1. Publishable Summary

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1 1. Publishable Summary 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 8 th 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. However, preliminary data from a MCC registry created within IMMOMEC demonstrate that besides an increasing incidence, the age distribution of patients is slowly shifting towards younger patients. 1. Specific objectives of IMMOMEC, which are also reflected in the respective work package structure, include: 2. Establish an effective therapy for MCC evaluated in a multicenter randomized clinical phase II trial 3. Establish the feasibility of effective immunotherapy for solid cancers 4. 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 5. Identification of prognostic and predictive biomarkers, i.e. search for markers foretelling the course of disease or treatment response in MCC, respectively 6. 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, indeed it took until month 36 to activate and initiate all clinical partners. Work performed since the beginning of the project and main results achieved so far The mainstay of the project (WP1) is a Phase II study of the tumor-targeting human F16IL2 monoclonal antibody-cytokine fusion protein in combination with paclitaxel versus paclitaxel alone to treat patients with MCC. The Clinical Trial was planned to take place in nine different sites, in seven countries; for each country, the approval of the different regulatory authorities had to be and was obtained. This commitment implied that an important number of documents were prepared and submitted the Competent Authorities and Ethics Committees that received and reviewed them and ask for further details or clarifications. Notably, the duration of the respective procedure varied not only from country to country but also from Ethics Committee to Ethics Committee within the same country. Within the reporting period, we received full approvals in all the seven sites where the Clinical Trial will be actually carried on. Within the reporting period, 4 centers successfully recruited patients into the trial. Unfortunately, two of the centers, i.e. Graz and Nottingham that were initially planned, will not take part of the multicenter study, due to internal difficulties. Major advances in cancer therapy over the past years were due to a better understanding of the tumor biology and immunology, thereby allowing a more personalized therapy. Consequently, within the IMMOMEC consortium we set out to identify biomarkers predicting patient prognosis, Draft date: :14 Page 6 of 103

2 treatment outcome and immune response (WP2). Within the reporting period, we performed a retrospective analysis of archived MCC tissue samples and thereby established techniques for measuring tissue derived biomarkers which are feasible using formalin-fixed paraffin-embedded (FFPE) tissue. Notably, it was possible to identify biomarkers, which allow to correlate systemic (i.e. detected in circulating blood) and tumor-pinpointed (i.e. within the tumor microenvironment). immune responses. Moreover, we established a pseudonymized on-line registry for MCC patients for but not restricted to the IMMOMEC consortium. In fact, the input boxes are open to any interested participant ( Methods for data validation and safeguarding the uniqueness of the data set had been developed and implemented. Based on data from this registry, we were able to demonstrate that the MCPyV status of MCC is not associated with the clinical course of the disease (Merkel cell polyomavirus status is not associated with clinical course of Merkel cell carcinoma. Schrama D, Peitsch WK, Zapatka M, Kneitz H, Houben R, Eib S, Haferkamp S, Moore PS, Shuda M, Thompson JF, Trefzer U, Pföhler C, Scolyer RA, Becker JC. J Invest Dermatol Aug;131(8): doi: /jid). 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. In order to allow the comprehensive immune monitoring of the immune modulating therapy, i.e. the tumor targeted delivery of the T-cell growth factor interleukin-2, it is mandatory to identify immune dominant epitopes of MCC cancer cells. Since we and others have previously demonstrated that the majority of MCC cancer cells are characterized by an oncogene addiction to the early, transforming gene products of the derived from the oncogenic proteins of the Merkel Cell Polyomavirus (MCPyV) (Merkel cell polyomavirus-infected Merkel cell carcinoma cells require expression of viral T antigens. Houben R, Shuda M, Weinkam R, Schrama D, Feng H, Chang Y, Moore PS, Becker JC. J Virol Jul;84(14): doi: /JVI ), we focused on T-cell epitopes derived from these proteins (WP3). To this end we performed an in silicio screening for possible peptide epitopes derived from the oncogenic small and large T antigens of MCPyV. After identification these peptide epitopes were validated for binding to the respective HLA class I molecules followed by construction of peptide/mhc class one multimers for detection of antigen specific T cells in MCC patients. These efforts were successful and resulted in unequivocal data demonstrating the presence of MCPyV-reactive T cells in the circulating blood obtained from the majority of MCC patients. Moreover, we were able to demonstrate that these MCPyV reactive T cells are functional active, i.e. able to exert cytotoxicity against HLA-matched MCC cancer cells. These results were recently published (T-cell responses to oncogenic merkel cell polyomavirus proteins distinguish patients with merkel cell carcinoma from healthy donors. Lyngaa R, Pedersen NW, Schrama D, Thrue CA, Ibrani D, Met O, Thor Straten P, Nghiem P, Becker JC, Hadrup SR. Clin Cancer Res Apr 1;20(7): doi: / CCR ). In the IMMOMEC clinical trial standardized and centralized analysis of specific and functional T lymphocytes will be performed in order to monitor each patient s immune competence during successful F16-IL2 delivery (WP4). To this end, a network of specialized cell culture laboratories has been successfully established for the standardized and GCP-compliant collection of patients peripheral blood mononuclear cells (PBMC) (WP4). As the available PBMC cell numbers per patient are expected to be limited and furthermore the number of immune-dominant T-cell epitopes identified from MCV and MCC tumor antigens Draft date: :14 Page 7 of 103

