Just Accepted by Current Medical Research & Opinion Review Tumor Necrosis Factor, Tumor Necrosis Factor Inhibition, and Cancer Risk Hervé Lebrec, Rafael Ponce, Bradley D. Preston, Jan Iles, Teresa L. Born, Michele Hooper doi: 10.1185/03007995.2015.1011778

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Abstract Objective: Tumor necrosis factor (TNF) is a highly pleiotropic cytokine with multiple activities other than its originally discovered role of tumor necrosis in rodents. TNF is now understood to play a contextual role in driving either tumor elimination or promotion. Using both animal and human data, this review examines the role of TNF in cancer development and the effect of TNF and TNF inhibitors (TNFis) on malignancy risk. Research design: A literature review was performed using relevant search terms for TNF and malignancy. Results: Although administration of TNF can cause tumor regression in specific rodent tumor models, human expression polymorphisms suggest that TNF can be a tumor-promoting cytokine, whereas blocking the TNF pathway in a variety of tumor models inhibits tumor growth. In addition to direct effects of TNF on tumors, TNF can variously affect immunity and the tumor microenvironment. Whereas TNF can promote immune surveillance designed to eliminate tumors, it can also drive chronic inflammation, autoimmunity, angiogenesis, and other processes that promote tumor initiation, growth, and spread. Key players in TNF signaling that shape this response include NF-κB and JNK, and malignant-inflammatory cell interactions, each of which may have different responses to TNF signaling. Focusing on rheumatoid arthritis (RA) patients, where clinical experience is most extensive, a review of the clinical literature shows no increased risk of overall malignancy or solid tumors such as breast and lung cancers with exposure to TNFis. Lymphoma rates are not increased with use of TNFis. Conflicting data exist regarding the risks of melanoma and nonmelanoma skin cancer. Data regarding the risk of recurrent malignancy are limited. Conclusions: Overall, the available data indicate that elevated TNF is a risk factor for cancer, whereas its inhibition in RA patients is not generally associated with an increased cancer risk. In particular, TNF inhibition is not associated with cancers linked to immune suppression. A better understanding of the tumor microenvironment, molecular events underlying specific tumors, and epidemiologic studies of malignancies within specific disease indications should enable more focused pharmacovigilance studies and a better understanding of the potential risks of TNFis.

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TNF and Cancer Risk

Review Tumor Necrosis Factor, Tumor Necrosis Factor Inhibition, and Cancer Risk Hervé Lebrec

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Rafael Ponce

Jan Iles

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Teresa L. Born

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Michele Hooper

Amgen Inc., Thousand Oaks, CA USA

Address for correspondence: Hervé Lebrec, PhD, Scientific Director, Amgen Inc., One, Amgen

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Center Dr, Thousand Oaks, California, USA. Tel: +(650) 244-2043

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Email: [email protected]

Key words: TNF, malignancy, tumor, TNF inhibition, inflammation, cancer [Short title: TNF and Cancer Risk]

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Bradley D. Preston

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TNF and Cancer Risk

Abstract Objective: Tumor necrosis factor (TNF) is a highly pleiotropic cytokine with multiple activities other than its originally discovered role of tumor necrosis in rodents. TNF is now understood to play a contextual role in driving either tumor elimination or

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promotion. Using both animal and human data, this review examines the role of TNF in

risk.

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Research design: A literature review was performed using relevant search terms for TNF and malignancy.

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Results: Although administration of TNF can cause tumor regression in specific rodent tumor models, human expression polymorphisms suggest that TNF can be a tumorpromoting cytokine, whereas blocking the TNF pathway in a variety of tumor models

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inhibits tumor growth. In addition to direct effects of TNF on tumors, TNF can variously affect immunity and the tumor microenvironment. Whereas TNF can promote immune

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surveillance designed to eliminate tumors, it can also drive chronic inflammation, autoimmunity, angiogenesis, and other processes that promote tumor initiation, growth, and spread. Key players in TNF signaling that shape this response include NF-κB and

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cancer development and the effect of TNF and TNF inhibitors (TNFis) on malignancy

JNK, and malignant-inflammatory cell interactions, each of which may have different responses to TNF signaling. Focusing on rheumatoid arthritis (RA) patients, where clinical experience is most extensive, a review of the clinical literature shows no increased risk of overall malignancy or solid tumors such as breast and lung cancers with exposure to TNFis. Lymphoma rates are not increased with use of TNFis. Conflicting

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TNF and Cancer Risk

data exist regarding the risks of melanoma and nonmelanoma skin cancer. Data regarding the risk of recurrent malignancy are limited. Conclusions: Overall, the available data indicate that elevated TNF is a risk factor for cancer, whereas its inhibition in RA patients is not generally associated with an increased

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cancer risk. In particular, TNF inhibition is not associated with cancers linked to immune

underlying specific tumors, and epidemiologic studies of malignancies within specific

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disease indications should enable more focused pharmacovigilance studies and a better

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understanding of the potential risks of TNFis.

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suppression. A better understanding of the tumor microenvironment, molecular events

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TNF and Cancer Risk

Introduction Various lines of evidence demonstrate a relationship between the immune system and cancer risk in humans and animal models1,2. In humans, an increased risk of various cancers is observed in patients with chronic inflammatory conditions3-5, primary

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(congenital) immune deficiencies6,7, acquired deficiencies (eg, HIV/AIDS)8-10, or with

disorders or to support organ engraftment11-14. Additionally, emerging data demonstrate

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the potential for immunotherapy in the treatment of specific cancers15-17 and the strong prognostic value of characterizing the immune composition in the tumor

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microenvironment in predicting patient survival18,19.

Collectively, several juxtaposing models have been proposed to describe the relationship between specific arms of immunity and cancer1. In the tumor

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immunosurveillance/immunoediting model, elements of the innate and adaptive immune system protect the host by eliminating transformed cells, with a mutual evolution of the

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immune response and the cancer as disease progresses20,21. Host immunity can also protect the host by eliminating, or at least suppressing, infection with oncogenic viruses22,23. However, chronic inflammation can contribute to cancer initiation and tumor progression by creating a permissive microenvironment for tumor invasion and

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therapeutics used to suppress inflammation in patients with various inflammatory

metastasis24-27. Finally, chronic antigenic stimulation, as seen with autoimmunity or unresolved pathogenic infection, can drive lymphomagenesis1. Contextual relationships

between specific immune alterations and specific cancers challenge the development of generalizations regarding cancer risk with immune alterations. This challenge is becoming more acute as therapeutic strategies evolve from broad-spectrum immune 4

TNF and Cancer Risk

suppression, used in the treatment of grievous conditions such as organ transplantation, to limited immunomodulation targeting specific cytokines or immune subsets. Tumor necrosis factor (TNF, cachectin, TNF-α) is a central proinflammatory cytokine involved in various inflammatory conditions, including autoimmunity; inhibitors of TNF

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(TNFi) can markedly reduce the inflammation and manifestations of disease in patients

and exists in both soluble and membrane-associated forms. TNF was originally

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identified as a glycoprotein found in the serum of Bacillus Calmette-Guerin–infected mice given endotoxin (also known as lipopolysaccharide). When such serum was administered intravenously, necrosis of sarcomas that had been transplanted

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subcutaneously into mice was observed29,30. Cloning of human TNF was reported 10 years later by several groups31,32. TNF is now known to have potent cytotoxic and proinflammatory effects. The observations that TNF could induce inflammatory

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responses and was elevated at sites of inflammation led researchers to explore the potential therapeutic benefit of inhibiting TNF activity in vivo33,34. A secreted cytotoxic

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protein expressed by lymphocytes was also being characterized, purified, and subsequently cloned35-37. This factor, called lymphotoxin (LT), also demonstrated tumor

necrosis activity and had noticeable sequence identity to TNF38,39. Both LT and TNF

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with these conditions28. TNF is a trimeric protein, expressed from a wide variety of cells,

have been shown to bind and activate TNFR1 and TNFR2, inducing similar in vitro responses such as cytotoxicity in L929 cells38. Both lymphotoxin (LT or LT-α, TNF-β) and TNF bind to the same two receptors: TNF receptor (TNFR) superfamily 1a (TNFRSF1a; p55 or p60, type I, TNFR1, CD120a, ubiquitous expression) and TNFRSF1b (p75 or p80, type II, TNFR2, CD120b, expression 5

TNF and Cancer Risk

is restricted to immune cells)28,40, inducing similar in vitro responses such as cytotoxicity in L929 cells38. Soluble TNFRs are shed forms of the extracellular portion of the receptor40,41 that bind TNF and inhibit its activity, thus regulating the bioavailability of soluble TNF40.

