Biologics Targeting TNF
TNF, as its name implies, was discovered as a serum factor from lipopolysaccharide-treated mice that causes tumor necrosis [
97], and was originally intensively studied because of its potential use as anti-tumor agent [
98]. However, initial enthusiasm about its clinical use as anti-tumor agent was curbed due to significant toxicities and lack of efficacy of systemic treatment. Clinical use of TNF for cancer treatment is therefore limited to the setting of hyperthermic isolated limb perfusion for the regional treatment of locally advanced soft tissue sarcomas, metastatic melanomas and other irresectable tumors to avoid limb amputation [
99]. Moreover, a paradoxical tumor-promoting role of TNF became apparent, which may reflect the role of TNF as a key pro-inflammatory mediator and the tumor-promoting role of inflammation [
100]. TNF is a key mediator of inflammation, which is barely detectable in circulation under normal conditions, but is produced by macrophages, activated T cells, natural killer cells, mast cells, and stromal cells during innate or adaptive immune responses [
101,
102].
TNF acts on multiple cell types by binding to specific cell surface receptors that activate multiple signaling pathways that culminate in the activation of MAP kinase, NF-κB and other transcription factors. At high doses, TNF causes the death of tumor blood vessels, although at lower doses, it can act as a tumor promoter and enhancer of metastasis [
16]. Furthermore, certain polymorphisms in the TNF gene are associated with hepatocellular cancer [
103‐
106], non-Hodgkin’s lymphoma [
107], breast cancer [
108], and gastric cancer [
109].
TNF is an important mediator of the dysregulated immune and inflammatory function in IMIDs. Drugs that target TNF are the most widely used biologics for treating IMIDs, with five drugs currently approved for clinical treatment of IMIDs (Table
2) [
110]. Although anti-TNF therapy is used in different IMIDs, not all anti-TNF agents have the same efficacy in all IMIDs [
111].
Table 2
Biologics used in the treatment of IMIDs
Infliximab (Remicade®) | Chimeric monoclonal antibody against TNF | RA, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, Crohn’s disease, plaque psoriasis |
Adalimumab (Humira®) | Human monoclonal antibody against TNF | RA, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, plaque psoriasis, polyarticular juvenile idiopathic arthritis |
Golimumab (Simponi®) | Human monoclonal antibody against TNF | RA, psoriatic arthritis, ankylosing spondylitis |
Certolizumab pegol (Cimzia®) | Pegylated humanized Fab’ monoclonal antibody fragment against TNF | RA, Crohn’s disease |
Etanercept (Enbrel®) | Fusion protein of two TNF receptor 2 extracellular domains and the Fc portion of human IgG | RA, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, plaque psoriasis |
Tocilizumab (Actemra® or RoActemra®) | Humanized monoclonal antibody against the interleukin-6 receptor | Juvenile idiopathic arthritis, RA |
Rituximab (Rituxan® or MabThera®) | Chimeric anti-CD20 monoclonal antibody | RA, granulomatosis with polyangiitis (Wegener) |
Abatacept (Orencia®) | Fusion of extracellular domain of human CTLA-4 and the Fc domain of IgG | RA |
Alefacept (Amevive®) | Fusion of CD2-binding region of LFA-3 and the CH2 and CH3 domains of IgG1 | Psoriasis |
Anakinra (Kineret®) | Recombinant, non-glycosylated human IL-1 receptor antagonist | RA |
Studies on the effect of TNF-blockers on the incidence of malignancy began to appear in the late 1990s. Bickston et al. reported the occurrence of lymphoma after infliximab treatment in patients with CD in 1999 [
112]. Other individual reports of lymphoproliferative diseases in patients treated with infliximab or etanercept followed soon thereafter [
113‐
115]. A large prospective observational study including 18,572 patients from the US National Data Bank for Rheumatic Diseases found a 2.9-fold increase in the incidence of lymphoma in patients treated with etanercept or infliximab [
116]. Updates three years later from this same database found the contrary – that infliximab and etanercept, after a median exposure of three years, were not associated with a risk of lymphoma in patients with RA [
117,
118]. Two additional observational studies reported that anti-TNF-biologics do not increase the risk of solid cancer, lymphoma or leukemia [
30,
32].
Thus, while some of the studies suggested a link between the use of anti-TNF biologics and cancer, others did not. Interpretation and reconciliation of these different findings is difficult because randomized clinical trials are usually too small or brief to obtain sufficient data to accurately determine the effects of a treatment on cancer and because most observational studies usually lack adequate control groups. Meta-analyses have therefore been performed on pooled data from multiple randomized clinical studies or prospective observational studies to better assess the risks of cancer associated with the treatment of IMIDs by biologics (Table
3).
