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FP7

IMMOMEC Sintesi della relazione

Project ID: 277775
Finanziato nell'ambito di: FP7-HEALTH
Paese: Austria

Periodic Report Summary 1 - IMMOMEC (IMmune MOdulating strategies for treatment of MErkel cell Carcinoma)

Project Context and Objectives:

Description of the project objectives
Epidemiologic data suggest that there are approximately 2500 new MCC cases per year within the EU; approximately 1000 of these patients will die from their disease. The incidence of MCC is considerably increasing: The reported incidence has more than tripled over the past 20 years. This increase can partially be explained by the demographic development since MCC usually affects the elderly; the median age at diagnosis is in in the 8th decade of life, and there is a 5- to 10-fold increase in incidence after age 70 as compared with an age less than 60 years. Thus, it is likely that in an ageing European population the impact of this deadly cancer will continue to increase.
Specific objectives of IMMOMEC, which are also reflected in the respective work package structure, include:
1. Establish an effective therapy for MCC evaluated in a multicenter randomized clinical phase II trial
2. Establish the feasibility of effective immunotherapy for solid cancers
3. Identification and characterization of HLA-restricted immune dominant T cell epitopes specific for MCC to monitor the immune modulating effect and to develop specific therapeutics
4. Identification of prognostic and predictive biomarkers, i.e. search for markers foretelling the course of disease or treatment response in MCC, respectively
5. Establish a European network for research and therapy of MCC
IMMOMEC is structured in three periods: (i) preparatory, (ii) active therapy and (iii) observation and analysis. The preparatory phase was planned for 12 months; however, due to administrative and regulatory hurdles to be overcome in each country, this preparatory period had to be extended to 18 months. Hence, the objectives of the reporting period were mainly focused on preparing the actual trial.

Project Results:
Work performed since the beginning of the project and main results achieved so far
Specifically work for the following objectives was undertaken:
i. Prerequisite work necessary for initiation of the clinical trial with respect to:
• Production of the investigational product in GMP quality
• Preparation of the clinical trial protocol, including the respective Case Report Forms, Patient Information Sheet, and Informed Consent Form
• Submission to the respective Ethics Committees/Internal Review Boards
• Submission to the respective Regulatory Agencies
ii. Prerequisite work necessary for immune monitoring of the clinical trial with respect to:
• Training of the clinical sites to obtain high quality PBMCs
• Logistics for the transport of PBMCs
• Set up of immune monitoring assays
iii. Retrospective analysis of archived MCC tissue samples to:
• Establish techniques for measuring tissue derived biomarkers
• Validation of possible tissue derived biomarkers with the clinical course of the disease
• Establish an on-line registry and central database for clinical, therapeutic and biologic data on MCC cases for but not restricted to the consortium
iv. Initial work for identification of immune dominant epitopes derived from the oncogenic proteins of the Merkel Cell Polyomavirus
• in silicio screening for possible peptide epitopes derived from MCC associated onco-proteins
• validation of the binding of the predicted epitopes to HLA class I molecules
• construction of peptide/MHC class one multimers for detection of antigen specific T cells in MCC patients
v. Prerequisites for internal and external communication
• Design and implementation of the IMMOMEC website
• Design, translation and print of the IMMOMEC flyer
• Implementation of EMDESK as management tool
• Kick-off meeting (aka 1st Annual Meeting)
• Constitution and Invitation of the external/scientific advisory board
• 2nd Annual Meeting and 1st Workshop
• Planning of the 2nd Workshop as 1,5 day meeting in conjunction with (i.e. as a Primer of) the 7th International Conference on “HPV, Polyomavirus and UV in Skin Cancer” in Novara
IMMOMEC is based on a prospectively randomized phase II trial for the therapy of advanced Merkel cell carcinoma (MCC), which will compare a commonly used chemotherapeutic intervention alone with a combination of this chemotherapeutic with an immune modulator, i.e. the targeted delivery of IL2 to the tumor microenvironment by the Tenascin C-specific immunocytokine F16-IL2. Moreover, the comprehensive translational research program associated with the clinical trial will address prognostic and predictive biomarkers for the clinical course of the disease.
According to these preconditions, IMMOMEC is structured in three periods: (i) preparatory, (ii) active therapy and (iii) observation and analysis. The preparatory phase was planned for 12 months; however, due to administrative and regulatory hurdles to be overcome in each country, this preparatory period had to be extended to 18 months.
Since the actual start of the work all partners performed their respective parts as outlined in the work program. The coordinator is pleased to report that no significant problems have occurred with the execution of the tasks and that – apart from the 4 months delay in the actual start of the work described above – all scientific of IMMOMEC adhered to the timeline as planned. However, we underestimated the time needed for regulatory and ethical approval as well as to overcome administrative obstacles. Particularly, discussions with the different ethical committees within the different countries were time consuming due to the lack of harmonization of the requested changes or explanations.
In the first 18 months most of the work was dedicated to meet the demands to initiate the conduct of the clinical trial and the associated translational research program. Thus, the most evident progresses have been achieved in WP1 (Randomized phase II trial paclitaxel alone versus paclitaxel in combination with F16-IL2), WP2 (Identification of biomarkers predicting patient prognosis, treatment outcome and immune response), WP4 (Immunomonitoring of MCC patients under therapy) and WP6 (Management of the project and the consortium). To this end, the protocol for the clinical trial was written, discussed and agreed upon by the consortium; the discussion of the protocol took advantage of the IMMOMEC website. Subsequently, the Patient Information Sheet (PIS), the Informed Consent Form (ICF) and the Case Report Forms (CRF) were drafted, circulated and consented. By the end of 2012, the clinical trial was submitted for approval at the respective Ethical Committees/Internal Review Boards (EC/IRB) and the respective regulatory authorities responsible for the clinical partners of the IMMOMEC consortium; notably, we obtained positive votes and regulatory approval from most clinical partners. In parallel, the investigational product F16-IL2 has been produced according to Good Manufacturing Procedure (GMP) standards.
The translational research program is focusing on one hand on the identification and validation of MCC-specific T cell epitopes, e.g. derived from the oncogenic T antigens encoded by the Merkel cell polyomavirus, and on the other hand on the identification of prognostic and predictive biomarkers as well as the detailed analysis of possible immune escape mechanisms with a focus on the in situ situation. To this end, the training of the clinical sites to obtain high quality PBMCs, the set up of the logistics for the transport of PBMCs to the central center for immune monitoring, as well as the set up of the respective immune monitoring assays was successfully performed.
Albeit not as obvious, substantial progress has been made in WP2 (Identification of biomarkers predicting patient prognosis, treatment outcome and immune response) and WP3 (Identification and characterization of HLA-restricted immunodominant MCC-associated T cell epitopes). Given the difficulty in obtaining biological specimens from MCC patients, it is obligatory that specimens are not squandered on unfocused exploratory studies or are evaluated using assays that are seriously lacking in robustness and reproducibility. In order to ensure that the specimens collected during the active clinical trial phase will perform well, standard operating procedures (SOPs) for the collection, processing, and storage of specimens have been established. These initial investigations were done on archived material; thus, ethical approval for these retrospective analyses was obtained immediately after the start of IMMOMEC.
With respect to WP6, the focus had been to facilitate internal and external communication. This was done by the design and implementation of the IMMOMEC website (www.immomec.eu), implementation of EMDESK as management tool, and organization of the kick-off meeting. Moreover, since the kick-off meeting the consortium was actively seeking external advise. Indeed, the constitution of the external/scientific advisory board has been consented, the respective experts invited, and all agreed. Indeed, the full external/scientific advisory board already participated in the 2nd Annual Meeting and the 1st Workshop held in Frankfurt in June 2013.