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There are five TNFis that are currently licensed for use in the United States: three

(certolizumab) is a PEGylated Fab' fragment45, and one (etanercept) is a soluble receptor

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Fc fusion protein46. In addition to blocking TNF, only etanercept also inhibits LT; the properties of these agents are outlined in Table 1. Since the approval of the first

marketed TNFi in 1998, globally there have been over 4 million patient-years of exposure

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to etanercept alone47. The broad clinical administration of these therapies, which are used chronically in a variety of inflammatory conditions (Table 1), combined with the identified association of systemic immune suppression (ie, with congenital

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immunodeficiencies or acquired/induced profound immunosuppression) and increased cancer risk, has promoted interest in the potential long-term risks to patients treated with

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TNFis.

In this review, we analyze the current understanding of cancer risk with TNFis based on (a) information relating TNF and tumorigenesis in experimental models, (b)

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(adalimumab, golimumab, and infliximab) are monoclonal antibodies42-44, one

understanding of the relationship between TNF, immunity, and cancer (TNF and tumor immune surveillance, TNF and antiviral immunity, TNF promoter polymorphisms and cancer risk), and (c) the accumulated clinical experience of TNFis over the last 16 years, notably in the treatment of rheumatoid arthritis (RA). A topic search was completed in the MEDLINE and MEDLINE In-Process & Other Non-Indexed Citations on the Ovid 6

TNF and Cancer Risk

database system. The search strategy consisted of using MeSH descriptors for tumor necrosis factor–alpha, lymphotoxin-alpha, cancer, cancer proliferation, malignancy, and immunosurveillance. Relevant clinical literature was searched through Ovid using the following search string: ((etanercept or Enbrel or Remicade or infliximab or adalimumab

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or Humira or golimumab or Simponi or certolizumab or Cimzia) AND (malignancy or

malignant neoplasm or cancer or tumor malignant or neoplasm or unclassified tumor) and

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recurrence)).

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malignancies or neoplasm malignant or neoplasm cancer or malignant tumor or

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Tumor Necrosis Factor and Tumorigenesis in Experimental Studies Antitumor Activities of Tumor Necrosis Factor As mentioned above, TNF was originally identified as a glycoprotein found in the serum

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of Bacillus Calmette-Guerin–infected mice given endotoxin (also known as

transplanted subcutaneously into mice when administered intravenously29,30. The structurally related protein LT has also demonstrated tumor necrosis activity39.

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Experiments using purified TNF or cell lines expressing TNF demonstrate that in the

models of established tumors, TNF can induce tumor necrosis. High concentrations of

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TNF are capable of killing tumor cells in in vitro systems and in animal models48-50. Based on this potential for TNF to induce tumor cell death, the utilization of TNF as a cancer therapy has been explored in the clinical setting. Local administration by isolated

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limb perfusion of TNF in combination with the alkylating agent melphalan or with doxorubicin was effective treatment for patients with metastatic melanoma and

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unresectable soft-tissue sarcomas51-54. Similar results have been observed for liver metastases of colorectal tumors in which isolated hepatic perfusion of TNF and melphalan was introduced via laparotomy55. The predominant effects of TNF delivered

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lipopolysaccharide). Such serum could induce necrosis of sarcomas that had been

directly into tumors by isolated perfusion involve the tumor vasculature51,56. Specifically,

the procoagulant effects of TNFl50 may cause tumor necrosis through thrombus formation

within the vasculature57. Overall, the available experimental data indicate that TNF is at most weakly cytotoxic or cytostatic to malignant cells, and the presence of metabolic

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inhibitors, which suppress downstream TNF signaling factors, is required for TNFinduced apoptosis to proceed58. TNFR1 and TNFR2 are connected to multiple intracellular signaling pathways. TNFR1 can induce expression of genes involved in inflammation, survival, and proliferation

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through activation of kinase signaling cascades that ultimately activate nuclear factor

complex, TNFR1 can trigger cell death through apoptosis or necroptosis (programmed

necrotic cell death; Figure 1)59. On balance, TNF is a poor inducer of apoptosis unless

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accompanied by inhibition of NF-κB, RNA synthesis, or protein synthesis60-62. TNFR2, expressed on a more restricted subset of cells, activates pathways implicated in cell

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survival proliferation and migration and modulates regulatory T-cell function63. Multimerization of transmembrane TNF (caused by association of surface-expressed receptors or through binding to bivalent antibodies) may also induce intracellular

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signaling of TNF-expressing cells (ie, reverse signaling), leading to apoptosis, cell

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activation, or cytokine suppression28.

Although originally identified as a serum factor associated with hemorrhagic necrosis of tumors induced by endotoxin29, TNF is now understood to play a contextual role in driving either tumor elimination or promotion26,58,64-70.

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kappa B (NF-κB)59. Alternatively, through the formation of the death-inducing signaling

Impact of Blocking Tumor Necrosis Factor on Tumorigenesis The impact of blocking TNF on tumorigenesis has been examined using a number of models corresponding to different stages of tumor growth and different types of tumors, as summarized in Table 2. 9

TNF and Cancer Risk

While systemic or intratumoral injection of supraphysiological levels of TNF can cause inhibition of tumor growth, studies examining animal models of tumorigenesis demonstrate that eliminating TNF or its receptors through genetic manipulation (TNF–/– or TNFR–/– mice) is markedly inhibitory to tumor induction and growth.

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Suganuma et al71 and Moore et al72 have reported that TNF knockout (TNF–/–) mice were

carcinogenesis models with chemical induction/promotion. TNF–/– mice are protected

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from urethane-induced tumorigenesis73, and blocking TNF bioactivity with the p75 TNF receptor Fc fusion protein etanercept blocked tumor initiation/promotion and tumor progression in urethane-dosed mice through reduction of tumor microvascular density

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and cell proliferation74. The tumor-promoting activity of TNF was also demonstrated in a benzo[a]pyrene-7,8-diol-9,10-epoxide skin carcinogenesis model75. Endogenous TNFenhanced the malignancy of the lung carcinoma cell line 3LL cells introduced into

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TNF+/+ versus TNF–/– mice as the result of the induction of the promalignant gene secretory leukocyte protease inhibitor SLP176-80. Studies with TNFR-deficient mice

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show similar results. TNFR1/2–/– mice were found to have significantly fewer tumors in response to ultraviolet B irradiation81. TNFR1–/– mice were also resistant to liver tumor formation in a model in which oval cell proliferation is induced by a choline-deficient,

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more resistant to tumor formation compared with TNF+/+ mice when evaluated in skin

methionine-supplemented diet82. -derived factor for promoting an epithelial-

mesenchymal transition in a model of invasive colon cancer77. Inhibition of TNF by etanercept or the antibody infliximab exerted strong antitumoral effects in a pancreatic ductal adenocarcinoma (PDAC) model in severe combined immunodeficiency (SCID) 10

TNF and Cancer Risk

mice, illustrating the important role of tumor-derived TNF in tumor growth78. Administration of etanercept to wild-type (WT) mice after treatment with azoxymethane and dextran sulfate sodium (a model of ulcerative colitis leading to the development of colonic tumors) markedly reduced the number and size of tumors and reduced colonic

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infiltration by neutrophils and macrophages79. TNF also facilitates the clonal expansion

Taken together, these data indicate that in various models, TNF can stimulate or promote

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tumor formation, whereas the lack or inhibition of TNF can reduce tumor formation. Tumor Necrosis Factor and Metastatic Processes in Experimental Models

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Several lines of evidence demonstrate that TNF may promote metastasis of certain tumor cell types. As mentioned earlier, TNF treatment dramatically enhanced PDAC growth and metastasis in a mouse model, whereas TNFi treatment with infliximab or etanercept

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showed strong antitumoral effects, decreasing liver metastases and volumes of recurrent tumors78. Similarly, in a separate in vitro study, TNF treatment of cultured colon-26 cells

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enhanced metastatic properties involving production of metallomatrix protein-9, adhesion, migration, and invasion83-86. Chinese hamster ovary cells overexpressing TNF had a greater ability to invade and metastasize in mice compared with cells not

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and dominance of mutated Janus kinase 2 cells in myeloproliferative neoplasms80.

overexpressing TNF85, and metastatic lymphoma cells have been shown to have an even greater metastatic potential when coadministered with recombinant mouse TNF86. Inhibition of TNF using an anti-TNF fusion protein (human TNFR1 extracellular portion and human immunoglobulin G1 [IgG1] Fc) decreased metastasis to the lung in a B16BL6 mouse melanoma model, demonstrating a direct relationship between TNF and the

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TNF and Cancer Risk

metastatic process87,88. Myoblasts restrict prostate cancer growth and limit metastasis formation through paracrine TNF secretion88. Taken together, the results of these studies indicate that TNF can promote metastasis and

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that TNFi treatment in rodent models decreases metastatic potential.