Table 3
Meta-analyses on cancer risks associated with the use of biologics to treat IMIDs
Bongartz et al. 2006 [ 119] | RA | Prosp Obs | Infliximab Adalimumab | Increased risk of malignancies |
Peyrin-Biroulet et al. 2008 [ 120] | Crohn’s disease | RCTs | Infliximab, adalimumab, certolizumab, CDP571 | No increase in malignancy |
Leombruno et al. 2009 [ 121] | RA | RCTs | Etanercept, infliximab, adalimumab | No increased risk of melanoma, lymphoma, non-lymphoma skin cancer, or cutaneous cancer + melanoma |
Bongartz et al. 2009 [ 122] | RA | RCTs | Etanercept for ≥ 12 weeks | Non-significant increase in cancer |
| Adult Crohn’s disease | RCTs | Infliximab, adalimumab, certolizumab | Increase risk of non-Hodgkin’s lymphoma |
Mariette et al. 2011 [ 124] | RA | Prosp Obs | Anti-TNF | No increase in malignancy (including lymphoma). Increase in skin cancer (including melanoma) |
Dommasch et al. 2011 [ 125] | Plaque psoriasis, psoriatic arthritis | RCTs | Etanercept, Infliximab, adalimumab, certolizumab, golimumab | No increase in cancers for short-term use |
Askling et al. 2011 [ 126] | Any | RCTs | etanercept, infliximab, adalimumab | No increase in cancer with short-term use |
| RA | RCTs | Tocilizumab | No increase in risk of malignancy |
| RA | RCTs | Adalimumab, Certolizumab, Etanercept, Golimumab, Infliximab, Abatacept, Anakinra, Rituximab, Tocilizumab | No increased risk of malignancy in comparison with DMARDs or placebo |
| RA | RCTs | Anti-TNF | No excess cancer risk in either per protocol or intention to treat analysis, non-significant trend for increased non-melanoma skin cancer |
An initial meta-analysis published in 2006 by Bongartz et al. [
119] reported a 3.3-fold dose-dependent increase in malignancies associated with infliximab in RA patients. A 2011 meta-analysis by Mariette et al. [
124] analyzing data from 21 prospective observational studies on anti-TNF biologics in RA found that although anti-TNF biologics are not associated with an increase in malignancies, especially lymphoma, they are associated with an increase in the risk of skin cancer, including melanoma.
Meta-analyses of randomized clinical trials, however, found that the treatment of RA with anti-TNF biologics [
121,
126,
129] or biologics overall [
128] does not significantly increase the risk for any type of cancer in RA patients An important limitation of the RCT data in these studies, however, is the shortness of the follow-up period of the included studies in comparison with the latency period for emergence of cancer.
An integrated analysis of three patient databases found that the risk of malignancy in RA patients treated with anti-TNF biologics does not increase with time [
130].
The risk for cancer for individual anti-TNF biologics other than infliximab has been assessed in a few studies. An observational in 2004 found an increased risk of lymphoma associated with etanercept therapy in RA [
116], this was not supported by their 2007 updates from the same observational database, although they did find an increased risk of skin cancer [
117,
118]. A meta-analysis of randomized clinical trials from 2009 found that the use of etanercept for 12 weeks or more in patients with RA was associated with a non-significant increase in the incidence of cancer [
122]. Also, a 2010 report found that the use of golimumab at the FDA-approved dose to treat RA was not associated with a difference in the rate of cancer rate [
131].
A prospective observational study in France by Mariette et al. [
132] found that patients receiving adalimumab or infliximab have a higher risk for lymphoma than those treated with etanercept and that exposure to adalimumab or infliximab versus etanercept was an independent risk factor for lymphoma. The 2011 meta-analysis by Askling et al. [
126] did not find differences between the anti-TNF antibodies adalimumab, etanercept, and infliximab, although they suggest that this may have been due to differences in statistical precision or in baseline cancer risk between the various studies.
Few studies have examined the risk of cancer associated with the use of anti-TNF biologics in IMIDs other than RA. A 2008 meta-analysis of randomized clinical trials by Peyrin-Biroulet et al. reported that the treatment of CD by anti-TNF biologics does not increase the risk for cancer [
120]. However, a more recent meta-analysis of randomized clinical trials by Siegel et al. found that treatment of CD with anti-TNF biologics in combination with immunomodulators is associated with an increased risk of non-Hodgkin’s lymphoma [
123]. Analysis of data from the FDA Adverse Event Reporting System (AERS) showed that treatment with a combination of thiopurines and TNF inhibitors, but not with TNF inhibitors alone is associated with increased risk of non-Hodgkin lymphoma in IBD patients [
133]. Also, a meta-analysis of randomized clinical trials in plaque psoriasis and psoriatic arthritis found that short-term anti-TNF biologic use is not associated with a significant increased risk of cancer [
125].
Biologics in patients with cancer history
A 2010 study of data from the British Society for Rheumatology Biologics Register reported that in patients with RA, prior malignancy and an average of three years of follow up, the malignancy incidence rate did not increase in patients receiving anti-TNF therapy [
147]. The authors concluded that the way in which the patients were selected for anti-TNF therapy is not leading to an increased risk of incident malignancy but cautioned against concluding that it is safe to use anti-TNF biologics for RA patients with prior malignancy.
Up to now there is no clear evidence to guide the decision whether or not to use immunosuppressants or biologics in patients with previous history of cancer. Treatment decisions in these patients must taken on a case-by-case basis after discussion with a multidisciplinary team, taking into account the need for such treatment, the risk of cancer recurrence and the sensitivity of a specific cancer to immunosuppression, finally weighing benefits versus risks for the patient.