Potential Impact:
Expected final results and their potential impact and use
IMMOMEC is a project at the frontline of therapeutic, translational and medical research. The project establishes a novel immunotherapy taking advantage of the innovative concept of antibody-targeted cytokines to enrich the respective immune modulating agent at the tumor site.
Treatment MCC patients is currently based solely on anecdotal observations, and thus, on a very low level of evidence. The prospectively randomized European multicentre trial conducted within IMMOMEC will unequivocally establish the clinical impact and immunological effects following therapeutically intended immune modulation by targeted IL2. In case of a positive trial result, an easily applicable therapeutic option with a very favorable risk-to-benefit ratio will be immediately available improving patients’ prognosis and quality of life. Furthermore, IMMOMEC holds the promise to provide the proof-of-concept data that immune modulation, i.e. targeting IL2 to the tumor microenvironment, is an effective therapeutic strategy for solid cancers. Notably, this form of immune modulation can be readily conveyed to other tumor entities, such as prostate, lung or breast cancer. Moreover, targeting IL2 to the tumor microenvironment is likely to be an ideal combination partner for other immune therapeutic intervention such checkpoint blockade by anti-CTLA-4 or anti-PD-1 antibodies.
IMMOMEC will have a substantial impact on the standing of the European Community in the field of clinical and translational R&D in rare cancer research and tumor immunology. Most European centers caring for patients with MCC are organized within the EORTC. However, no multicentre trials for MCC have been organized by this European organization in the past.
IMMOMEC intensified the direct cooperation of centers from all over Europe with regard to both patient care and translational research. Today, most clinical trials initiated by large pharmaceuticals companies (‘big pharma’), even those with a European background, are coordinated by the US. Indeed, in most cases these trials are only expanded to European countries when initial results are promising, which leads to a systematic advantage of US research groups in the competition for research subsidies. Demonstration of a well functioning European network that is able to conduct a randomized clinical trial even in a very rare cancer within due time will improve the standing of European groups in general, and will render this MCC-network in particular more competitive for investments by big pharma .

List of Websites:

www.immomec.eu

Informazioni correlate

Documenti e pubblicazioni

Contatto

Juergen Becker, (Department Head)
Tel.: +4331638513400
Fax: +4331638513424
E-mail

Argomenti

Life Sciences