Despite its rarity and poor prognosis, malignant pleural mesothelioma (MPM) has generated significant interest, likely because of its association with asbestos exposure and the hypothesis that it originates from a chronic inflammatory state within the pleura. In an effort to clear asbestos fibers, macrophages make repeated failed attempts at phagocytosis, resulting in continued generation of reactive oxygen species with subsequent production of inflammatory cytokines and increased recruitment of immune cells.[1] This process, often referred to as “frustrated phagocytosis,” represents a chronic inflammatory state that results in malignant transformation of mesothelial cells. Currently, even with trimodality therapy (chemotherapy, surgical resection, and hemithoracic radiation), the median survival for patients with epitheloid MPM, the most common type of MPM, is only 17 months. For patients with MPM who present with unresectable disease, the combination of pemetrexed and cisplatin is the most effective therapy, although it achieves a median survival of only 12 months.[2] Responses to second-line and third-line treatment are rare in patients for whom chemotherapy has failed.

Despite the aggressive biologic nature of MPM, clinical and preclinical investigations have correlated antitumor immune responses with improved survival in patients with MPM,[3] similar to what has been observed in patients with other solid tumors (melanoma and ovarian cancer). In a cohort of 175 patients with epitheloid MPM, we observed that patients with high chronic stromal inflammatory responses had better median overall survival than those with low chronic inflammatory responses.[4] It is noteworthy that, on multivariate analysis, chronic stromal inflammation remained an independent predictor of survival. Furthermore, we and others have demonstrated that tumor infiltration of CD8-positive T lymphocytes is an independent prognostic factor for patients with MPM.[5-7] Efforts to promote immune responses have led to the investigation of immunotherapeutic strategies targeting cancer-associated antigens by using monoclonal antibodies, recombinant immunotoxins, vaccines, and genetically engineered T cells. Targeted antigens can be either cell-surface antigens like mesothelin (MSLN) or intracellular antigens like WT-1. Because of their ease of targeting, cell-surface antigens are favored for immunotherapeutic approaches.

An ideal cancer-associated antigen to target by immunotherapeutic approaches 1) is not expressed or is expressed at relatively lower levels in normal tissues compared with cancer cells, 2) is expressed in a majority of cancer patients, and 3) plays a role in promoting cancer aggressiveness. MSLN, one such cancer-associated antigen originally described by Pastan and colleagues[8, 9] that is being investigated in patients with MPM, is expressed at very low levels in normal mesothelial cells lining the pleura, peritoneum, and pericardium. MSLN is overexpressed in epitheloid mesotheliomas[10] and in other solid cancers, including ovarian, pancreatic, lung, stomach, and esophageal cancers; cholangiocarcinoma; and triple-negative breast cancer.[11-13] The MSLN gene encodes a 71-kDa precursor protein; this protein is processed into megakaryocytic potentiating factor (MPF), which is secreted from the cell into the blood, and MSLN, which is bound to the cell membrane by phosphatidyl inositol but is slowly shed from the cell surface by the action of tumor necrosis factor α-converting enzyme. It has been demonstrated that MSLN binds to mucin 16 (cancer antigen 125 [CA 125]), and this interaction has been implicated in the intracavitary spread of ovarian cancer.[14] Our group has demonstrated—both in an orthotopic MPM mouse model and in patients—that MSLN overexpression is correlated with locoregional invasion characteristics of MPM.[10] MSLN overexpression is associated with the expression of metalloproteinase-9 (a protein involved in the degradation of extracellular matrix), which facilitates cancer cell migration and local invasion. Studies of MSLN gene knockout (−/−) mice indicate that MSLN is not essential for normal development and reproduction,[15] but recent studies have demonstrated that MSLN may regulate cancer cell growth.[16] Our group observed that MSLN expression was correlated with tumor aggressiveness as well as decreased overall survival in a cohort of 1209 patients with early stage lung adenocarcinoma.[12]

