Tumor Associated Macrophages as a Novel Target for Cancer Therapy

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1 Tumor mass Tumor Associated Macrophage Tumor Associated Macrophages as a Novel Target for Cancer Therapy This booklet contains forward-looking statements that are based on Amgen s current expectations and beliefs and are subject to a number of risks, uncertainties, and assumptions that could cause actual results to differ materially from those described. All statements, other than statements of historical fact, are statements that could be deemed forward-looking statements. Forward-looking statements involve significant risks and uncertainties, including those more fully described in the Risk Factors found in the most recent Annual Report on Form 10-K and periodic reports on Form 10-Q and Form 8-K filed by Amgen with the U.S. Securities and Exchange Commission, and actual results may vary materially. Except where otherwise indicated, Amgen is providing this information as of March 31, 2017 and does not undertake any obligation to update any forward-looking statements contained in this booklet as a result of new information, future events, or otherwise. Provided as an educational resource. Do not copy or distribute Amgen Inc. All rights reserved. USA-OCF

2 The Immune System Can Detect and Destroy Cancer Cells Cancer development is strongly influenced by the immune system. Both innate and adaptive immunity contribute to immune surveillance, allowing the host to recognize and eliminate nascent tumors. 1 The complex interactions that facilitate effective immune-mediated destruction of malignant cells have been described as the cancer-immunity cycle. Each step of the cancer-immunity cycle requires the coordination of numerous factors that are both stimulatory and inhibitory in nature. A T cell response is initiated when tumor antigens are captured, processed, and presented to T cells on MHC I and II molecules. Dendritic cells (DCs) play a critical role in the activation of the adaptive immune system. Activated DCs travel to tumor-draining lymph nodes where they prime naïve T cells to become effector T cells capable of killing cancer cells. Activated effector T cells migrate to the tumor and infiltrate the tumor bed, where they kill cancer cells and trigger additional antigen release that can induce subsequent rounds of anticancer immunity. 2 ST EP 3 Priming of T cells Naïve T cell STEP 4 Co-stimulatory molecules influence the T cell response Mature T cell ST EP 2 Dendritic cell STEP 1 Tumor antigens are taken up by dendritic cells ST EP 5 Antigens STEP 6 Infiltration of T cells into tumors STEP 7 Tumor apoptosis Tumor cell

3 Cancer Cells Impede an Effective Anti-Tumor Immune Response The interaction between various cells in the tumor microenvironment promotes tumor growth and progression. Crosstalk between parenchymal and stromal cells representative of cancer cells, cancer stem cells, endothelial cells, immune inflammatory cells, pericytes, cancer-associated fibroblasts, stem cells and progenitor cells of the tumor stroma promotes tumor growth and progression. Cancer cells themselves act to evade immune cell attack by interfering with multiple components of the immune system and suppressing cytolytic T cells. Furthermore, recruitment of immunosuppressive T regulatory cells into the tumor can also contribute to the breakdown of an effective antitumor immune response. 1 While the immune system utilizes several mechanisms to mount an immune response, several processes can diminish the effectiveness of the host immune response. For example, poor detection of tumor antigens or misidentification of tumor antigens as self, can limit the effectiveness of antigen presentation, provoking an inhibitory T regulatory response rather than an effector T cell reaction. To further decrease the effectiveness of an immune response, T cells may fail to properly localize to the tumor microenvironment or they may not effectively infiltrate the microenvironment, thereby diminishing T cell access to cancer cell targets. Locally, factors produced in the tumor microenvironment may also abrogate the anti-tumor activities of effector T cells that do gain access. 2 Cancer cells may secrete immunosuppressive factors that inhibit cytotoxic T cells, and/or recruit immunosuppressive inflammatory cells that include macrophages, mast cells, and neutrophils. 1 Inhibition of T cell priming by interleukins T reg cells Dendritic cells may not recognize antigens as targets for destruction Naïve T cell Suppressive factors within the tumor microenvironment may inhibit effector cells that manage to access the tumor Dendritic cell Mature T cell Tumor cell