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Different Mechanisms Connecting Tumor Necrosis Factor, Immunity, and Cancer Tumor Necrosis Factor and Tumor Immune Surveillance In the immunosurveillance model, the host immune system protects against tumor growth

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and development21. Innate and adaptive immune cells, primarily natural killer (NK),

host protection from cancer, working in concert with key cytokines and mediators (eg, interferon [IFN]-γ, perforin, granzymes) to eliminate tumors. However, tumors can

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downregulate antigen presentation to evade the immune system or express cytokines (eg, tumor growth factor [TGF]-β, interleukin [IL]-10) to induce immunosuppressive cells

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(eg, myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells). This model is supported by mechanistic data evaluating tumor growth in various animal models with immunodeficiency (eg, recombination activation gene [RAG]1–/–,

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RAG2–/–, signal transducer and activator of transcription [STAT]1–/–, SCID, nude21). In addition, inflammatory cell infiltration within primary tumor samples from patients with

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colorectal, breast, and other cancer types shows that the presence of CD8+ and Th1 T cells is associated with good prognosis, and while the presence of Th17 and regulatory T cells in predicting patient outcome can vary between tumor types, generally poor outcomes have been reported18,19. Evidence supporting the importance of a strong

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cytotoxic T-lymphocyte (CTL), and natural killer T (NKT) cells, are the key mediators of

adaptive antitumor response is emerging from clinical data on approved immunotherapies, which augment antitumor immune responses, particularly dendritic cell (DC) and CD8+ T-cell interactions15,16. In addition, a variety of tumor-derived factors contribute to the emergence of immunosuppressive networks, including vascular endothelial growth factor, IL-10, TGF-β, prostaglandin E(2), soluble phosphatidylserine, 13

TNF and Cancer Risk

soluble Fas, soluble Fas ligand, and soluble major histocompatibility complex (MHC) class I–related chain A proteins. These factors can suppress protective host immune responses and promote tumor growth, invasion, and metastasis89,90. The specific role of TNF in regulating factors of immune surveillance of tumors has been

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studied in a variety of models (Table 3). Studies of TNF–/–, LT–/–, TNFR–/– mice provide

surveillance, which help identify their potential roles in tumorigenesis. In several rodent tumor models, TNF was associated with a protective immunosurveillance. Tumor

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rejection in TNF–/– mice was reported to be inhibited with the highly antigenic

fibrosarcoma MC57X91. In this model, tumor rejection is dependent on animals

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mounting an immune response to tumor antigens (ie, mice are immunized with irradiated tumor cells before implantation), and thus failure to reject may be the result of the blunted immune response in TNF–/– mice. The administration of a TNF antibody to WT

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mice also resulted in impaired tumor rejection in this model, and the administration of recombinant TNF (rTNF) to TNF–/– mice resulted in tumor rejection91. In addition, in a

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modified model of metastatic lung cancer using the 3LLA-9 Lewis lung carcinoma cell line, in which cells transfected with a lymphocytic choriomeningitis virus antigen can be rejected because of an immune response to the transfected antigen, tumor rejection failed

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information on the key roles of these genes in the immune system and immune

to occur in TNF–/– mice92. Using the methylcholanthrene (MCA)–induced sarcoma as a chemically induced cancer model sensitive to effects on innate and adaptive immune surveillance, TNF–/– mice showed increased susceptibility compared with TNF+/+ mice93. However, TNFR1–/–, TNFR2–/–, and TNFR1/2–/– animals did not show increased development of MCA-induced sarcoma compared with WT littermates94. Tumor-

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draining lymph node effector T cells cultured with TNF mediate increased regression of established mouse tumors95. In a model of LT deficiency, impaired NK function was associated with increased tumor growth and metastasis96. TNF–/– and/or LT–/– mice have specific immune function changes, including impaired NK

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and lymphokine-activated killer (LAK) cytotoxicity against various tumor cell lines

tumor killing. Similarly, CTL responses against DCs pulsed with cellular extracts from allogeneic splenocytes were also decreased compared with TNF+/+ littermates, while it

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was shown that TNF–/– effector lymphocytes still exhibit both perforin- and Fas ligand-

based cytotoxicity91. Similar to LAK and NK activities, CTL cytotoxicity was restored

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upon incubation of TNF–/– lymphocytes in vitro with rTNF during a cytotoxicity assay or upon treatment of TNF–/– mice with rTNF91.

NK cell development from bone marrow precursors is suppressed in LT–/– mice, and

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splenocytes from LT–/– mice exhibit lower NK cytotoxicity in vitro against YAC-1 cells, possibly as the result of a lower content of splenic NK cells, while perforin is detectable

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in NK cells from LT–/– mice96. In vitro cytotoxicity function against target cells P815

(MHC class I+, class II–) and TA3 (MHC class I+, class II+) is intact in LT–/– mice101. Characterization of the role of TNFR in immunosurveillance, using TNFR1–/–, TNFR2–/–,

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(L929, WEHI 164, P815 for LAK; YAC-1 for NK)91,97-100, supporting a role for TNF in

or TNFR1/2–/– mice, has been limited and more complex to interpret; TNFR2–/– CD8+ T cells are resistant to apoptosis, leading to increased protection against tumor growth102,103.

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Overall, the complete abrogation of TNF signaling may impair some components of immunosurveillance in rodents, although in some instances the disruption of TNF signaling may increase antitumor CTL activity (due to decreased apoptosis). In different experimental settings, TNF was associated with a negative effect on

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immunosurveillance. TNF expression was significantly associated with positive lymph

tumor-infiltrating CD8+ T cells104. TNF was demonstrated to favor proliferation of

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myelodysplastic syndrome blasts through induction of the immunoinhibitory molecule B7-H1, responsible for T-cell suppression via programmed cell death (PD-1)

molecules105. In a murine model of melanoma, treatment with DCs matured by TNF led

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to an increase in the number of lung metastases, an effect associated with increased lung IL-10+ T cells and not observed in IL-10–/– mice106. Lymphotoxin treatment was shown to decrease MHC I expression in HPV16-positive CaSki cells and to reduce CTL-specific

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lysis of CaSki cells107.

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These seemingly contradictory results, which demonstrate both positive and negative roles of TNF in immunosurveillance, suggest that the role of TNF in immune surveillance is complex, contextual and reflect the pleiotropic nature of TNF signaling.

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node stage and recurrence of colorectal cancer, possibly by induction of apoptosis of

Specific effects of TNFis on some components of immune surveillance have been evaluated through animal studies. Cynomolgus monkeys administered 3 mg/kg etanercept twice weekly showed no changes in total lymphocyte/lymphocyte-subtype populations, nor were there any changes in markers for “activation” or “memory” phenotypes when using the following markers: CD3 (T lymphocytes), CD3/CD4 (helper

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T cells), CD3/CD8 (cytotoxic T cells), CD4/CD44 (memory CD4 cells), CD8/CD44 (memory CD8 cells), CD4/CD69 (predominantly activated helper T cells), CD8/CD69 (activated cytotoxic T cells), CD14 (monocytes), CD16 (NK cells), CD16/CD69 (activated NK cells), and CD20 (B lymphocytes)47. To assess the possible influence of

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etanercept on immune function, animals were immunized with an antigenic preparation

hemocyanin and tetanus toxoid to assess capacity for production and maintenance of a primary or secondary T cell–dependent antibody response47. The administration of

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etanercept had no apparent effect on the ability of cynomolgus monkeys to mount a DTH response to an antigenic mixture of candida/trichophyton/diphtheria, an antibody

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response to a novel antigen, or to a recall antigen.

