Review Reports

Round 1

Reviewer 1 Report

This is a well-written review on the current status of treatment of mesothelioma by Banerji and colleagues. It summarises the changes that have occurred from the standard systematic chemotherapy to trials involving immune therapy.

1. Considering that ipi/nivo is a relatively recent first-line approval for mesothelioma, it is mentioned very late in the review and should be mentioned in the abstract and introductions sections. Considering that it is now approved, justification is required for continuing the search for other immune therapies.
2. Immune microenvironment should be discussed in more detail in the biology section. It is mentioned that PD-L1 is overexpressed in sarcomatoid subtype (line 72) - is there a relevance to this considering expression has not correlated to response (line 178). Ref for consideration: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6908501/
3. Therapeutic targets should be explained in more detail (VEGF, CTLA4, PD1, PD-L1) - what is their role in mesothelioma and what makes them good targets. This leads to the response rates of the clinical trials which are fairly low and suggests the need for predictive markers (which should also be discussed in more detail).
4. Oncolytic viruses should also be mentioned (phase III INFINITE trial (NCT03710876)) since DCT and CAR T cells are mentioned.

Author Response

We thank the reviewer for their helpful comments. Please see the attached file for changes made in the revised manuscript. 

Author Response File: Author Response.docx

Reviewer 2 Report

The authors reviewed the current evidences focusing on immunotherapy against mesothelioma including immune checkpoint inhibitor and cellular therapy. There are extensively summarizing distinct characteristics of therapy and certain clinical trials using immunotherapy against mesothelioma. This review is useful for the readers of Current Oncology since it is concise and has lucid explanation, and tables.

Comment

The potential immunotherapy is revealed in the round in this review, so please add some depictions of recent studies for improved immune checkpoint inhibitors and biomarkers efficiency as follows. These descriptions are useful for reader’s perception.

 

Enhanced efficacy of mesothelin-targeted immunotoxin LMB-100 and anti-PD-1 antibody in patients with mesothelioma and mouse tumor models. Sci Transl Med 2020 Jul 1;12(550):eaaz7252. doi:10.1126/scitranslmed.aaz7252.

Impressive clinical response to anti-PD-1 therapy in epithelioid mesotheliomawith high clonal PD-L1 expression and EML4-ALK rearrangement. Lung Cancer. 2020 Apr;142:47-50. doi: 10.1016/j.lungcan.2020.02.006. Epub 2020 Feb 14.PMID: 32088605

High-intensity statins are associated with improved clinical activity of PD-1inhibitors in malignant pleural mesothelioma and advanced non-small cell lung cancer patients. J Cancer. 2021 Feb;144:41-48. doi: 10.1016/j.ejca.2020.10.031. Epub 2020 Dec 14.PMID: 33326868

IFN-gamma upregulates membranous and soluble PD-L1 in mesotheliomacells: potential implications for the clinical response to PD-1/PD-L1 blockade. Cell Mol Immunol. 2020 Apr;17(4):410-411. doi: 10.1038/s41423-019-0245-x. Epub 2019 Jun 19.PMID: 31217525

Prognostic impact of PD-1 and PD-L1 expression in malignant pleural mesothelioma: an international multicenter study. Transl Lung Cancer Res. 2021 Apr;10(4):1594-1607. doi: 10.21037/tlcr-20-1114.PMID: 34012777 

Efficacy of nivolumab and ipilimumab in patients with malignant pleural mesothelioma is related to a subtype of effector memory cytotoxic T cells: Translational evidence from two clinical trials. BioMedicine. 2020 Dec;62:103040. doi: 10.1016/j.ebiom.2020.103040. Epub 2020 Nov 7.PMID: 33166791

The Search for an Interesting Partner to Combine with PD-L1 Blockade in Mesothelioma: Focus on TIM-3 and LAG-3. Cancers (Basel). 2021 Jan 14;13(2):282. doi: 10.3390/cancers13020282.PMID: 33466653

A Phase I Trial of Regional Mesothelin-Targeted CAR T-cell Therapy in Patients with Malignant Pleural Disease, in Combination with the Anti-PD-1 Agent Pembrolizumab. Cancer Discov. 2021 Jul 15. doi: 10.1158/2159-8290.CD-21-0407. Online ahead of print.PMID: 34266984

Author Response

We thank the reviewer for their suggested references. A selection have been incorporated into the manuscript as described in the attached document.

Author Response File: Author Response.docx