4 s Are Key Components of the Tumor Microenvironment Tumor mass Tumor-associated macrophages (s) have been shown to play an important role in tumor progression by promoting tumor invasion, migration and angiogenesis. Direct contact between cancer cells and s can facilitate tumor metastasis, wherein pre-metastatic tumor cells direct recruitment through the secretion of numerous chemokines or cytokines. 3 Hypoxic Area s express a variety of mediators that promote an immunosuppressive microenvironment that abrogates an effective host anti-tumor immune response. 4 Local expression of potent immunosuppressive factors, including interleukin-10 and TGF-ß, directly inhibit the anti-tumor activities of effector T cells and suppress the capacity for effective tumor-associated antigen presentation. 4 6 Within the tumor microenvironment, the production of immunostimulatory molecules such as IL-12 is suppressed by s, impeding the proliferation and cytotoxic actions of T cells and NK cells. 6 Furthermore, s express inhibitory ligands for receptors on T cells, including the programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4). When activated immune effector cells bind these ligands to s, immune cell receptor signaling is disrupted and T cell cytotoxic activity is inhibited, further promoting an immunosuppressive environment. 7 s also produce an array of molecules that encourage recruitment of, and enhance the survival of regulatory T cells, diminishing effective host immune anti-tumor activity. 4,7 Together with other stromal components including cancer-associated fibroblasts and endothelial cells, s prevent recruitment and infiltration of cytotoxic T cells into the tumor. 8,9 In addition to undermining the effectiveness of the host anti-tumor response, s act directly to support the growth of tumor cells, enhance their invasive capacity, and facilitate development of tumor vasculature. Invasion is further enhanced as s secrete proteases and other factors that break down the basement membrane in areas of brisk tumor cell proliferation. These factors include matrix metalloproteinases, cathepsins, epidermal growth factor, and tumor necrosis factor-α. 4,5,10,11 Some of these molecules facilitate intravasation of tumor cells into the circulation and direct tumor migration and clustering near blood vessels, thereby accelerating invasion. 7,12 The production of TGF-ß is one means by which s mediate the epithelial-mesenchymal transition (EMT), allowing the detachment of epithelial cells from adjacent cells and promoting migration, invasion and metastasis. 7,10,13 Tumor cell synthesis of colony stimulating factor-1 (CSF1) stimulates s to produce EGF, which further drives EMT and invasion. 11 s also promote metastasis by preparing distant sites to accept colonizing metastatic tumor cells. The arrival and activity of macrophages is a critical milestone in preparation of the pre-metastatic niche to ensure a welcoming environment for development of successful metastatic outposts. 7,11,14 16 Monocyte Immunosuppression Angiogensis Invasion Metastasis s promote angiogenesis, especially in hypoxic areas within the tumor microenvironment, by secreting factors including IL-8, TNF-ß, thymidine phosphorylase, and vascular endothelial growth factor (VEGF). Importantly, CSF1 stimulates VEGF production by s, promoting angiogenesis. 4,7,10,11

5 The CSF1R Signaling Pathway Drives the Recruitment of S to the Tumor Microenvironment Tumor mass The CSF1R-signaling pathway is responsible for the recruitment of circulating monocytes to tumors, as well as their development into macrophages and their subsequent differentiation. 7 Within the microenvironment, growth factors, cytokines and chemokines are believed to reprogram s towards specific phenotypic and functional roles, whether tumorigenic or tumoristatic. 7,17 In return, tumorigenic s further support tumor development using a variety of mechanisms including creation of an immunosuppressive milieu, production of mitogenic factors, as well as promoting angiogenesis, and degrading the tumor extracellular matrix thereby aiding invasion and metastasis. 4 6 Tumor cell Recruitment of monocytes/macrophages Monocyte c-fms

6 CSF1R: A Therapeutic Target to Modulate the Tumor Microenvironment Therapeutic strategies aimed at inhibiting the CSF1R-CSF1 axis may result in diminished s infiltration in tumors and may decrease the tumor-supporting actions of s. Agents currently under investigation include monoclonal antibodies, antisense oligonucleotides, peptides, and kinase inhibitors. 17,18 Studies specific to inhibition of CSF1R-CSF1 signaling demonstrated a marked diminution in the number of s within hours of exposure. 10,19 Interruption the CSF1R-CSF1 pathway thus may support the immune response to cancer from targeting PD1, PD-L1, or CTLA4. 7 Tumor mass Invasion c-fms X X X Angiogensis Metastasis Immunosuppression Interuption of the CSF1R-CSF1 pathway

7 Tumor Associated Macrophages as a Novel Target for Cancer Therapy Although cytotoxic T cells play a central role in the anti-tumor effects of the immune system, tumors themselves promote development of microenvironments that actively impede the host immune response. s are a phenotypically diverse group of cells that populate the tumor microenvironment and can inhibit anti-tumor immune responses and promote tumor growth. The CSF1R signaling pathway drives recruitment of s to the tumor microenvironment and promotes the differentiation of these cells toward a pro-tumorigenic phenotype. As such, targeting the CSF1R-CSF1 axis may result in diminished infiltration into tumors and may allow for enhanced host anti-tumor immune responses. Interfering with CSF1R may represent a promising strategy to abrogate the tumor-supporting activities of s. Tumor apoptosis c-fms

8 References 1. Hanahan D, Weinberg RA. Cell. 2011;144: Chen DS, Mellman I. Immunity. 2013;39: Bingle L, Brown NJ, Lewis CE. J Pathol. 2002;196: Raggi C, Mousa HS, Correnti M, et al. Oncogene. 2016;23: Jinushi M, Komohara Y. Biochim Biophys Acta. 2015;1855: Lewis CE, Pollard JW. Cancer Res. 2006;66: Noy R, Pollard JW. Immunity. 2014;41: Joyce JA, Fearon DT. Science. 2015;348: Kraman M, Bambrough PJ, Arnold JN, et al. Science. 2010;330: Panni RZ, Linehan DC, DeNardo DG. Immunotherapy. 2013;5: Chanmee T, Ontong P, Konno K, et al. Cancers. 2014;6: Wyckoff JB, Wang Y, Lin EY, et al. Cancer Res. 2007;67: Bonde AK, Tischler V, Kumar S, et al. BMC Cancer. 2012;12: Joyce JA, Pollard JW. Nat. Rev. Cancer. 2009;9: Qian B, Deng Y, Im JH, et al. PLoS ONE. 2009;4: e Ruffell B, Coussens LM. Cancer Cell. 2015;27: Ostuni R, Kratochvill F, Murray PJ, et al. Trends Immunol. 2015;36: Mantovani A, Allavena P. J Experimental Medicine. 2015;212: Mitchem JB, Brennan DJ, Knolhoff BL, et al. Cancer Res. 2013;73:

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