Given its high level of expression in cancer and its limited expression in normal tissues, MSLN provides a safe target for tumor-specific therapies. SS1P is a recombinant anti-MSLN immunotoxin that consists of a murine anti-MSLN variable antibody fragment (Fv) linked to PE38, a truncated portion of Pseudomonas exotoxin A. In a phase 1 clinical trial of patients with advanced, therapy-resistant, MSLN-expressing cancer, the administration of SS1P for a total of 3 doses was well tolerated.[17] Pleuritis was the dose-limiting toxicity in that trial, and the most commonly reported adverse events were hypoalbuminemia and fatigue. SS1P had limited antitumor activity, the investigators hypothesized that the lack of activity of SS1P could be attributed to the limited tumor penetration caused by tumor cell density, high interstitial pressure, and lack of functional lymphatics within tumors. In mice with MSLN-expressing human tumor xenografts, SS1P had modest antitumor activity by itself; however, when it was combined with chemotherapy, synergy was observed.[18] Investigators led by Drs. Pastan and Hassan demonstrated that, by killing tumor cells, chemotherapy disrupts the close packing of tumor cells, allowing better penetration of immunotoxin into the tumor.

In this issue of Cancer, in the first evaluation of SS1P in combination with pemetrexed and cisplatin in patients with chemotherapy-naive MPM, Hassan et al report objective tumor responses that are higher than would be expected with chemotherapy alone, with no overlapping toxicities.[19] The primary objective of this phase 1 study was to determine the safety and MTD of SS1P in combination with pemetrexed and cisplatin in chemotherapy-naive patients with advanced MPM. The secondary objectives were to assess the tumor radiologic response, SS1P pharmacokinetics, and serum biomarkers of response (MSLN, MPF, and CA 125). Although this was a phase 1 study designed to evaluate the feasibility and safety of combination chemoimmunotherapy, the results from the trial (response rates of 60% in all evaluable patients vs 77% in patients who received the MTD) compare favorably with those from the pivotal trial of pemetrexed and cisplatin in MPM (objective response rate, 41% vs 17% in patients who received cisplatin alone). In addition, Hassan et al demonstrate the utility of incorporating the biomarkers of response into an early phase clinical trial. Although baseline MSLN, MPF, and CA 125 levels did not predict the response to SS1P and chemotherapy in this small cohort of patients, the investigators observed that changes in MSLN and MPF levels were better reflectors of tumor response compared with changes in CA 125 levels.

Immunotoxins such as SS1P, which combine a bacterial toxin with an antibody, can provoke the patient's immune system by generating antibodies against them, destroying them before they can reach their target and deliver toxin to the tumor. In their publication in Science Translational Medicine,[20] Hassan et al demonstrated a novel approach to overcome this obstacle: treating patients who have chemotherapy-resistant MPM with pentostatin and cyclophosphamide—chemotherapeutic agents that can deplete lymphocytes and prevent the formation of antibodies after the administration of SS1P. This treatment combination delayed the formation of antibody, allowing the patients to receive multiple cycles of SS1P and resulting in improved outcomes. Some of the responses demonstrated in these 2 publications are remarkable for an aggressive malignancy such as MPM.[20] Other methods of preventing antibody response developed by this group include mutating immunodominant epitopes to generate a less immunogenic antibody-toxin conjugate and removing immunotoxin domains that are not necessary for cytolytic function.[21]

However, impressive results with MSLN-targeted therapies are not unique to patients with MPM. In a phase 2 trial of pancreatic cancer, a comparably aggressive malignancy, MSLN-targeted vaccine combined with granulocyte-macrophage colony–stimulating factor-expressing cells produced promising results, with prolonged survival observed in patients who had MSLN-specific immune cell responses.[22] Although it has been demonstrated that MSLN-specific T-cell responses are beneficial in patients with pancreatic cancer, no such data are available on patients with MPM.

