How is Merck supporting innovation in oncology?

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2 How is Merck supporting innovation in oncology? We sponsor research and advanced medical education globally, reflecting our commitment to science, education and patient care We support the development and delivery of independent advanced medical training for scientists, physicians, nurses, pharmacists and other healthcare professionals

3 Collaborating for success What do we mean by collaborating for success? Combining insights, experience and skills through partnerships with oncology experts, patients and healthcare professionals Taking a global approach to building strong alliances Strategic alliance with Pfizer to develop and commercialise the investigational agent avelumab (anti-programmed death-ligand 1 [PD-L1] monoclonal antibody) Collaboration with the National Cancer Institute, USA: sponsorship of M9241 (immunocytokine) clinical trials

4 As one for patients We are deeply committed to changing the cancer landscape We have a proven track record in developing novel anticancer medicines We have invested in a vibrant, diverse and innovative pipeline, which is being investigated in a variety of cancers Our vision is to foster strong and productive collaborations 33With patients 33With oncology experts 33With healthcare professionals 33With pharma partners

5 Merck global grants The Grant for Oncology Innovation (GOI) builds on the success of other grants we support, which are awarded annually to researchers and clinicians worldwide Grant for Fertility Innovation GGI GRANT FOR GROWTH INNOVATION Grant for Multiple Sclerosis Innovation (GMSI)

6 History of the GOI G I O The GOI is an initiative funded by Merck to identify and support innovative projects to advance research on personalised treatment for solid tumours

7 Which research topics do we consider? Molecular biomarkers or new targeted treatments Technology platforms for routine analysis of molecular biomarkers Side-effect management Platforms or tools allowing patients to access individualised treatment

8 In 2017, we received 100 scientifically diverse applications from 17 countries across the globe

9 Our commitment to supporting the GOI winners A total, annual grant of up to 1,000,000 will be shared by a number of selected projects Academic freedom* Commitment to publication *Subject to appropriate auditing and monitoring

10 What makes a GOI winner? Relevance to patient care Scientific impact Relevance for the personalisation of treatment Innovative approach Feasibility

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13 Renata Maria Grifantini Alena Gros Anguraj Sadanandam Naureen Starling

14 Renata Maria Grifantini, Italy Renata Maria Grifantini has a doctoral thesis in Biology, a PhD in Molecular and Cellular Biology, and a professional certification as a biologist. During and after her university degree, she was a visiting scientist at the Max Plank Institute, Berlin, Germany. Most of her research activity has taken place in industry. From at ENI-Research, Milan, Italy, she conducted research in the field of biotechnology. The research focused on the optimisation of pharmacologically active proteins through the use of molecular engineering and structural proteomic approaches. Following this, she was Project Leader at Novartis Vaccines & Diagnostics ( ), formerly Chiron Vaccines, in Siena, Italy, leading research on the identification and preclinical development of vaccine candidates against different bacterial pathogens. After this role, from , she became Research Director at Externautics SpA, Siena, a biotech company focused on the development of novel cancer markers and therapeutic targets, as well as the generation and preclinical development of marker-specific monoclonal antibodies with therapeutic potential. In June 2016, she joined the National Institute of Molecular Genetics, Milan, as Head of Translational Research. She is mainly involved in the identification and validation of novel markers for cancer and autoimmune diseases, as well as novel potential targets for immunotherapy.