Studies in mice have shown that etanercept can modulate the immune response to specific challenges. For example, in murine models of collagen-induced arthritis,

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suppression of the immune-based destruction of joint tissue is the basis for therapeutic activity. However, in these models, normal levels of T-cell responses to mitogens and

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type II collagen are found108. Together, these data show that pharmacologic inhibition of TNF is not associated with broad immunosuppression. Tumor Necrosis Factor and Antiviral Immunity

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for delayed-type hypersensitivity (DTH) response assessment, and with keyhole-limpet

The host response to viral infection is mediated by both innate (NK, NKT, and granulocyte) and adaptive (CTL) antiviral responses, which contribute to viral clearance. The production of proinflammatory cytokines such as TNF, IL-12, IL-18, and IL-6 and

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the cellular production of IFN-α both directly interfere with viral replication and promote antiviral immunity22,23. Administration of etanercept in an acute model of murine cytomegalovirus infection resulted in increased viral load in the liver in only the very early phase of infection (day

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3), and the effects did not extend to later times; no infected cells were seen at day 7 in

been examined, and at present, there are no established rodent viral models for potential

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human oncogenic viruses in which the human protein etanercept was examined.

In a clinical study, patients who received infliximab, adalimumab, or etanercept showed

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no difference in Epstein-Barr virus (EBV) viral load and no difference in numbers of EBV-specific interferon-gamma–producing T cells (for both latent-cycle and lytic-cycle peptides) between baseline and treatment week 12109. Other clinical studies showed that

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TNFi therapy did not increase the EBV burden in patients with RA or ankylosing spondylitis110,111.

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Tumor Necrosis Factor Promoter Polymorphisms and Cancer Risk Inflammation contributes to tumor development and growth through the expression of cytokines such as TNF and other inflammatory mediators, which establish a permissive

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either treated or control groups47. However, the effects on a latent infection have not

environment for tumor growth and metastases, angiogenesis, increased cell survival, reduced cell death, altered differentiation, and altered response to hormones and chemotherapeutic agents24,26,27,58,112-115. Clinical data indicate that inflammation

associated with increased TNF is a negative prognostic indicator of patient outcomes across a variety of tumor types. The TNF-308 A>G promoter region polymorphism, 18

TNF and Cancer Risk

associated with two- to three-fold increased transcription and up to two-fold increased circulating TNF levels (for G/A vs G/G) in healthy humans116,117, has been positively associated with various malignancies. Meta-analyses covering eight cancer classifications (cervical, breast, lung, hepatocellular, gastric, aerodigestive, non-Hodgkin

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lymphoma, and colorectal) and involving over 50,000 cases and 66,000 controls have

A allele polymorphisms ranging from 1.1 to >4, with some variability across allelic forms (ie, A/A, G/A, or either) and subgroup factors (eg, menopausal status, race)118-127. These

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data indicate a broad and complex role for TNF-308 G/A polymorphisms that regulate

TNF transcription and production, although the relationship of these polymorphisms with

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genetic and other factors, such as ethnicity, that affect cancer risk remain poorly understood128.

Other TNF polymorphisms have been linked with an increased cancer risk (ie, 238 G/A,

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857 C/T, 863 A/C, 1031 C/T, 1210 C/T), although meta-analyses have not identified clear associations of these polymorphisms with cancer risk118,121,122,125,129,130. In addition

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to TNF polymorphisms, the LT-α NcoI A/A genotype, and its associated high production of LT-α, are associated with an increased risk of developing esophageal adenocarcinoma131.

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established a statistically significant increased cancer risk (expressed as an odds ratio) for

Whereas TNF polymorphisms have been associated with increased TNF production and cancer risk, increased systemic TNF from other causes also increases cancer risk. In Bcell chronic lymphocytic leukemia and hairy cell leukemia, overproduction of TNF by the malignant cells has been reported to result in more severe disease progression and decreased survival132,133. Freedman et al found that cells from patients with juvenile 19

TNF and Cancer Risk

role in the pathogenesis of the disease by acting as an autocrine growth factor134. These effects were inhibited following treatment with an anti-TNF antibody. TNF also maintains TNFR1-dependent IL-17 production in CD4+ T cells, which leads to myeloid

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cell recruitment into the tumor microenvironment and enhances tumor growth in ovarian

factor contributing to gastric cancer, it was demonstrated that TNF mRNA and protein expressions were significantly increased in chronic gastritis, intestinal metaplasia,

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dysplasia, and gastric adenocarcinoma patients and that the degree of overexpression of TNF showed significant association with various stages of gastric carcinogenesis136. In

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the context of H pylori, the TNF-inducing protein (Tip-α) was identified as a carcinogenic factor that acts through strong induction of TNF137. Overall, these data indicate that TNF in the inflammatory microenvironment may favor

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tumor growth in several models, and TNF expression is a poor prognostic factor for

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several tumor types in humans.

Taken as a whole, the studies summarized above indicate that TNF can activate pathways leading to three contextually different cellular responses: cell survival and activation/proliferation, transcription of proinflammatory genes, and cell death. These

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cancer in mice and humans135. Although Helicobacter pylori is considered to be a major

various effects are critical for controlling effectors of immune surveillance of tumors, tumor growth, and nonvirally-mediated lymphomagenesis as summarized below and illustrated in Figure 2.

20

TNF and Cancer Risk

Although some models indicate that abrogation of the TNF pathway can reduce NK- and CTL-mediated cytotoxicity against tumor cells, other models indicate that CTL activity is intact when the TNF pathway is inhibited and, furthermore, that TNF can inhibit antitumor immunity through expansion of suppressor cells

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and induction of T–cell inhibitory molecules. Pharmacologic modulation of the

leukocytes (including NK cells and CTLs) in nonhuman primates and does not interfere with T-cell responses and antiviral immunity.

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TNF shows antitumor activity in vivo in vascularized tumors through disruption

of endothelial cell adhesiveness and procoagulation effects. It is weakly cytotoxic

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against many tumor cell lines unless combined with antimetabolic agents. TNF (and inflammation in general) favors tumor growth and metastasis in several models, and available clinical data indicate that inflammation associated with

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TNF is a negative prognostic indicator of patient outcomes across a variety of tumor types. In particular, the TNF-308 G/A promoter region polymorphism,

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associated with a two- to three-fold increased transcription and up to two-fold increased circulating TNF levels in healthy humans, has been positively associated with various malignancies.

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TNF pathway (eg, with etanercept) does not affect the number of circulating

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TNF and Cancer Risk

Tumor Necrosis Factor Inhibitors: Clinical Trials and Epidemiology Data While nonclinical models contribute to the understanding of the biological consequences of TNF inhibition, many of these models rely on rodent systems and/or are contrived, therefore their translatability to human disease is uncertain. The following section

Overall Risk of Malignancy in Rheumatoid Arthritis Patients

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Randomized clinical trials are underpowered and too short to determine the risk of rare

events such as malignancy. Meta-analyses, large registries, and administrative database analyses have provided substantial evidence that malignancy rates are not increased

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overall with TNFis. Here, we focus on data from RA because this population is well defined regarding background rates of malignancy and has the largest amount of data examining the risk of malignancy associated with TNFis relative to other indications.

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The attribution of malignancy risk to TNFis is complicated by the increased risk of malignancy in RA patients relative to the general population, as observed in the Danish

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Biologics (DANBIO) register (standardized incidence ratio [SIR] = 1.27; 95% CI, 1.08– 1.49)138 and the British Society for Rheumatology Biologics Register (BSRBR; SIR=1.28; 95% CI, 1.10–1.48)139. This is further confounded by the fact that these

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as well as the risk for specific tumor types.

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focuses on human data and reviews the overall risk of malignancy associated with TNFis,

patients are also exposed to other cytotoxic or immunosuppressive drugs. Hematologic Malignancy: Lymphoma risk is increased in RA patients at least two-fold overall, and increased disease severity is correlated with increased risk of lymphoma140. The RA population also has a higher rate of leukemia relative to the general population in the United States (SIR=1.7 [95% CI, 1.2–2.4]) and Sweden (SIR=2.1 [95% CI, 1.7–2.5] 22

TNF and Cancer Risk

and 2.2 [95% CI, 0.6–5.7] for prevalent and incident RA, respectively)141,142. In particular, patients with RA have a higher risk of acute myeloid leukemia, with an SIR of 2.4 (95% CI, 1.79–3.15)143,144. Taken together, these data show that patients with RA have an increased risk of leukemia and lymphoma relative to the general population.

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Solid Tumors: A decreased risk of colon and breast cancers in RA patients relative to the

Biological Therapies in Rheumatic Diseases (BIOBADASER) and the US National Data Bank (NDB) for Rheumatic Diseases141,145. The observed decrease in colon cancer may

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be attributed to nonsteroidal anti-inflammatory drug use in this population146,147.