3 identified in WP3 may vary, immatics routine immune monitoring assays were adapted to include important cell-saving technologies in preparation for the IMMOMEC clinical trial: Successful implementation and validation of a new Multimer Multiplexing technology and following comparison of its sensitivity to immatics currently used routine Multimer technology. Additionally, immatics has finalized its investigations on further cell-saving technologies (e.g. ex vivo analysis of rare cells), with the objective that a maximal data set can be generated out of the inherently limited biological material within the IMMOMEC clinical trial. The data from the WP will be used for correlation of systemic immunological responses and clinical benefit (WP5); however, to the delay in the initiation of the clinical trial this WP could not be started yet. In the first reporting period we established the prerequisites for internal and external communication: (i) Design and implementation of the IMMOMEC website, (ii) Design, translation and print of the IMMOMEC flyer, (iii) Implementation of EMDESK as management tool, and (iv) Constitution of the external/scientific advisory board. In the second reporting period the focus of WP6 had been to facilitate internal and external communication. This was done by maintaining and extending of the IMMOMEC website ( maintaining and upgrading EMDESK as management tool, and organization of the annual meetings. Moreover, since the kick-off meeting the consortium was actively seeking external advice, i.e. by constitution an external/scientific advisory board. Indeed, the external/scientific advisory board participated in the 2 nd Annual Meeting and the 1 st Workshop held in Frankfurt in June 2013 as well as the 3 rd Annual Meeting and the 2 nd Workshop held in Essen in June In the first 36 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. In parallel, the investigational product F16-IL2 has been produced according to Good Manufacturing Procedure (GMP) standards. 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 (Immune monitoring of MCC patients under therapy) and WP6 (Management of the project and the consortium); all methodical prerequisites for the planned work in WP5 have been established and will start with full force once sufficient number of patients have be recruited into the trial and the respective material have been shipped to Essen. 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 the only, but unfortunately major significant problem was the delayed initiation of the clinical trial as outlined above and described in detail under WP1. This is due to the fact that, we underestimated the time needed for regulatory and ethical approval as well as to overcome administrative obstacles in an international study. However, now 7 out of 9 clinical sites have been initiated and 4 of them have already recruited patients into the trial. Unfortunately, two of the centers, i.e. Graz and Nottingham that were initially planned, will not take part of the multicenter study, due to internal difficulties. Nevertheless, all scientific work packages of IMMOMEC not depending on material from the clinical trial adhered to the timeline as planned. 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. Draft date: :14 Page 8 of 103

4 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 antibodytargeted 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. This 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. In this respect, it is important to note, that we were able to launch an Investigator Initiated Trial (IIT) for adjuvant therapy of MCC patients with no evidence of disease (ADMEC, EudraCT ) testing in a randomized fashion the effect of the anti-ctla-4 antibody ipilimumab. This trial is conducted largely with participation of the IMMOMEC consortium funded by an educational grant provided by Bristol-Myers Squibb. Notably, this trial would not have been possible without the network established in IMMOMEC. Moreover, the experience gained during the initiation of the IMMOMEC trial allowed us to initiated the ADMEC trial in France, Germany and Poland within one year. Draft date: :14 Page 9 of 103

5 Project logo, contact details, address of project public website The IMMOMEC logo (Figure 1) was designed in order to identify the project. It is used together with the Grant Agreement number HEALTH-F , the FP7 logo and the European flag, on any printed and electronic issues for the communication with the European Commission and for any other official contact. Figure 1: IMMOMEC Logo Public awareness of IMMOMEC has been addressed by the website This web page is hosted by beneficiary 1 (MUG) and contains general information about the IMMOMECproject, its beneficiaries and contact persons. Contact details - Project Coordinator Medical University of Graz Prof. Dr. Dr. Jürgen C. Becker Auenbruggerplatz 8, 8036 Graz, AUSTRIA Phone: Fax: juergen.becker@medunigraz.at Essen University Hospital Prof. Dr. Dr. Jürgen C. Becker Translational Skin Cancer Research - tscr / L441 Department Head Deutsches Konsortium für Translationale Krebsforschung - DKTK Phone: j.becker@dkfz.de Draft date: :14 Page 10 of 103