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INTRODUCTION

Utilizing the body’s own immune responses to combat malignancies is not a recent phenomenon. In the late 1880s, Dr. William B. Coley utilized staphylococcal toxins following his observation of tumor regression in patients who had been exposed to infectious pathogens.1 In recent years, the application of immunotherapy has evolved to include many different biologic facets such as modulating the tumor immune microenvironment (TME) and shifting its balance toward an antitumor state (Fig. 121-1). Current immunotherapeutic treatments for malignant pleural mesothelioma (MPM) involve cell- and antibody-mediated immunotherapies.

Figure 121-1

Multiplex immunofluorescent image showing the tumor microenvironment of malignant pleural mesothelioma. MSLN, mesothelin; CD-4, helper T cell; CD-8, cytotoxic T cell; SMA, smooth muscle actin; DAPI, 4′,6-diamidino-2-phenylindole, nuclear marker.

Rationale for Immunotherapy

A review of the National Cancer Database showed using a propensity score–matched analysis that trimodality therapy with a combination of cancer-directed surgery, pemetrexed-based chemotherapy, and hemithoracic radiation improves overall survival (OS) in epithelioid malignant pleural mesothelioma (MPM).2 However, a median OS of 14 to 21 months following trimodality therapy warrants investigation of other novel therapies.

It has been hypothesized that MPM develops from a frustrated phagocytosis process where macrophages attempt to phagocytose asbestos fibers, which leads to persistent reactive oxygen species and production of proinflammatory cytokines that have been shown to be associated with malignant mesothelial cell proliferation in vitro and in vivo.35 Antitumor immune responses are documented in MPM patients, albeit in small cohorts.6 In a systematic investigation of immune responses in MPM, as a first step our group evaluated 175 hematoxylin and eosin (H&E)-stained slides from patients with epithelioid MPM. On multivariate analysis, we showed that chronic inflammation in the stroma was an independent predictor of survival (hazard ratio [HR], 0.659; 95% confidence interval [CI], 0.464–0.937; p = 0.02).7 Subsequently, we assessed 230 patient samples for 8 types of infiltrating immune cells and tumor expression of 5 cytokine or chemokine receptors.8 The ratio of effector to suppressor immune cells was prognostic; patient tumors with high CD163 macrophages and low CD8 cytotoxic T cells were associated with a worse prognosis (median OS, 8.8 months [high-risk index] vs. 17.0 months [low-risk index]; p = 0.009). Conversely, low CD163 and high CD20 B cells had a better prognosis (median OS, 25.0 months [low-risk index] vs. 15.0 months [high-risk index]; p < 0.001). A multivariate analysis confirmed that stage (HR, 1.57; 95% CI, 1.15–2.14, p = 0.005), CD163 to CD8 ratio (HR, 1.64; 95% CI, 1.01–2.44; p = 0.044), and CD163 to CD20 ratio (HR, 1.64; 95% CI, 1.10–2.44; p = 0.015) were independent prognostic factors for survival.8 The aforementioned studies underscored the rationale to promote effector immune responses in MPM.

IMMUNOTHERAPY

Immunoediting and Immunosurveillance

The theory ...

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