Immune responses and immunotherapeutic interventions in malignant pleural mesothelioma

Our plain-English summary of Immune responses and immunotherapeutic interventions in malignant pleural mesothelioma, by A.J. Bograd, K. Suzuki, E. Vertes, et al (Cancer Immunology, Immunotherapy, 2011).

The study

• Authors: A.J. Bograd, K. Suzuki, E. Vertes, C. Colovos, E.A. Morales, M. Sadelain, P.S. Adusumilli
• Journal: Cancer Immunology, Immunotherapy
• Published: 2011;60(11):1509-27
• Type of article: Review
• Cited by: 40 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive, primary pleural malignancy with poor prognosis, hypothesized to originate from a chronic inflammatory state within the pleura. Similar to what has been observed in other solid tumors (melanoma, ovarian and colorectal cancer), clinical and pre-clinical MPM investigations have correlated anti-tumor immune responses with improved survival. As such, a better understanding of the complex MPM tumor microenvironment is imperative in strategizing successful immunotherapies. Herein, we review the immune responses vital to the development and progression of MPM, as well as assess the role of immunomodulatory therapies, highlighting recent pre-clinical and clinical immunotherapy investigations.

In plain English

This article was a review, not a new study. The authors reviewed published research on immune responses in malignant pleural mesothelioma and on immunotherapies tested in mice and patients. An opening section reviewed evidence linking asbestos to mesothelioma in several animal species. It also described macrophages failing to clear asbestos fibers, causing chronic inflammation that had been shown to make mesothelial cells malignant in laboratory studies. One reviewed human study came from the authors' own laboratory. It examined 175 epithelioid mesothelioma specimens. Patients with high chronic inflammation in the tumor stroma had longer median survival (19.4 vs. 15.0 months), and this inflammation independently predicted survival. Another study, of 32 patients given induction chemotherapy then extrapleural pneumonectomy, reported 3-year survival of 83% with high versus 28% with low CD8 T-cell infiltration. Several treatments improved survival in mice. Early human trials showed limited results; one anti-mesothelin antibody produced no complete or partial responses. The authors concluded that intrapleural cytokine therapies were safe and well tolerated but of unproven efficacy. They noted that human studies were scarce and that most mouse models were not pleural.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Review of published pre-clinical (mouse) and clinical studies on immune responses and immunotherapy in malignant pleural mesothelioma (MPM)
• Who was studied: No new population. The review covered published studies of human MPM tumor specimens, mouse models of mesothelioma, and early-phase clinical immunotherapy trials in MPM patients.
• Exposure: The review studied immunotherapies, including regulatory T-cell depletion, dendritic cell vaccines, mesothelin-targeted agents, and cytokines such as interferon-beta and IL-2. An opening section reviewed earlier work on asbestos: the link between asbestos and mesothelioma in multiple animal species (by inhalation or inoculation), and 'frustrated phagocytosis'. In frustrated phagocytosis, macrophages repeatedly fail to clear asbestos fibers, which causes reactive oxygen species, inflammatory cytokines and chronic inflammation that had been shown to transform mesothelial cells in vitro. The review reported no new asbestos experiments and named no specific fiber type in its text.
• Main results:
  • A study from the authors' own laboratory examined 175 epithelioid MPM specimens. Patients with high chronic inflammatory responses in the tumor stroma had longer median overall survival than those with low responses (19.4 vs. 15.0 months). On multivariate analysis, chronic stromal inflammation remained an independent predictor of survival (P = 0.02, HR = 0.659, 95% CI 0.464 to 0.937).
  • A reviewed study followed 32 patients who had induction chemotherapy followed by extrapleural pneumonectomy. Three-year overall survival was 83% with high versus 28% with low tumor-infiltrating CD8 T cells.
  • A reviewed study of 173 MPM patients undergoing systemic therapy compared blood neutrophil-to-lymphocyte ratios. Median overall survival was 16.7 months for a ratio below 5 versus 6.6 months for a ratio of 5 or more.
  • In mice, depleting regulatory T cells before mesothelioma tumors were introduced increased median survival from 19 to 33 days.
  • In a phase I trial of intrapleural interferon-beta gene transfer, successful gene transfer was detected in seven of ten patients.
  • In a phase I dendritic cell vaccine trial in 10 MPM patients, no survival benefit was noted.
  • A phase I dose-escalation trial of the anti-mesothelin antibody MORAb-009 in MPM, pancreatic and ovarian cancer patients showed no complete or partial responses.
• The authors' conclusion: The authors concluded that intrapleural cytokine therapies had been shown to be safe and well tolerated but that their efficacy was unproven. They suggested that an effective immunotherapy may need to both boost anti-tumor immune activity and dampen pro-tumor immune effects.
• Limitations the authors state:
  • Human studies on the balance of immune cells in MPM tumors were scarce.
  • Most mouse studies used flank or peritoneal tumor models. The authors said future studies should use orthotopic models that better mimic the pleural tumor environment.
  • The neutrophil-to-lymphocyte ratio finding needed to be reproduced by other investigators.
  • The dendritic cell vaccine trial was hard to interpret because of its small size and highly selected patients.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Prognosis, Pleura, Colorectal Cancer, Tumor Microenvironment, Immunotherapy.

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