15 Abstract: Novel targets of tumour-infiltrating CD4+ regulatory T cells for immunotherapy Cancer cells express specific antigens that may be targeted by T-cell-mediated immune response. However, cancer cells can escape immune surveillance through activation of specific inhibitory signalling pathways, termed immune checkpoints. Therapeutic strategies blocking immune checkpoints, such as programmed death-1/programmed death-ligand 1 and CTLA-4, are emerging as breakthroughs in cancer immunotherapy and, at present, four monoclonal antibodies (mabs) targeting these molecules have been approved by the US Food & Drug Administration for the treatment of several types of cancer. Despite important therapeutic effects, immune checkpoint inhibition is often associated with a unique spectrum of immune-related adverse events (iraes), likely due to a general depression of the immune system that could prevent prolonged treatments. Although steroids can be used to treat iraes, the associated immunosuppression can compromise the antitumour response. Moreover, the number of patients who do not respond to available mabs is still high. CD4+ regulatory T lymphocytes (Tregs), which are physiologically engaged in the maintenance of immunological self-tolerance and immune homeostasis, are potent suppressors of effector cells and infiltrate at high frequencies in various types of cancers. A selective targeting tumour-infiltrating Treg cell should de-repress the immune response in the tumour area and have a safer therapeutic profile. This project intends to exploit antigens overexpressed in tumour Tregs identified at the Istituto Nazionale di Genetica Molecolare 1 as novel targets for therapeutic mabs. Specific objectives are: 1) validate tumour Treg-associated antigens as novel immune checkpoints; and 2) select mabs able to selectively deplete tumour Tregs in proof-of-concept efficacy models. These mabs could offer new opportunities both in single-agent and combinatorial oncologic therapy. 1. De Simone M et al. Immunity, 2016;45:

16 Alena Gros, Spain Alena Gros received her PhD from the University of Barcelona, Barcelona, Spain. Following that, Alena joined Dr Steven Rosenberg s group at the National Institutes of Health, National Cancer Institute (NCI), Bethesda, MD, USA, where she worked for 7 years. Her work at the NCI led to the identification of biomarkers that can guide the detection and isolation of tumour-reactive and mutation-specific T cells from the tumour and peripheral blood of cancer patients. These findings may have important implications for making T-cell-based immunotherapies more widely available. Alena joined the Cancer Immunotherapy Program at the Vall d Hebron Institute of Oncology (VHIO), Barcelona, in October At VHIO, her work focuses on developing personalised T-cell-based cancer immunotherapies for patients with solid cancers. In addition, she is also studying whether the presence or specific T-cell qualities of mutation-specific lymphocytes influence antitumour T-cell responses and clinical outcomes in patients treated with immune checkpoint inhibitors.

17 Abstract: Personalised non-invasive T-cell therapies targeting the mutanome Tumours accumulate genetic alterations, some of which can generate non-self neoantigens, which can trigger an antitumour T-cell response. Neoantigens play an important role in the antitumour efficacy of cancer immunotherapies and this has accelerated the development of personalised vaccines and T-cell-based therapies targeting neoantigens. Adoptive transfer of mutation-specific lymphocytes that recognise a mutation in ERBB2IP- or KRAS-induced durable tumour regression in a patient with metastatic cholangiocarcinoma and colorectal cancer, respectively. Despite their promising efficacy, frequent detection of neoantigen-specific lymphocytes, which could be exploited therapeutically, is largely limited to the tumour site. However, tumour resection is an invasive process and it is often not possible, limiting the broad application of this therapy. To overcome this limitation, we propose to develop non-invasive personalised T-cell therapies targeting the mutanome to treat patients with metastatic breast, endometrial and colorectal cancer (non-microsatellite instability), who have a poor prognosis and are refractory to standard treatment. Our research plan includes: 1) exploring previously described and novel cell surface receptors that could be used to enrich neoantigen-specific lymphocytes from the peripheral blood of patients with metastatic breast and colorectal cancer; 2) investigating the whole exome sequencing from recently archived paraffin-embedded tumour tissue and circulating tumour cells, and comparison with exome sequencing of fresh tumour biopsies as two alternative non-invasive strategies to identify the somatic non-synonymous mutations used to screen for reactivity against neoantigens; 3) assessing the specificity and functionality of the neoantigen-specific cells isolated from the tumour and peripheral blood; and 4) analysing tumour cell line recognition by the peripheral blood-derived neoantigenspecific lymphocytes. Our recent preliminary data supports that neoantigen-specific lymphocytes can be detected in peripheral blood of patients with metastatic gastrointestinal cancers. The results derived from this project will be exploited to design a clinical trial to treat metastatic solid cancers with non-invasive T-cell therapies targeting the mutanome.