Similarly, decreased rates of prostate and female genital cancers were observed in RA

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patients in the BSRBR registry139. Lung cancer may be increased in patients with RA compared with the general population, although conflicting results have been observed145. Increased rates of smoking may explain increased lung cancer rates, because smoking is a

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risk factor for RA148. An increased risk of nonmelanoma skin cancer (NMSC) in RA (irrespective of treatment) has been reported149. Further, compared to patients with

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osteoarthritis, RA patients have an increased risk of developing NMSC (hazard ratio [HR]=1.19 [95% CI, 1.01–1.41])150. Disease duration is also associated with NMSC

(HR=1.01 [95% CI, 1.00–1.02; P=0.004])150.

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general population was reported in both the Spanish Registry for Adverse Events of

Cancer Risk Associated With Tumor Necrosis Factor Inhibitors Meta-analyses of pooled clinical trial data across combined approved indications do not indicate an overall increased risk of malignancy with TNFis138,142,145,151-163 (Table 4).

Moreover, increased duration of TNFi exposure does not appear to increase malignancy

23

TNF and Cancer Risk

risk. Results from the DANBIO registry showed no overall increased risk of malignancy based on the cumulative duration of TNFi exposure138, a finding similar to that of an analysis of a large US observational study141. Additionally, individual TNFis do not show differences in risk; no significantly increased risk of malignancy was observed for

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the individual TNFis adalimumab, etanercept, or infliximab in the BIOBADASER 2.0

Database, the risk of newly diagnosed cancer was compared between RA patients taking biologics (predominantly TNFis alone; 13.1% received rituximab) and matched subjects

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taking nonbiologic disease-modifying antirheumatic drug (nbDMARDs) only. The

overall risk of cancer was significantly reduced in subjects receiving TNFis (HR=0.63

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[95% CI, 0.49–0.80])152.

Hematologic Malignancies—Lymphoma: Across clinical trials, observational studies, meta-analyses, and postmarketing analyses, the risk of lymphoma does not appear

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increased with TNFis relative to background therapy. Analyses that compared patients with RA treated with TNFis to the general population reported SIRs ranging from 3.5 to

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5.8 154,165. However, patients with more severe disease are more likely to receive TNFis, thus complicating calculations of true risk of malignancy. Data do exist that compare the risk associated with TNFis to other RA medications. In a meta-analysis of 10

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study164. In a study conducted using the Taiwan National Health Insurance Research

randomized controlled RA trials, the odds ratio (OR) for lymphoma for all TNFis combined was not statistically significant (2.14 [95% CI, 0.55–8.38]) compared with

patients with RA who received an nbDMARD or placebo166,167. Similarly, Leombruno et al found no significantly increased risk for lymphoma; the exposure-adjusted relative risk (RR) was 1.26 (95% CI, 0.53–3.01) for all TNFis combined166. There were also no major

24

TNF and Cancer Risk

differences found for the individual TNFi agents, nor did high doses of TNFis confer a greater risk of lymphoma relative to patients who received nbDMARDs166. A pooled analysis of three registries reported no increased risk of lymphoma associated with TNFis in patients with RA compared with nbDMARDs (RR=1.11 [95% CI, 0.70–1.51])156. In

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the Safety Assessment of Biological Therapeutics (SABER) study, the risk associated

2.20])155. In an analysis of a Swedish registry of 757 patients with RA treated with

TNFis compared with 800 treated with nbDMARDs, a trend for an increased risk was

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found; the adjusted HR for lymphoma was 5.0 (95% CI, 0.9–27.9: P=0.06) with an SIR

of 11.5 (95% CI, 3.7–26.9); however, the population examined in this study was smaller

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than in other studies160. In the Taiwan National Health Insurance Research Database Study, the SIR for lymphoma was higher in subjects receiving TNFis (6.13 [95% CI, 3.26–10.49]) than in subjects receiving nbDMARDs (2.52 [95% CI, 1.56–3.85]), which

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was significant152. Thus, there is no consistent evidence that TNFis increase the risk of lymphoma above the generally high background rate in the RA population.

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Although hepatosplenic T-cell lymphoma was initially thought to be associated with TNFi in patients with inflammatory bowel disease, more recent evidence indicates an increased risk with TNFis when used in combination with a thiopurine (or with the

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with TNFis versus nbDMARDs was also nonsignificant (HR=1.25 [95% CI, 0.71–

thiopurine alone) but not with TNFi monotherapy168. Hematologic Malignancy—Leukemia: The risk of leukemia was not found to be increased with biologic TNFis in an analysis of the NDB for Rheumatic Diseases (OR=1.2 [95% CI, 0.5–3.1])141 and in a North American study (versus the general population; SIR=1.3 [95% CI, 0.85–1.97])163. 25

TNF and Cancer Risk

Solid Tumors: There does not appear to be an overall increased risk of solid tumors associated with TNFis compared with nbDMARDs. An analysis of the BSRBR for RA demonstrated no significant difference in proportion or RR for any of the common sitespecific solid cancers in RA patients treated with TNFis compared with nbDMARDs146.

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Similarly, SABER reported no significant increase for any solid cancer associated with

Registry found a decreased risk of solid cancer associated with TNFis compared with

methotrexate (HR=0.21 [95% CI, 0.07–0.64])158. Conversely, in the DANBIO registry,

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colon cancer was increased in patients treated with TNFis compared with nbDMARDs; however, the number of overall cases was low among the TNFi and nbDMARD

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groups138. Registry data have not indicated an increased incidence of lung cancer related to TNFi therapy above the already increased risk in the RA population141,146; the risks of breast and lung cancers were reported to be decreased in patients treated with TNFis

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compared with methotrexate in the Corrona registry158. Nonmelanoma Skin Cancer: Overall, there appears to be a potential increased risk of

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NMSC associated with TNFis compared with nbDMARDs in RA patients. Two metaanalyses of randomized clinical trials reported no increased risk of NMSC166,167, and

another reported a significant two-fold increase in the risk of NMSC associated with

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TNFis compared with nbDMARDs155, while the most recent analysis of the Corrona RA

TNFis relative to comparator arms (HR=2.02 [95% CI, 1.11–3.95])153. Registry data from the BSRBR and administrative data from the SABER study showed nonstatistically significant increased risks of NMSC with TNFis compared with nbDMARDs149,155, and the Corrona registry showed a decreased risk of NMSC compared with methotrexate158. Conversely, a study from the NDB reported a statistically significant increased risk of

26

TNF and Cancer Risk

NMSC associated with TNFis, although this was relative to the general US population141. A pooled analysis of four registries reported a statistically significant increased risk of NMSC (pooled estimate = 1.33 [95% CI, 1.06–1.60]). This analysis included data from the three registries (Corrona registry, BSRBR, and Antirheumatic Therapies in Sweden

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study [ARTIS]) with results that were nonsignificant compared with RA patients treated

significant result included in the analysis156,169. A separate analysis from the NDB reported a trend toward an increased risk of NMSC associated with TNFis without

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concomitant methotrexate (HR=1.24 [95% CI, 0.97–1.58]) or when used in combination

with methotrexate (HR=1.97 [95% CI, 1.51–2.58])150. The potential association between

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TNFis and NMSC requires further observation.

