Immunotherapy strategies for mesothelioma - the role of tumor specific neoantigens in a new era of precision medicine

Our plain-English summary of Immunotherapy strategies for mesothelioma - the role of tumor specific neoantigens in a new era of precision medicine, by L. Ye, S. Ma, B.W. Robinson, et al (Expert Review of Respiratory Medicine, 2019).

The study

• Authors: L. Ye, S. Ma, B.W. Robinson, J. Creaney
• Journal: Expert Review of Respiratory Medicine
• Published: 2019;13(2):181-192
• Type of article: Review
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Immunotherapy has long been considered a potential therapy for malignant mesothelioma and is currently being pursued as such. Some of the early phase clinical trials involving immunomodulators have demonstrated encouraging results and numerous clinical trials are underway to further investigate this treatment approach in various treatment settings and larger patient cohorts. Areas covered: This review summarizes the current and emerging clinical evidence for checkpoint blockade and other immunotherapeutic strategies in mesothelioma. The mesothelioma tumor immune microenvironment and mutational landscape are also discussed, including their impact on treatment strategies. We also provide an evaluation of the current evidence for neoantigen targeted personalized immunotherapy. Expert opinion: Immune checkpoint inhibitors work by unleashing the host immune response against probable neoantigens. Despite impressive activity in a small subset of patients and the potential for prolonged responses, most patients experience treatment failure. Neoantigen vaccines provide a potential complementary therapeutic strategy by increasing the immunogenic antigen load, which can lead to an increased tumor specific immune response. Further research is needed explore this treatment option in mesothelioma and technological advances are required to translate this concept into clinical practice.

In plain English

This article is a review, not a new study. The authors summarized published and ongoing clinical trials of immune-based treatments for malignant mesothelioma, a cancer the article describes as mostly related to asbestos exposure. They also discussed neoantigens, which are abnormal proteins made only by tumor cells, as possible treatment targets. In the authors' summary, early trials of checkpoint inhibitor drugs in previously treated patients reported response rates of 4–30% and median overall survival of 7 to 17 months. A placebo-controlled trial of tremelimumab (DETERMINE) did not meet its overall survival goal. Interim results of the DREAM trial reported a response rate of 61% when durvalumab was added to first-line cisplatin and pemetrexed. The authors noted that most studies were single-arm or non-comparative. They also noted that no T cell response to neoantigens had yet been published from mesothelioma patients' samples, although one had been shown in a mouse model. The authors concluded that early trials suggest possible clinical benefit and that clinical trials are needed to evaluate the safety and efficacy of neoantigen vaccines.

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: Narrative review of clinical trials and research on immunotherapy for mesothelioma, including neoantigen-targeted approaches
• Who was studied: Published and ongoing clinical trials and laboratory studies in mesothelioma patients, mostly malignant pleural mesothelioma (MPM). The authors identified 28 open clinical trials for mesothelioma on clinicaltrials.gov.
• Exposure: The review did not study asbestos exposure. It reviewed treatments: checkpoint inhibitors (tremelimumab, ipilimumab, pembrolizumab, nivolumab, avelumab, durvalumab), anti-mesothelin therapies, CAR T cells, dendritic cell therapy, oncolytic viruses, tumor associated antigen vaccines and neoantigen vaccines. It states that most mesothelioma cases are related to asbestos exposure, without naming fiber types.
• Main results:
  • In the article's summary box, early phase trials of checkpoint inhibitors in pretreated patients showed response rates of 4–30% and median overall survival of 7 to 17 months.
  • The DETERMINE trial, which compared tremelimumab to placebo in patients with pretreated malignant pleural mesothelioma, failed to reach its primary endpoint of overall survival.
  • In KEYNOTE-028, pembrolizumab alone produced an overall response rate of 20% in 25 patients with pretreated malignant pleural mesothelioma whose tumors had PD-L1 expression of at least 1%.
  • In the MAPS-2 trial, preliminary results showed an overall response rate of 28% with nivolumab plus ipilimumab and 18.5% with nivolumab alone.
  • In the interim analysis of the DREAM trial (first-line cisplatin and pemetrexed plus durvalumab), the overall response rate was 61% and 6-month progression free survival was 71%.
  • Pembrolizumab is approved only for mesothelioma with mismatch repair deficiency or high microsatellite instability, which occurs in only 0–3% of mesotheliomas.
  • No T cell response to neoantigens in clinical samples from mesothelioma patients had been published. A neoantigen-specific immune response had been shown in a mouse mesothelioma model.
  • In their conclusion section, the authors stated that early trials suggest possible clinical benefit from checkpoint blockade and other immunomodulating agents.
• The authors' conclusion: The authors concluded that clinical trials are needed to evaluate the safety and efficacy of neoantigen vaccines in mesothelioma. They suggested that combining such vaccines with checkpoint blockade may improve outcomes.
• Limitations the authors state:
  • Most studies reviewed were single-arm or non-comparative trials, generally in heavily pretreated patients, which makes it difficult to compare agents with each other or with standard care.
  • Neoantigens have not been extensively studied in mesothelioma.

Topics

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

Medical terms in this study, explained in our Lexicon: Immunotherapy, Mesothelioma, Clinical Trial, checkpoint inhibitors.

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