Immunotherapy approaches for malignant pleural mesothelioma

Fennell, Dean A.; Dulloo, Sean; Harber, James

doi:10.1038/s41571-022-00649-7

Cited by 32 publications

(33 citation statements)

References 128 publications

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“…Specifically, neoantigens produced by SVs are predicted to be presented by tumors on MHC proteins, which are closely related to clonal expansion of TILs, and effector T cells against these neoantigens are found in the circulation of cancer patients. 110,113 Therefore, SV-derived neoantigens may also serve as valuable targets for anti-tumor immunotherapy.…”

Section: The Source Of Neoantigensmentioning

confidence: 99%

Neoantigens: promising targets for cancer therapy

Xie

Shen

Gao

et al. 2023

Sig Transduct Target Ther

248

150

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Recent advances in neoantigen research have accelerated the development and regulatory approval of tumor immunotherapies, including cancer vaccines, adoptive cell therapy and antibody-based therapies, especially for solid tumors. Neoantigens are newly formed antigens generated by tumor cells as a result of various tumor-specific alterations, such as genomic mutation, dysregulated RNA splicing, disordered post-translational modification, and integrated viral open reading frames. Neoantigens are recognized as non-self and trigger an immune response that is not subject to central and peripheral tolerance. The quick identification and prediction of tumor-specific neoantigens have been made possible by the advanced development of next-generation sequencing and bioinformatic technologies. Compared to tumor-associated antigens, the highly immunogenic and tumor-specific neoantigens provide emerging targets for personalized cancer immunotherapies, and serve as prospective predictors for tumor survival prognosis and immune checkpoint blockade responses. The development of cancer therapies will be aided by understanding the mechanism underlying neoantigen-induced anti-tumor immune response and by streamlining the process of neoantigen-based immunotherapies. This review provides an overview on the identification and characterization of neoantigens and outlines the clinical applications of prospective immunotherapeutic strategies based on neoantigens. We also explore their current status, inherent challenges, and clinical translation potential.

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Section: The Source Of Neoantigensmentioning

confidence: 99%

Neoantigens: promising targets for cancer therapy

Xie

Shen

Gao

et al. 2023

Sig Transduct Target Ther

248

150

View full text Add to dashboard Cite

show abstract

“…The low incidence and slow-forming nature of MPM are factors that keep these tumors undiagnosed until they are detected in an advanced stage that is resistant to therapy and has very poor survival rate ( 9 ). Conventional treatment continues to be limited to cytoreductive surgery followed by cisplatin/pemetrexed chemotherapy ( 43 ), nowadays combined with checkpoint-inhibitor immunotherapy ( 44 ). Nevertheless, conventional treatments still lack –or have minimal– supporting molecular information to identify responder patients or to direct the course of therapy ( 45 ).…”

Section: Discussionmentioning

confidence: 99%

The extracellular matrix protein fibulin-3/EFEMP1 promotes pleural mesothelioma growth by activation of PI3K/Akt signaling

et al. 2022

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Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis and limited therapeutic options. The extracellular matrix protein fibulin-3/EFEMP1 accumulates in the pleural effusions of MPM patients and has been proposed as a prognostic biomarker of these tumors. However, it is entirely unknown whether fibulin-3 plays a functional role on MPM growth and progression. Here, we demonstrate that fibulin-3 is upregulated in MPM tissue, promotes the malignant behavior of MPM cells, and can be targeted to reduce tumor progression. Overexpression of fibulin-3 increased the viability, clonogenic capacity and invasion of mesothelial cells, whereas fibulin-3 knockdown decreased these phenotypic traits as well as chemoresistance in MPM cells. At the molecular level, fibulin-3 activated PI3K/Akt signaling and increased the expression of a PI3K-dependent gene signature associated with cell adhesion, motility, and invasion. These pro-tumoral effects of fibulin-3 on MPM cells were disrupted by PI3K inhibition as well as by a novel, function-blocking, anti-fibulin-3 chimeric antibody. Anti-fibulin-3 antibody therapy tested in two orthotopic models of MPM inhibited fibulin-3 signaling, resulting in decreased tumor cell proliferation, reduced tumor growth, and extended animal survival. Taken together, these results demonstrate for the first time that fibulin-3 is not only a prognostic factor of MPM but also a relevant molecular target in these tumors. Further development of anti-fibulin-3 approaches are proposed to increase early detection and therapeutic impact against MPM.

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“…We believe that the treatment options for MPM have not yet been achieved, in part as their superiority versus current standard-of-care is taken for granted despite to our minds a lack of solid evidence. We think that these sort of statements are not only baseless but can also generate hopes and expectations not underpinned by facts [ 26 , 31 , 76 – 78 ].…”

Section: Discussionmentioning

confidence: 99%

Analysis of new treatments proposed for malignant pleural mesothelioma raises concerns about the conduction of clinical trials in oncology

et al. 2022

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In this commentary, using existing clinical trial data and FDA approvals we propose that there is currently a critical need for an appropriate balancing between the financial impact of new cancer drugs and their actual benefit for patients. By adopting “pleural mesothelioma” as our clinical model we summarize the most relevant pertinent and available literature on this topic, and use an analysis of the reliability of the trials submitted for registration and/or recently published as a case in point to raise concerns with respect to appropriate trial design, biomarker based stratification and to highlight the ongoing need for balancing the benefit/cost ratio for both patients and healthcare providers.

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Immunotherapy approaches for malignant pleural mesothelioma

Cited by 32 publications

References 128 publications

Neoantigens: promising targets for cancer therapy

Neoantigens: promising targets for cancer therapy

The extracellular matrix protein fibulin-3/EFEMP1 promotes pleural mesothelioma growth by activation of PI3K/Akt signaling

Analysis of new treatments proposed for malignant pleural mesothelioma raises concerns about the conduction of clinical trials in oncology

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