Melanoma: There have been mixed findings with respect to the association of TNFis and melanoma, and the overall risk is difficult to determine. An analysis of 29,423 patients

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with RA in 63 randomized controlled trials found an OR for melanoma associated with TNFi agents of 1.08 (95% CI, 0.11–10.21)167. A separate meta-analysis reported a trend

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toward an increased risk of melanoma with TNFis based on the inclusion of two studies (pooled estimate = 1.79 [95% CI, 0.92–2.67])156. Infliximab and etanercept were both associated with a nonsignificant increased risk of melanoma in the NDB, with ORs of 2.6

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with nbDMARDs and a previous result from the NDB, which was the only study with a

(95% CI, 1.0–6.7) and 2.4 (95% CI, 1.0–5.8), respectively141. An analysis of the ARTIS registry found an increased risk of invasive melanoma compared with RA patients not treated with biologic drugs (HR=1.5 [95% CI, 1.0–2.2]) but no significantly increased risk of melanoma in situ (HR=1.1 [95% CI, 0.5–2.1]) associated with TNFis compared with other RA therapies170. Taken together, current evidence suggests a potential

27

TNF and Cancer Risk

increased risk of melanoma overall, but the evidence is conflicting. However, although there does not appear to be an increased risk of in situ melanoma associated with TNFis, there may be increased risk of invasive melanoma. Malignancy Associated With Viral Infection: Patients treated with TNFis are at increased

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risk for certain viral infections such as herpes zoster171 and reactivation of hepatitis B172,

may lead to malignancy: EBV and lymphoma, HPV and cervical and anogenital cancers,

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polyomavirus and Merkel cell cancer, HHV-8 and Kaposi's sarcoma. Certain types of

HPV cause all cervical cancers; most anal cancers; and some vaginal, vulvar, penile, and oropharyngeal cancers173. However, there is no evidence for an increased risk of these

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viral infection–associated malignancies with TNFi. In one study, patients who received infliximab, adalimumab, or etanercept showed no difference in EBV viral load and no difference in numbers of EBV-specific interferon-gamma–producing T cells (for both

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latent-cycle and lytic-cycle peptides) between baseline and treatment week 12109. Other clinical studies showed that TNFi therapy did not increase the EBV burden in patients

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with RA or ankylosing spondylitis110,111. Lower rates of female genital cancer (including cervical) were reported in the BSRBR139, and there was no increase in female genital cancers in women with prior cervical carcinoma in situ treated with TNFis compared

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raising the question of susceptibility to oncogenic viruses. Infection with certain viruses

with those treated with nbDMARDs, although the number of patients was small174. Merkel cell carcinomas are rare, aggressive, cutaneous neuroendocrine tumors. Although rates of occurrence are not available, postmarketing case reports of Merkel cell carcinoma have occurred with TNFis, leading to mention of this development in the prescribing information for the majority of TNFis42,43,46.

28

TNF and Cancer Risk

Recurrent Malignancy: The data are limited, and it is unknown if there is an overall increased risk of malignancy recurrence with TNFis across all indications; current guidelines do not provide clear guidance regarding the use of TNFis in patients with recent malignancies. Current European League Against Rheumatism guidelines have no

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specific recommendations regarding the treatment of patients with prior malignancies,

British Society of Rheumatology guidelines recommend caution in the use of TNFis in patients with previous malignancies176. The American College of Rheumatology

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recommends the use of any biologic agent in patients with a history of a treated solid

malignancy or NMSC >5 years ago177; rituximab is recommended for patients with a

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more recent history (≤5 years) of a treated malignancy based on lack of evidence associating the use of this biologic DMARD with cancer177. Safety registries provide insight regarding the risk of malignancy recurrence with TNFis.

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In the BSRBR, Dixon et al reported an incidence rate ratio (IRR) of incident cancer in TNFi-treated patients with RA with prior malignancies of 0.45 (95% CI, 0.09–2.17)178.

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This study reported only incident malignancy occurring after the start of TNFi treatment (nbDMARD as control) and was not designed specifically to examine recurrence; in fact, many of the malignancies in those who reported prior malignancies could be classified as

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although rituximab (a non-TNFi biologic) may be preferred in this scenario175. The

second primary tumors178. In the Rheumatoid Arthritis Observation of Biologic Therapy (RABBIT) study, malignancy recurrence rates were similar between patients with RA who received TNFis (45.5/1000 patient-years) and those who received nbDMARD therapy (31.4/1000 patient-years), with an IRR=1.4 (95% CI, 0.5–5.5)162. Most (14 of 15) of the second tumors were true recurrences of the primary tumor; nine patients

29

TNF and Cancer Risk

received TNFis and five received nbDMARDs162. The recurrent malignancies in patients treated with TNFis were breast (n=4) and lung, bladder, liposarcoma, melanoma, and testicular cancers (n=1 each)162. A pooled analysis of the RABBIT and BSRBR studies reported an estimated IRR of 0.62 (95% CI, 0.04–1.20)156. Data regarding cancer

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recurrence are also available from BIOBADASER 2.0, which compared patients with

psoriatic arthritis) and psoriasis treated with TNFis to a cohort of patients not exposed to

TNFis. In the TNFi-treated patients, 24 of 4694 were found to have a malignancy before

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TNFi exposure. The IRR for recurrent cancer in patients with prior malignancies was 5.22 (95% CI, 0.79–34.34), a nonsignificant trend that was complicated by small

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numbers145. A recent analysis of the ARTIS registry evaluated cancer recurrence in patients with RA and at least one diagnosis of breast cancer before initiating TNFi treatment. Comparing TNFi-treated patients with biologics-naive patients and adjusting

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for nodal status, type of surgery, and chemotherapy at index cancer, the HR was 1.1 (95% CI, 0.4–2.8). The authors of this report indicated that these results support current

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clinical guidelines, which state that TNFis may be initiated in patients with a >5-year history of treated breast cancer179. Analyses of the BSRBR and ARTIS registries also

specifically examined melanoma recurrence. In a small data set of patients with prior

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rheumatic diseases (including RA, juvenile idiopathic arthritis, ankylosing spondylitis,

melanoma in the BSRBR, there were two definite (and one probable) melanoma recurrences in 17 patients exposed to TNFis and none in 10 patients not exposed to TNFis178. An analysis of the ARTIS registry reported a nonsignificant three-fold increase in the risk of a second primary melanoma associated with TNFis relative to nbDMARDs

30

TNF and Cancer Risk

in patients with RA, although only a total of 13 cases were reported (3 TNFi and 10 nbDMARD)170. Owing to the small number of cases reported, further analyses are needed to determine

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the recurrence risk, if any, of TNFi therapies in patients with prior malignancies.

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TNF and Cancer Risk

Discussion and Conclusions Clinical and experimental animal data demonstrate that TNF can both promote and prevent tumor formation and that a complex, contextual integration of signals drives a cellular response toward apoptosis/necrosis or survival, inflammation, and growth

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promotion (Figure 1). Mechanistic data indicate that key players in TNF signaling that

normal or transformed cells64,180. In addition to direct effects of TNF on tumors, TNF can variously affect immunity and the tumor microenvironment. Whereas TNF can

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promote immune surveillance designed to eliminate tumors, it can also drive chronic inflammation, autoimmunity, angiogenesis, and other processes that promote tumor

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initiation, growth, and spread (Figure 2). The context-specific role of TNF in tumor regression or growth is evident in variable outcomes observed in rodent models (Table 2).

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Human expression polymorphisms suggest that TNF is generally a tumor-promoting cytokine. Additionally, data from population studies, administrative databases, registries,

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meta-analyses, and observational studies demonstrate that overall rates of malignancy are not higher with TNFi therapy use among patients with RA, who have an elevated risk of certain malignancies compared with the general population. These data indicate that the

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shape this response include NF-κB and Jun kinase, as well as other factors intrinsic to

risk of cancer associated with TNFi use is markedly different than the cancer risks experienced by individuals with primary (congenital) immune deficiencies, acquired deficiencies (eg, HIV/AIDS), or those treated with therapeutics used to support organ engraftment, who have increased risks of both virally associated and nonviral cancers5-14.

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TNF and Cancer Risk

Taken as a whole, the available data indicate that elevated TNF is a risk factor for cancer, whereas its inhibition among patients with RA is not generally associated with an increased cancer risk, particularly for the range of cancers linked with immune suppression. More information is required to fully understand the risk of TNFi use

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regarding risk of skin malignancies and risk of cancer recurrence. Although this review

indications showing no increased rate in malignancy with TNFis in juvenile idiopathic

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arthritis181, psoriatic arthritis155, and Crohn’s disease or inflammatory bowel disease155,182. Because the immune system can both suppress and promote cancer, it is obligatory that an assessment of cancer risk among RA patients consider the risk of undertreating their

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inflammatory disease balanced against the use of immunosuppressive agents that impair immune surveillance. Such data, including outcomes with individual TNFis as presented here, are critical for informing patients and clinicians regarding the overall cancer risks

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they face given their disease and treatment options.

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Developing an understanding of the cancer risk associated with TNFi use is confounded by a number of factors, including the nature of the underlying disease (and its severity), history of oncogenic viral infection, and the use of concomitant therapies1. Because more potent immunosuppressive agents are typically used in the treatment of more severe

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focused on RA, which has the most robust data, there are reports in other disease

disease, dissociation of their effects as drivers of malignancy is especially challenging. As personalized medicine evolves and individual tumors are evaluated for markers, the role of TNF may be further understood.

