used to determine cut-off, a CA125 concentration of 5.6 U/ml was found. This value is well within range considered normal for healthy individuals, however, the CA125 level may represent a predispositional factor influencing disease progression in the advanced stage of CRC. In overall survival, the normalized value of CA15-3 poly-LacNAc was significant. The normalization done by dividing the LEL detection signal by the concentration was thought to reflect the glycan density or number of ‘variable number tandem repeat’ (VNTR) units per mucin molecule.
For NSCLC and GC, a significant difference in PFS was found for the normalized value of CA125 STn/Tn, CA125 poly-LacNAc and also CA125 concentration alone. The added value of glycan’s was not shown using some technics as bootstrap.
To conclude, an assay for glyco-protein biomarker detection was developed in a technological platform suitable for analysis of clinical samples (serum and plasma). Mucin glycoforms may be potential prognostic biomarkers in both breast- and colorectal cancer. Regarding the relation between CA15-3STn/Tn and pCR, the robustness of the statistical analysis should be enhanced by increasing the patient number, and likewise, the CA15-3 poly-LacNAc relation to OS in colorectal cancer must be validated in other similar cohorts.

Potential Impact:
Description of the potential impact of IMMUNOCAN programme

Since its inception, IMMUNOCAN has been pursuing 4 major objectives of theFP7 Capacities call for projects and expects to have significant impact on the scientific immuno-oncology community at a global scale:


Objective 1: Broadening of European participation in the joint institute while ensuring gender balance.

For 4 years and beyond, IMMUNOCAN has been deeply anchored into a context of Sino-European (and more specifically Sino-French) collaboration.
The IMMUNOCAN project expresses the keen interest of its French and Chinese co-founders to open the joint institute to new European partners. The joint institute co-founders have been actively put this strategy into action by initially integrating 3 European research teams:
• Fondazione IRCCS #3 in Italy,
• UCPH #4 in Denmark
• MHH #5 in Germany.

The integration of these teams, experts in their cancer prognosis field, from the submission of IMMUNOCAN to the EC, demonstrates the joint institute’s ability to attract renowned research teams and proves the scientific interest for the joint institute to open to new members, in order to enhance its excellence. These first 3 partnerships were the core seed to enlarge the partners’ scope of the project, as these teams are the IMMUNOCAN and joint institute’s ambassadors to their already existing collaborations with other scientific teams in Europe. The best example of this impact is the recent participation of IRCAN (Nice, France) to IMMUNOCAN programme and their concrete involvement in the research activities.

Through the joint implementation of knowledge exchanges actions and beyond the-state-of-the-art research activities, a double dynamic has been created within IMMUNOCAN:
- Favorable conditions were created to make durable the commitment of the European partners in the joint institute, in the perspective of their entry in the joint institute. - TRANSGENE #1 and FDUSCC #2 had the common will to be able, through this project, to identify new partners that could officially join the Institute.
- Opportunities to develop new partnerships were multiplied through a broad recruitment for researcher positions, the opening of seminars and summer schools to other teams’ own networks and a broad advertisement of dissemination events, in particular the Shanghai conference on personalized cancer prognosis. On that matter, IMMUNOCAN team does consider that new collaborations and partners would arise in a near future from the dissemination activities that are provided elsewhere. Furthermore, throughout the entire IMMUNOCAN project and especially during recruitment processes, a close attention was applied to ensure gender balance in the scientific teams.

Objective 2: Foster future collaborative research projects between European and third countries in areas of mutual interest and for mutual benefit.

IMMUNOCAN actions and dynamics were and are still designed to enhance and enlarge future collaborative research projects on cancer prognosis in the FDUSCC-IM joint institute.

First of all, partners are convinced that the first step to start a lasting collaboration is to learn how to work together. This is why they decided to initiate collaborative research activities in China. This programme is and remains a first step to further and more ambitious programs. Beyond the mutual interest to create durable collaborative links and increase both Chinese and European competences and expertise, IMMUNOCAN contributed to the development of new therapeutic strategies for cancer patients, this being one of the 21th century major health issues for developed and emerging countries. In fact, China counts 1.3 billion inhabitants and its rapid development creates a strong need to improve health care offer and access. Cancer pathologies are unsurprisingly a major health issue in China too, constituting a growing need to find new cancer diagnostic and care solutions.

With IMMUNOCAN, it should be expected that an international research partnership would support the reinforcement of public health and personalized medicine, and to meet the need of patients and clinicians.

The FDUSCC-IM laboratory is dedicated to oncology maker discovery and validation. Identifying these biomarkers should make it possible to perform faster, more accurate cancer diagnosis and help physicians in prescribing new treatments for those patients who are likely to benefit from them. While trials are still ongoing, the IMMUNOCAN team expects the results to provide relevant insights on how immuno-oncology biomarkers can support decision-making at clinical stage to improve treatment protocols and at the end patient quality of life and cancer outcomes.

With the IMMUNOCAN project allowing the combination of European and Chinese expertise in clinical practices and innovative technologies, means to improve the care of Chinese cancer patients should be enhanced. At the same time, IMMUNOCAN benefitted from the European research community and cancer patients. Such a collaboration project has been profitable in both directions: mobilizing material and human development of new prognostic methods and new care trails out of a better comprehension of cancers’ mechanisms.