Some of these responses are attributed to endogenous immune responses generated to cancer-associated antigens from lysed cancer cells. The development of a broad tumor-specific, adaptive immune response, caused by epitope spreading after tumor destruction and inflammation, has been proposed as an important secondary mechanism underlying the potency of immunotherapy. In a novel approach of targeting MSLN with adoptively transferred, MSLN-specific, chimeric antigen receptor messenger RNA–engineered T-cells, investigators from the University of Pennsylvania have demonstrated antibody responses to several self-proteins after chimeric antigen receptor T-cell infusion in patients.[23]

Although chemotherapy has long been considered to be immune-suppressive, recent data indicate that cytotoxic drugs treat cancer, at least in part, by facilitating an immune response to the tumor. Chemotherapy-induced tumor cell lysis can induce an adaptive immune response that is specific to the tumor. In addition, chemotherapy drugs can promote antitumor immunity through largely unappreciated immunologic effects on both malignant and normal cells present within the tumor microenvironment, including enhanced cytokine and chemokine secretion by the tumoral stroma, enhanced proimmune surface proteins, and altering tumor vasculature. These subtle immunomodulatory effects depend on the drug itself, its dose, and its schedule. Preclinical evidence suggests that cisplatin favorably modulates the immune system by up-regulating major histocompatibility complex (MHC) class I expression; by increasing the recruitment, infiltration, and proliferation of various effector cells; by improving the lytic activity of cytotoxic effectors; and by down-regulating the immunosuppressive microenvironment.[24] Although cisplatin is a widely used chemotherapeutic agent that has been studied for its immunomodulatory effects in solid malignancies, similar tumor immunity reengineering approaches with other chemotherapeutic agents, such as doxorubicin, fludarabine, and oxaliplatin, have been attempted in hematologic and solid malignancies. Lymphodepleting agents, like those used by Hassan et al in patients with MPM, likely have beneficial immunomodulatory effects aside from their well characterized ability to prevent an immunotoxin antibody response. Lymphodepletion can deplete T-regulatory cells and enhance the availability of prosurvival and proliferative homeostatic cytokines to tumor-specific T cells and natural killer cells. To date, these advantages have been documented in models of adoptive T-cell therapy. Further studies are needed to document their role in enhancing anti-MSLN immunotoxin therapy.

The recent approval of checkpoint blockade agents heralds a new era in chemoimmunotherapeutic approaches and has led to heightened interest in immunotherapy as a valid approach to cancer treatment. The results of ongoing preclinical studies suggest that rationally combining chemotherapy-induced immune activation with checkpoint blockade agents has synergistic efficacy to maximize the benefits of endogenously generated antigen responses. Radiotherapy is another standard-of-care therapy that has been shown to activate the immune system. In a recent phase 2 clinical trial from the University of Toronto, immediate preoperative hemithoracic intensity-modulated radiation therapy followed by extrapleural pneumonectomy was investigated in highly selected patients, and a 3-year overall survival rate of 84% was reported.[25] Although this treatment strategy does not yield better local control than the more conventional approach of surgical resection followed by hemithoracic radiation, it is associated with remarkably good survival, resulting in a speculative hypothesis that preoperative radiation therapy may activate the immune system against cancer—an idea supported by recent preclinical findings that demonstrate synergistic efficacy in solid tumors when radiation therapy and immune checkpoint blockade are combined.

With their systematic bench-to-bedside-and-back-to-bench investigative approach, the group at the National Cancer Institute led by Pastan and Hassan has demonstrated an ideal paradigm for translational immunotherapeutics that not only can benefit patients with mesothelioma but also holds promise for many other solid cancers. Our improved ability to perform immune monitoring of both the systemic and tumoral microenvironment in conjunction with tumor biomarkers has provided an opportunity to measure antitumor immune responses even in early phase clinical trials. A detailed understanding of the cellular and molecular bases of the interactions between chemotherapy drugs, radiation therapy, and the immune system is essential to be able to devise an optimal strategy for integrating new immune-based therapies into the standard of care for various cancers and to ensure the greatest long-term clinical benefit in the treatment of patients with traditionally therapy-resistant cancer.


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Dr. Adusumilli is supported by grants from the National Institutes of Health (R21 CA164568-01A1, R21 CA164585-01A1, U54 CA137788, and P50 CA086438-13), the US Department of Defense (PR101053 and LC110202), and the Mr. William H. Goodwin and Mrs. Alice Goodwin, the Commonwealth Foundation for Cancer Research, and the Experimental Therapeutics Center of Memorial Sloan Kettering Cancer Center.


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The author made no disclosures.


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