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TNF and Cancer Risk

Transparency Declaration of Funding:

Declaration of Financial/Other Relationships:

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The preparation of the manuscript was funded by Amgen Inc.

this manuscript have received an honorarium from CMRO for their review work, but

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have no other relevant financial or other relationships to disclose. Acknowledgments:

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The authors acknowledge editorial assistance from Tim Peoples, MS, ELS, CMPP, of Amgen Inc., and Miranda Tradewell, PhD, of Complete Healthcare Communications,

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Inc., whose work was funded by Amgen Inc.

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All authors are employees of and own stock in Amgen Inc. CMRO Peer Reviewers on

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Autoimmun Rev 2010;9:175-80

Strangfeld A, Hierse F, Rau R, et al. Risk of incident or recurrent malignancies

CC

162.

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antagonist therapy and cancer development: analysis of the LORHEN registry.

among patients with rheumatoid arthritis exposed to biologic therapy in the German biologics register RABBIT. Arthritis Res Ther 2010;12:R5 Setoguchi S, Solomon DH, Weinblatt ME, et al. Tumor necrosis factor alpha

A

163.

antagonist use and cancer in patients with rheumatoid arthritis. Arthritis Rheum

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2006;54:2757-64 164.

Wiens A, Venson R, Correr CJ, et al. Meta-analysis of the efficacy and safety of

adalimumab, etanercept, and infliximab for the treatment of rheumatoid arthritis.

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associated with an increased risk of lymphomas. Ann Rheum Dis 2005;64:699-

Pharmacotherapy 2010;30:339-53

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Weinblatt ME, Bathon JM, Kremer JM, et al. Safety and efficacy of etanercept

beyond 10 years of therapy in North American patients with early and longstanding rheumatoid arthritis. Arthritis Care Res (Hoboken) 2011;63:373-82

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166.

Leombruno JP, Einarson TR, Keystone EC. The safety of anti-tumour necrosis factor treatments in rheumatoid arthritis: meta and exposure-adjusted pooled analyses of serious adverse events. Ann Rheum Dis 2009;68:1136-45

167.

Lopez-Olivo MA, Tayar JH, Martinez-Lopez JA, et al. Risk of malignancies in

168.

Deepak P, Sifuentes H, Sherid M, et al. T-cell non-Hodgkin's lymphomas

reported to the FDA AERS with tumor necrosis factor-alpha (TNF-α) inhibitors:

169.

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results of the REFURBISH study. Am J Gastroenterol 2013;108:99-105

Mariette X, Reynolds AV, Emery P. Updated meta-analysis of non-melanoma

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skin cancer rates reported from prospective observational studies in patients treated with tumour necrosis factor inhibitors. Ann Rheum Dis 2012;71:e2 170.

Raaschou P, Simard JF, Holmqvist M, et al. Rheumatoid arthritis, anti-tumour

A

necrosis factor therapy, and risk of malignant melanoma: nationwide population based prospective cohort study from Sweden. BMJ 2013;346:f1939 Ramiro S, Gaujoux-Viala C, Nam JL, et al. Safety of synthetic and biological

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DMARDs: a systematic literature review informing the 2013 update of the EULAR recommendations for management of rheumatoid arthritis. Ann Rheum

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JAMA 2012;308:898-908

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patients with rheumatoid arthritis treated with biologic therapy: a meta-analysis.

Dis 2014;73:529-35

172.

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173.

National Cancer Institute. HPV and Cancer: Fact Sheet. 2014. Available at: http://www.cancer.gov/cancertopics/factsheet/Risk/HPV/print [Last accessed June 6, 2014]

174.

Mercer LK, Low ASL, Galloway JB, et al. Anti-TNF therapy in women with

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rheumatoid arthritis with a history of carcinoma in situ of the cervix. Ann Rheum

175.

Smolen JS, Landewé R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-

176.

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modifying antirheumatic drugs. Ann Rheum Dis 2010;69:964-75

Ding T, Ledingham J, Luqmani R, et al. BSR and BHPR rheumatoid arthritis

177.

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guidelines on safety of anti-TNF therapies. Rheumatology 2010;49:2217-9 Singh JA, Furst DE, Bharat A, et al. 2012 Update of the 2008 American College of Rheumatology recommendations for the use of disease‐modifying

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antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res 2012;64:625-39 Dixon W, Watson K, Lunt M, et al. Influence of anti–tumor necrosis factor

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178.

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Dis 2013;72:143-4

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Karin M. NF-kappaB as a critical link between inflammation and cancer. Cold Spring Harb Perspect Biol 2009;1:a000141

181.

Beukelman T, Haynes K, Curtis JR, et al. Rates of malignancy associated with juvenile idiopathic arthritis and its treatment. Arthritis Rheum 2012;64:1263-71 Peyrin–Biroulet L, Deltenre P, De Suray N, et al. Efficacy and safety of tumor

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182.

trials. Clin Gastroenterol Hepatol 2008;6:644-53 183.

Iizuka K, Chaplin DD, Wang Y, et al. Requirement for membrane lymphotoxin in

184.

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natural killer cell development. Proc Natl Acad Sci U S A 1999;96:6336-40

Zhao X, Rong L, Zhao X, et al. TNF signaling drives myeloid-derived suppressor

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A

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cell accumulation. J Clin Invest 2012;122:4094-104

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necrosis factor antagonists in Crohn's disease: meta-analysis of placebo-controlled

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TNF and Cancer Risk

Structure

Target(s)

Approved Indications*

Active AS, moderate to severe CD, moderate to severely active Adalimumab44

Fully human IgG1

TNF

polyarticular JIA, active PsA, moderate to severe PsO, moderate to

Certolizumab4 PEGylated Fab' fragment

TNF

5

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severely active RA, moderate to severe UC

Human soluble p75 TNF Etanercept46

Infliximab43

Active AS, moderate to severe JIA in patients ≥2 y, active PsA,

TNF/LT

Fully human IgG1

moderate to severe PsO, moderate to severe RA

TNF

A

Receptor linked to human Fc Golimumab42

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Patients with AS, moderate to severe CD, PsA, severe RA

Chimeric mouse-human IgG1

TNF

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Agent

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Table 1. Summary of Currently Approved TNFi Therapies in the United States

Active AS, active PsA, moderate to severe RA, moderate to severe UC Active AS, moderate to severe adult and pediatric CD (≥6 y), active PsA, chronic severe PsO, moderate to severe RA, moderate to severe adult and pediatric UC

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TNF and Cancer Risk

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AS=ankylosing spondylitis; CD=Crohn's disease; Fab'=fragment antigen binding; IgG1=immunoglobulin G1; JIA=juvenile idiopathic

inhibitor; UC=ulcerative colitis.

A

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*Approved in adults unless otherwise indicated.

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arthritis; LT=lymphotoxin; PsA=psoriatic arthritis; PsO=psoriasis; RA=rheumatoid arthritis; TNF=tumor necrosis factor; TNFi=TNF

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TNF and Cancer Risk

Manipulation of TNF

Outcome

Chemically induced skin

TNF–/– mice

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Protumorigenic Effects of TNF

TNF–/– or TNFi

tumors Choline-deficient,

81

Decreased tumor formation 73,74

A

Urethane-induced pulmonary

71,72

Decreased tumor formation

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TNFR1–/– or TNFR2–/– mice

References

Decreased tumor formation

tumors UVB-induced skin tumors

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Model

TNFR1–/– mice

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Table 2. Role of TNF in Tumorigenesis in Nonclinical Tumor Models

Decreased tumor formation 82

methionine-supplemented diet–induced liver tumors PDAC in SCID mice

TNFi

Decreased tumor formation, decreased

78

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TNF and Cancer Risk

Chemically induced ulcerative TNFi

Increased PDAC growth and metastasis

Decreased tumor formation and associated

79

colitis and colonic tumors TNF–/– mice

Decreased malignancy

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Lung carcinoma cell lines

neutrophil/macrophage infiltrates

Antitumorigenic Effects of TNF Systemic TNF

sarcoma

administration

Syngeneic mouse melanoma

Systemic TNF

76

Tumor necrosis

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Methylcholanthrene-induced

29,30

Tumor growth inhibition 48

Human xenografts in nude mice

A

administration

Intratumoral TNF

Tumor regression 49

injection

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TNF administration

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metastasis

Co-culture of myoblasts and

TNFi

prostate carcinoma cell lines

Recovery of tumor growth blocked by myoblast88

derived TNF

PDAC=pancreatic ductal adenocarcinoma; SCID=severe combined immunodeficiency; TNF=tumor necrosis factor; TNFi=TNF inhibitor; TNFR=TNF receptor; UVB=ultraviolet B.