Objective 3: Increased cooperation with targeted third countries.

Based on a firm collaboration between TRANSGENE #1 and FDUSCC #2, the FDUSCC-IM joint institute has initiated European cooperation with China for more than 4 years.

Additional European involvement had already begun before the start of the IMMUNOCAN project: for instance, Fondazione IRCCS #3 has already been leading research activities with FDUSCC #2 research teams on breast cancer in the recent past.

From this already solid collaboration starting-point, IMMUNOCAN has demonstrated the partners’ sustainable will to increase European research cooperation within the Shanghai joint institute, notably through hosting young and experienced researchers in their lab.

In addition, the promotion actions that were carried in workpackage 4 towards both Chinese and each European member’s national institutions did not only emphasize the successful existing partnership in but also beyond cancer research and possibly beyond the research field itself.

This way, IMMUNOCAN actively participated in increasing European cooperation with China. The renewed interest from joint institute co-founders to pursue in that direction is a clear marker that IMMUNOCAN laid down first stones of a sustainable collaboration between Europe in China.

Objective 4: Help maximizing the initial investment of a small number of Member States to benefit the whole European Union.

In the first place, French initial investment in China through TRANSGENE #1 actions were maximized in the European scientific community through the following elements, implemented in IMMUNOCAN throughout its four years lifespan:
- Public events such as summer schools, seminars and conferences, where European students and scientists have been invited. While details on programs and attendees is provided elsewhere, it has been demonstrated that IMMUNOCAN succeeded in bringing together global experts of immuno-oncology to share knowledge and challenge the program research activities while reinforcing the collaborative spirit of IMMUNOCAN.
- Benefit from each partner’s own existing collaborative network.
- Increased awareness by making the joint institute known to European members and Chinese institutions.

Additionally, as IMMUNOCAN has been and remains an example of mutually benefiting experience for both China and Europe, it allows a wider ambition and becomes an ambassador project for other Euro-Chinese partnerships, possibly not exclusively scientific. With the promotion of European investment to Chinese institutions, Euro-Chinese collaborative actions will be eased, facilitating new initiatives.
Other objectives: Increased visibility and scientific excellence of the joint institute: spreading excellence, exploiting results, disseminating knowledge

Dissemination of knowledge and excellence as well as exploitation of results, which were actually among the essential objectives addressed by the FP7 Capacities call for projects, were not ignored in the scientific project that is IMMUNOCAN and remained the core of its actions during the last four years.

Dissemination of knowledge and spreading excellence

Through the global implementation of its 5 work- packages (notably the workpackages 1 and 4), IMMUNOCAN was able to enhance knowledge dissemination and spread excellence in cancer prognosis:
- By recruiting promising young researchers for the offered PhD and post-doctorate positions,
- By hosting European research staff in China to conduct beyond the state-of-the-art research and technological activities jointly with the current Chinese medical and scientific team,
- By sharing competences and technologies between IMMUNOCAN partners to improve the knowledge on cancer prognosis and care strategies, to obtain a better understanding of immunology mechanisms in cancer prognosis and optimize the advances and results hoped in this field so the project could be recognized world widely.
- By organizing two summer schools, two seminars and one Euro-Asian conference on personalized cancer prognosis, to communicate of IMMUNOCAN research results as well as network and host interventions of renowned lecturers. Seminar and summer schools have involved high level expertise scientists from Karolinska Institute, the National Institute for Medical Research, as well as the partners from the IMMUNOCAN program. The Euro-Asian international conference on personalized biomarker for cancer prognosis was largely open to registration.
- By submitting publications in peer-reviewed scientific journals, subject to the terms and conditions of the Consortium Agreement. Two publications based on IMMUNOCAN works are currently pending review and hopefully, the final statistical analyse post-patient recruitment will allow for further publications
- By participating in other international events (with lectures, communications, or posters).
- By setting-up a website dedicated to the dissemination of the acquired knowledge. This website has be developed by Transgene and FDUSCC and has been maintained updated all along the program lifespan. A database of the stakeholders and contact information has been made available.
- By editing a biannual newsletter summarizing the Euro-Asian network developed thanks the IMMUNOCAN international program. This newsletter has been primarily sent to the stakeholders involved in the field of prognosis biomarkers in cancer.

Exploiting results

IMMUNOCAN expected to achieve 2 main goals:
- Establish a durable collaboration between the FDUSCC-IM joint institute and European research institutions.
- Obtain a better understanding of immunology mechanisms in cancer.

The strengthening of the collaboration has been concretized by the entry of new European members in the joint institute (IRCAN, Nice, France), whereas significant progress in cancer prognosis will hopefully lead to the development of new prognostic methods and new care trails, allowing an improvement of cancer patients handling.

As IMMUNOCAN results in a partnership between public research institutions and a private company, the research results’ exploitation strategy has been considered from the construction of the IMMUNOCAN project. That is why Intellectual Property management has been implemented and integrated in a Consortium Agreement, in order to conciliate economic exploitation of research results and research excellence promotion. The distribution of accrued benefits has been cleared with the establishment of the consortium agreement.

List of Websites:
http://immunocan.transgene.fr

Coordinator contact
Romain MICOL
romain.micol@gmail.com

Benoît SANSAS
sansas@transgene.fr