Anti-inflammatory biologic therapies and immune surveillance of melanoma

Throughout the past 20 years, elucidation of the immunopathogenesis underlying chronic inflammatory diseases, such as ankylosing spondylitis (AS), inflammatory bowel disease (IBD), juvenile idiopathic arthritis (JIA), psoriasis, psoriatic arthritis (PsA) and rheumatoid arthritis (RA), has led to the emergence of new therapies targeting the immune effector cells and molecules that induce and maintain inflammatory disease [1–5]. During the past decade, especially the last few years, the market sales and regulatory approval of new human medicines indicates an increasing number of biologic therapies, that is, recombinant proteins and monoclonal antibodies (mAb) specifically designed to interfere with T-cell activation and function, as well as with cytokines, such as IL-12, IL-23 and TNF-α [1–5]. In fact, the global sale of mAb-derived biologic therapies in 2006 was US$20.6 billion, indicating a real paradigm shift in industrial R&D from pharmaceutical to biologic therapies [6,101].

The major biological agents currently available in the USA for the treatment of AS, IBD, JIA, PsA and RA include [1,2]:

•	Efalizumab, a humanized mAb that binds to the CD11a portion of leukocyte function-associated antigen (LFA)-1 and interferes with the LFA-1/ICAM-1 interaction;
•	Alefacept, a recombinant fusion protein composed of the first extracellular domain of LFA-3 fused to the human IgG1 hinge, CH2 and CH3 domains, which binds CD2 on CD45RO+ memory T cells;
•	Etanercept, a recombinant fusion protein that is composed of two p75 TNF-α receptors fused to human IgG1;
•	Infliximab, a chimeric human/mouse TNF-α-specific mAb;
•	Adalimumab, a human IgG1 TNF-specific mAb.

These biologic therapeutic agents have been very successful at effectively treating recalcitrant inflammatory disease and, in some patients, achieving remission [1,2]; however, their use is not without risk. The most common adverse events in the short term are injection-site and infusion reactions [1,2]. The most concerning short-term risk is serious infection [1,2], which includes sepsis, infection from opportunistic organisms and reactivation of latent TB. The risk of infection is higher in patients with predisposing underlying conditions, such as diabetes mellitus, congestive heart failure, a history of active or chronic infections or concurrent use of immunosuppressive drugs [1,2]. Other classwide safety concerns include the risk of demyelinating disease and exacerbation or development of congestive heart failure [1,2].

Given their inhibitory effects on molecules crucial for immune responses, biologic therapies may predispose patients to an increased risk of malignancies or accelerate their development. This risk may be greatest in those malignancies in which immunological events appear to play a role in the clinical course of the disease and may occasionally cause clinical regressions, such as melanoma [7,8]. To date, there is no consensus on the estimated risk of malignancy, such as lymphoma and solid tumors, in patients treated with biologic therapeutics. Several large observational databases and a case–control study did not demonstrate an increased incidence of solid tumors in patients receiving TNF-α-blocking agents compared with matched controls [9–14]. By contrast, two meta-analyses found a 3.3-fold increase in the incidence of solid malignancies, including melanoma, in general, among transplantation recipients who were treated with infliximab or adalimumab, compared with those who received nonbiologic therapy [15]. One population-based study showed that the incidence of both melanoma and non-melanoma skin cancer were slightly increased when TNF-α-blocking agents were used [10]. Moreover, biologic treatment of RA patients has spurred an increased incidence of melanoma and other skin cancers, according to a recent observational study of 13,001 patients [16]. Nevertheless, conclusions are difficult to draw in light of confounding factors, such as age, gender, family history, dysplastic nevi as well as amount of UV light exposure. Although national registries to date show no increase in the incidence of solid cancers versus the general population, several case reports of eruptive latent metastatic melanoma [17], as well as recurrence of melanoma in patients after the initiation of TNF-α inhibitors, have been published [18].