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TNF and Cancer Risk

Manipulation of TNF

Outcome

Increased Immune Surveillance by TNF TNF–/– mice

tumor cell lines

against target cells

LT–/– mice

Decreased NK cell development

TNF–/–, TNFR1–/–, TNFR2–/–

DC membrane TNF mediates NK activity

activation in murine DC and NK

mice, TNF gene transfer

through TNFR2

CTL cytotoxicity assay

A

In vitro cytotoxicity and NK

cultures

TNF–/– LT–/– mice

In vitro cultures of allospecific CTL

TNF–/– mice

183

100

Attenuated antiviral CTL response 99

following in vivo infection (LCMV)

91

cytotoxicity

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Murine NK counts and activity

References

Impaired NK- or LAK-mediated

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In vitro cytotoxicity against

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Model

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Table 3. Impact of TNF on Immune Surveillance (Nonclinical Models)

Decreased CTL-mediated cytotoxicity 91

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TNF and Cancer Risk

TNF–/– mice

Decreased tumor rejection

CTL cytotoxicity against

TNF–/– mice

LT–/– mice

allogeneic target

expressing tumor cells

TNFR2–/– mice

101

Decreased activation-induced cell death of

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CTL development in OVA-

98

No impact on cytotoxicity

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CTL cytotoxicity against

91

No impact on cytotoxicity

allogeneic target

CTLs and increased control of tumor cell

102

growth

Systemic TNFi

A

Nonhuman primate toxicology study

No changes in lymphocyte populations, DTH response, T-dependent antibody

47

responses

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Lack of Effect or Negative Impact of TNF on Immune Surveillance

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In vivo tumor models

MCMV infection model

Systemic TNFi

No lasting effect on viral infection

Cultures of myelodysplastic

Culture with TNF

Increased expression of immunoinhibitory

syndrome cells

47

105

molecule B7-H1

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TNF and Cancer Risk

TNFR1/2–/– mice

TNF drives myeloid-derived suppressor

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Murine tumor models

184

CTL=cytotoxic T-lymphocyte; DC=dendritic cell; DTH=delayed-type hypersensitivity; LAK=lymphokine-activated killer; LCMV=lymphocytic choriomeningitis virus; LT=lymphotoxin; MCMV=mouse cytomegalovirus; NK=natural killer;

A

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OVA=ovalbumin; TNF=tumor necrosis factor; TNFi=TNF inhibitor; TNFR=TNF receptor.

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cell accumulation

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TNF and Cancer Risk

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Table 4. Relative Risk of Malignancies in Patients With RA and Other Inflammatory Conditions (Key Studies)

Study; Population

Tumor Type

TNFi

Group

All

ADA,

Control arms

Askling et al153; all indications for TNFi

Risk or Incidence Ratio

N

(95% CI)

22,904

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Clinical Trial Meta-Analyses

HR=1.30 (0.89–1.95)

ETN

SEER database

13,977

HR=1.00 (0.83–1.19)

ADA

SEER database

14,109

SIR=0.93 (0.82–1.06) for

ETN,

All

Burmester et al157; RA

All

Database and Registry Analyses BSRBR146; RA

DANBIO138; RA, AS, PsA, and

RA

A

Gottlieb et al154; AS, RA, JIA, PsA,

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IFX

Solid tumors

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Reference

All

ADA,

nbDMARD

15,015

HR=0.83 (0.64–1.07)

nbDMARD

9696

HR=1.02 (0.80–1.30)

ETN, IFX TNFi

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BIOBADASER 2.0145; RA

All

TNFi

nbDMARD

3320

IRR=0.48 (0.09–2.45)

SABER155; RA, PsO, PsA, IBD

All

TNFi

nbDMARD

29,555

HR=0.94 (0.79–1.12) for any solid tumor in RA

Corrona158; RA ARTIS159; RA

All

ARTIS142; RA

TNFi

A

Mariette et al156; RA

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patients; HR=1.25 (0.71–

nbDMARD

>40,000

TNFi

Methotrexate

Solid tumors

ADA,

General Swedish 4160

ETN,

population

Hematopoietic

2.20) for any lymphoma in RA patients Pooled risk estimate = 0.95 (0.85–1.05)

All

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other arthritides

5327

HR=0.29 (0.14–0.60) SIR=0.9 (0.7–1.2)

IFX ADA,

General Swedish 4160

SIR=2.1 (1.1–3.8)

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TNF and Cancer Risk

LOHREN161; RA

All

All

ETN and

RA patients not

IFX

exposed to TNFi

ADA,

General

ETN,

NA database163; RA

All

SIR=1.1 (0.6–1.8)

1064

SIR=1.09 (0.64–1.72)

population

CC

IFX

1557

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SSTAG160; RA

ETN and

Methotrexate

7830

HR=0.99 (0.71–1.36)

nbDMARD

5120

HR=0.70 (0.44–1.12)

nbDMARD

22,130

HR=0.63 (0.49–0.80)

IFX

Taiwan National Health Insurance Research Database152; RA

All

TNFi

A

RABBIT162; RA

All

ADA, ETN

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IFX

population

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ETN,

ADA=adalimumab; ARTIS=Antirheumatic Therapies in Sweden; AS=ankylosing spondylitis; BIOBADASER=Spanish Registry for Adverse Events of Biological Therapies in Rheumatic Diseases; BSRBR=British Society for Rheumatology Biologics Register; CD=Crohn's disease; ETN=etanercept; HR=hazard ratio; IBD=inflammatory bowel disease; IFX=infliximab; IRR=incidence rate ratio; JIA=juvenile idiopathic arthritis; LOHREN=Lombardy Rheumatology Network; NA=North America; nbDMARD=nonbiologic

67

TNF and Cancer Risk

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disease-modifying antirheumatic drug; PsA=psoriatic arthritis; PsO=psoriasis; RA=rheumatoid arthritis; RABBIT=Rheumatoid

Epidemiology, and End Results; SIR=standardized incidence ratio; SSTAG=South Swedish Arthritis Group; TNFi=tumor necrosis

A

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factor inhibitor.

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Arthritis Observation of Biologic Therapy; SABER=Safety Assessment of Biological Therapeutics; SEER=Surveillance,

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TNF and Cancer Risk

Figure Legends Figure 1. TNFRSF1a signal transduction. Activation of TNFRSF1a results in NF-κB activation and ultimately inflammation, angiogenesis, and cell survival. The apoptotic pathway is suppressed by FLIP. A decrease in NF-κB activation results in reduction of

DD=death domain; FADD=Fas-associated death domain; FLIP=FADD-like IL-



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converting enzyme; JNK=Jun kinase; NF-κB=nuclear factor kappa B; TNF=tumor

necrosis factor; TNFRSF1a=TNF receptor superfamily 1a; TRADD=TNF receptor–

CC

associated death domain; TRAF=TNF receptor–associated factor.

Reprinted (with modification) from Cell. 114(2), Micheau O, Tschopp J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes, Page 188 ©

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2003 with permission from Elsevier.

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resulting in caspase-dependent apoptosis.

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FLIP, which then favors signaling through the dissociated intracellular DD complex,

69

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A

Figure 2. TNF and tumorigenesis. A) TNF can impact multiple effectors of immune surveillance and exhibits either pro- (increased NK and CTL function), or anti- (increased

ST

suppressor cells, induction of PD-L1/B7-H1) surveillance activities. B) TNF directly affects tumors through a complex contextual integration of signals driving a cellular response toward apoptosis/necrosis or survival, inflammation, and growth promotion. C)

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TNF and Cancer Risk

TNF can initiate and progress autoimmunity, which can drive lymphoma development. AICD=activation-induced cell death; CTL=cytotoxic T-lymphocyte; DC=dendritic cell; IL=interleukin; MDSC=myeloid-derived suppressor cell; NK=natural killer; Th=T-helper lymphocyte; TNF=tumor necrosis factor.

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TNF and Cancer Risk

Adapted from Arthritis Research and Therapy. 5(4), Aringer M, Smolen J. Complex cytokine effects in a complex autoimmune disease: tumor necrosis factor in systemic

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lupus erythematosus, page 174 © 2003 with permission from BioMed Central Ltd.

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TNF and Cancer Risk

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TNF and Cancer Risk

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TNF and Cancer Risk

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Tumor necrosis factor, tumor necrosis factor inhibition, and cancer risk.

Tumor necrosis factor (TNF) is a highly pleiotropic cytokine with multiple activities other than its originally discovered role of tumor necrosis in r...
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