Fully Human Antibodies for Malignant Pleural Mesothelioma Targeting

Our plain-English summary of Fully Human Antibodies for Malignant Pleural Mesothelioma Targeting, by F. Nicolini, M. Bocchini, D. Angeli, et al (Cancers, 2020).

The study

• Authors: F. Nicolini, M. Bocchini, D. Angeli, G. Bronte, A. Delmonte, L. Crinò, M. Mazza
• Journal: Cancers
• Published: 2020;12(4)
• Type of article: Review
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Immunotherapy is the most promising therapeutic approach against malignant pleural mesothelioma (MPM). Despite technological progress, the number of targetable antigens or specific antibodies is limited, thus hindering the full potential of recent therapeutic interventions. All possibilities of finding new targeting molecules must be exploited. The specificity of targeting is guaranteed by the use of monoclonal antibodies, while fully human antibodies are preferred, as they are functional and generate no neutralizing antibodies. The aim of this review is to appraise the latest advances in screening methods dedicated to the identification and harnessing of fully human antibodies. The scope of identifying useful molecules proceeds along two avenues, i.e., through the antigen-first or binding-first approaches. The first relies on screening human antibody libraries or plasma from immunized transgenic mice or humans to isolate binders to specific antigens. The latter takes advantage of specific binding to tumor cells of antibodies present in phage display libraries or in responders' plasma samples without prior knowledge of the antigens. Additionally, next-generation sequencing analysis of B-cell receptor repertoire pre- and post-therapy in memory B-cells from responders allows for the identification of clones expanded and matured upon treatment. Human antibodies identified can be subsequently reformatted to generate a plethora of therapeutics like antibody-drug conjugates, immunotoxins, and advanced cell-therapeutics such as chimeric antigen receptor-transduced T-cells.

In plain English

This was a narrative review, not a study of patients. The authors reviewed the state of immunotherapy for malignant pleural mesothelioma (MPM) and, mainly, the laboratory methods available for finding fully human antibodies that bind MPM cells. In the introduction they noted that MPM has a median overall survival of 14 months and that its onset is associated with asbestos exposure, that Europe currently carries most of the global asbestos-related disease burden, and that about 60% of MPM patients carry BAP1 mutations. They summarised published work on checkpoint inhibitors and on mesothelin-directed CAR-T cells, citing a phase I trial in patients with MPM and in patients with pleural metastases from lung or breast cancer in which pembrolizumab plus anti-mesothelin CAR-T cells gave an objective response rate of 63% (10/16) and disease control of 75% (12/16); they also summarised reports of lymphoid aggregates in about 70% of MPM tumours and an unbiased phage-display screen that identified mesothelioma-targeting scFvs. The authors concluded that a future advance would come from cell therapies aimed at antigens still unknown, identified by unbiased screening.

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 published literature
• Who was studied: No study population; the review covered published literature on MPM patients, murine models and antibody-screening platforms
• Exposure: Not an exposure study; the review stated that MPM onset is associated with asbestos exposure
• Main results:
  • The review stated that Europe currently carries most of the global asbestos-related disease burden and that an MPM incidence peak is expected in the 2020s because of the long latency
  • The review reported that about 60% of MPM patients carry BAP1 mutations
  • From a cited phase I trial of anti-mesothelin CAR-T cells plus pembrolizumab in patients with MPM and pleural metastases from lung or breast cancer: objective response rate 63% (10/16), disease control rate 75% (12/16)
  • The cited CAR-T trial enrolled patients with MPM and patients with pleural metastases from lung or breast cancer
  • The review reported that lymphoid aggregates occur in about 70% of MPM tumours, with germinal centres in about 30% of cases
  • The review described an unbiased phage-display screen that found antibody fragments binding sarcomatoid and epithelioid mesothelioma, with MCAM/CD146 later identified as one antigen
  • The review noted that the TCGA-MESO dataset holds expression analyses of 87 MPM patients that could be mined for B-cell receptor sequences
• The authors' conclusion: The authors concluded that a curative MPM treatment remains an unmet clinical need and that, in their view, future progress will come from cell therapies directed at as-yet unknown antigens found by unbiased screening
• Limitations the authors state:
  • The authors noted that the CAR-T results they cited came from a limited number of patients
  • The authors noted that transgenic-mouse platforms cannot raise antibodies to antigens highly conserved between human and mouse
  • The authors noted that immunodominance has limited wider use of patient-derived phage antibody libraries

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Immunotherapy, Monoclonal Antibody, Next-Generation Sequencing (NGS).

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