The role of TNF-α inhibitors in the development and progression of melanoma is in agreement with the growing experimental and clinical evidence accumulated during the last few years that immunological events are involved in the pathogenesis and clinical course of the disease and may occasionally cause clinical regressions [7,8,19]. First, melanoma antigen (MA)-specific T cells, both CD4⁺ T helper cells and CD8⁺ cytotoxic T cells, have been shown to play an active role in eliminating tumors and metastases in melanoma animal models [7,8,19]. Second, in vitro studies employing human peripheral blood lymphocytes isolated from patients with melanoma have been reported to contain MA-specific CD8⁺ and CD4⁺ T-cell precursors as well as natural killer cells and macrophages that are capable of killing autologous melanoma cells after appropriate in vitro activation [7,8,19]. Third, lymphocyte infiltration of primary melanoma lesions is associated with their histopathological characteristics and with the clinical course of the disease [7,8,19]. Fourth, defects in HLA class I antigen expression, which occur in approximately 16 and 40% of primary and of metastatic melanoma lesions [19], respectively, argue in favor of the possibility that the MA-specific patient’s T-cell-mediated immune response favors the outgrowth of the tumor cells that have developed an immune escape mechanism [20]. Lastly, induction or enhancement of MA-specific humoral and cellular immunity may be associated with metastasis regression and/or with favorable prognosis [7,8,19]. The above findings, along with the lack of effective treatment for advanced-stage melanoma by conventional therapies [7,8], have provided the rationale for the development and application of immunotherapy for the treatment of melanoma [7,8,19].

The precise role that TNF-α plays in immune surveillance of melanoma, and thereby the mechanism(s) by which its inhibition may promote melanoma, are not well understood. One might envision several mechanisms by which the manipulation of TNF-α expression through the use of biologic therapies may have dramatic consequences on the ability of the host’s immune system to control tumor growth and development. First, inhibition of TNF-α might affect the anti-tumor activities of MA-specific CD8⁺ T cells, macrophages and/or natural killer cells, since this cytokine plays a pivotal role in the generation of type-1 immune responses [21–23]. An alternative, but nonexclusive mechanism, is the reduced susceptibility of melanoma cells to apoptosis, since TNF-α promotes the killing of tumor cells by sensitizing them to Fas-mediated apoptosis [21–23]. Furthermore, one might expect a MA-specific immune response biased towards an ineffective type-2 [21], antibody-mediated, immune response, due to a reduced TNF-α level in the tumor microenvironment. In this regard, it is of note that tumor-infiltrating lymphocytes isolated from patients with malignant disease have been shown to display a predominant type-2 or -3, that is, antibody or suppressive, respectively, functional phenotype rather than the mixed type-1/type-2 responsiveness observed in normal donors [21]. Therefore, the use of TNF-α inhibitors may further augment established type-2 or -3 immune response in patients with malignant disease and/or premalignant lesions.

Undoubtedly, the use of TNF-α inhibitors has been very successful at effectively treating recalcitrant inflammatory disease in patients. Nonetheless, these agents should not be administered without caution given the crucial role TNF-α plays in the generation and maintenance of effective tumor-specific immune responses. At present, conclusions are difficult to draw since, in some cases of chronic inflammation, such as those observed in the tumor microenvironment, dysregulated overexpression of type-1 cytokines, such as TNF-α and IFN-γ, may lead to tumor and stromal cell production of a panoply of soluble factors promoting tumor growth and development [22,23]. However, the role this dysregulated overexpression of type-1 cytokines plays in melanoma development and progression has yet to be determined. A confounding problem in interpreting malignancy after treatment with TNF-α inhibitors is that the underlying disease for which TNF-α inhibitors are used are themselves sometimes associated with malignancy [9–14]. Nevertheless, a better understanding of how the loss of TNF-α effects the pathogenesis and clinical course of melanoma as well as the institution of prospective cohort studies are of critical importance to the optimization of effective inflammatory disease therapies in the future. These studies should not be limited to the analysis of the effects of TNF-α on the pathogenesis and clinical course of melanoma, but should also take into account MA-specific immune responses mounted by the host. While these new biologic therapies provide physicians with additional options for patients for whom traditional therapies are not sufficient, their use is not without risk and both physicians and patients should be aware of the risks involved with each medicine.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.