18 Anguraj Sadanandam and Naureen Starling, UK Anguraj Sadanandam, PhD, is a team leader at the Institute of Cancer Research (ICR) with Honorary Appointment at The Royal Marsden Hospital, London, UK. He completed his interdisciplinary (experimental/computational biology) PhD and Postdoctoral Fellowships in the USA and Switzerland. As breakthrough studies, he defined molecular subtypes associated with cellular origin/phenotypes and developed biomarker assays in colorectal, pancreatic and breast cancers. He has suggested potential precise therapies in these cancers, which are being explored for prospective applications in the clinic. Currently, he is focusing on studying inter- and intra-tumoural heterogeneity, cancer evolution related to metastasis and therapeutic responses (companion diagnostic-based personalised responses) in gastrointestinal cancers, and integrating genome phenome by using in silico, in vivo and in vitro techniques.

19 Naureen Starling is Consultant Medical Oncologist at The Royal Marsden Hospital, London, UK, specialising in the treatment of gastrointestinal (GI) cancers, and Honorary Clinical Senior Lecturer at the Institute of Cancer Research (ICR), London. She is also the Associate Director of Clinical Research at The Royal Marsden Hospital and ICR. She graduated from University College London with First Class Honours in physiology (BSc) and distinctions in clinical pharmacology/therapeutics and pathology. Her research interests in GI cancers (oesophageal, gastric, pancreatic, neuroendocrine and colorectal) focus on earlier phase clinical trials, novel therapeutics and the delivery of individualised medicine to patients with GI cancers. Dr Starling is a principal investigator on numerous international clinical trials of novel drugs in GI cancers and actively involved in translational research in GI cancers.

20 Abstract: Characterising the evolution of metastatic colorectal cancer and its immune microenvironment for therapeutic vulnerability Colorectal cancer (CRC) is a highly recurrent and metastatic disease. Every year, there are approximately 690,000 deaths due to CRC worldwide. Despite decades of scientific and clinical research, palliative chemotherapy combined with anti-vascular endothelial growth factor or anti-epidermal growth factor receptor therapy (RAS wild-type metastatic CRC [mcrc]) remains the mainstay of treatment of mcrc. Whilst survival gains have been observed, progress has been limited and therapy-associated toxicity remains significant. A step change is urgently required to identify subgroups of mcrc patients predicted to respond to both available/novel therapies, including immunotherapy, whilst minimising toxicity. Our group has significantly contributed to this area by defining four consensus molecular subtypes associated with prognosis and therapy response. 1,2 Our subtypes were validated by multiple groups and were associated with response to combination chemotherapy. However, subtypes were based largely on early-stage CRC and the applicability to mcrc is currently unknown.

21 Our proposal extends our research to subtyping mcrc, building on our experience of similarly studying primary versus metastatic diseases in pancreatic cancer. 3,4 We propose that this will have greater therapeutic relevance for patients with mcrc. We will use in vivo models, single cell transcriptomics and in-house novel bioinformatics tools to: Characterise the presence of different gene expression subtypes in mcrc and how they evolve spatially and temporally during tumour progression from the primary to the metastatic lesion Understand the interactions between metastatic cells and their microenvironment, including immune cell infiltrates Test the consequences of disrupting the metastatic/immune cell interactions using specific targeted immunotherapies Overall, this proposal will provide an extensive understanding of patient subgroups and the microenvironment of mcrc, and will investigate how best to target different subgroups especially with immunotherapy, a current significant challenge for this disease. 1. Sadanandam A et al. Nat Med 2013;19:619 25; 2. Guinney J et al. Nat Med 2015;21:1350 6; 3. Sadanandam A et al. Cancer Discov 2015;5: ; 4. Collisson EA et al. Nat Med 2011;17:500 3.

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