Prospects for Treatment of Lung Cancer Using Activated Lymphocytes Combined with Other Anti-Cancer Modalities

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The article by Ganina et al. on “Prospects for Combined Treatment of Non-Small Cell Lung Cancer Using Autologous Activated Lymphocytes” is an interesting literature review, which, however, requires several significant changes to increase its readability and reception, as well as scientific soundness.

- lines 60-77 require citation;

- line 86 the abbreviation NSCLC, which has already been introduced, does not require expansion in this line;

- line 88 expand the abbreviation PD-1/PD-L1;

- line 119 expand the abbreviation DCs;

- the introduction is quite extensive, but I lacked a clearly defined purpose of this literature review;

- line 160 expand the abbreviation: MHC;

- line 201 TNFa should be α;

- cytotoxic T lymphocytes (CTL) is explained in line 334 instead of 199, where it appears first; similarly with NK cells etc. I kindly ask you to review the manuscript from this perspective;

- just as to review the manuscript from the perspective of expanding the abbreviations used throughout the work, currently it is chaos;

- the main text of the manuscript is interesting, but difficult to read, the authors should consider introducing figures into the manuscript, which will allow for easier reading of some of the information, which is bulleted almost every paragraph, if not using Arabic numerals, then dots, dashes, then (i), (ii) etc.

- Some of the information could also be presented in the form of a table, instead of solid continuous text, which would increase the readability of the work.

- my main question to the authors, however, concerns the selection of articles for this review, what were the inclusion and exclusion criteria, what filters they used, what was their strategy, because for a literature review on lung cancer, about which there are thousands of pieces of information in the literature, the selection of 75 literature items is definitely surprising and requires explanation. Moreover, 36 literature items (i.e. approximately 48%) of the articles selected by the authors are older than the last 10 articles.

Comments on the Quality of English Language

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Author Response

REVIEWER #1

The article by Ganina et al. on “Prospects for Combined Treatment of Non-Small Cell Lung Cancer Using Autologous Activated Lymphocytes” is an interesting literature review, which, however, requires several significant changes to increase its readability and reception, as well as scientific soundness.

- lines 60-77 require citation;

- line 86 the abbreviation NSCLC, which has already been introduced, does not require expansion in this line;

- line 88 expand the abbreviation PD-1/PD-L1;

- line 119 expand the abbreviation DCs;

- line 160 expand the abbreviation: MHC;

- line 201 TNFa should be α;

Authors’ response: All the suggested correction were done.

 

- the introduction is quite extensive, but I lacked a clearly defined purpose of this literature review;

Authors’ response: We thank for this critical comment. We extensively modified the introductory section and split it into two separate sections – the first briefly introduces to the problem of diagnostics and treatment of lung cancer while the second is focused advantages of immunotherapy combined with other therapies.

 

- cytotoxic T lymphocytes (CTL) is explained in line 334 instead of 199, where it appears first; similarly with NK cells etc. I kindly ask you to review the manuscript from this perspective;

Authors’ response: We thank for this critical comment. In R1 version of our review, the text was substantially modified and rearranged to make it much clearer and more comprehensive.

 

- just as to review the manuscript from the perspective of expanding the abbreviations used throughout the work, currently it is chaos;

Authors’ response: We carefully revised the text for minimizing extensive use of abbreviations, also we have added the Abbreviation section to the manuscript.

 

- the main text of the manuscript is interesting, but difficult to read, the authors should consider introducing figures into the manuscript, which will allow for easier reading of some of the information, which is bulleted almost every paragraph, if not using Arabic numerals, then dots, dashes, then (i), (ii) etc.

Authors’ response: We modified the text to make reading easier. Also, we carefully revised the text for uniformity in basic terms, like T cell (not T-cell), Tregs (not T-regs), etc. In addition, we removed using excessive abbreviations. Although we did not introduce any figure, we have added a table (please see next reply).

 

- Some of the information could also be presented in the form of a table, instead of solid continuous text, which would increase the readability of the work.

Authors’ response: We thank for this suggestion. A table was added for clearer representation of main activation factors and active anti-tumor mechanisms of various immune system cells used in the activated lymphocytes therapies.

 

- my main question to the authors, however, concerns the selection of articles for this review, what were the inclusion and exclusion criteria, what filters they used, what was their strategy, because for a literature review on lung cancer, about which there are thousands of pieces of information in the literature, the selection of 75 literature items is definitely surprising and requires explanation. Moreover, 36 literature items (i.e. approximately 48%) of the articles selected by the authors are older than the last 10 articles.

Authors’ response: We refined our selection for literature sources and added many new items (almost doubling the used sources), mostly recent papers, in particular in those places where we refer to new discussions in the review. We used most informative and appropriate papers, i.e. directly related to the immunotherapy in lung cancer, and therefore discarded those (often very interesting yet) papers where other cancers have been investigated. Also, we have updated our reference list with more recent papers.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The review titled “Prospects for Combined Treatment of Non-Small Cell Lung Cancer Using Autologous Activated Lymphocytes” discussed activating lymphocytes in lung cancer therapy. This review is informative, but here are some concerns that need to be addressed:

Major concerns:

1.      In line 50, where does the “85%” conclusion come from? There seems to be a lack of references here. The same question is for “25-30%” in line 53.

2.      In line 217, what group of lymphocytes are CD56+ cells here?

3.      In line 358, what methods did these studies use in “T-cell activation”, and how to get the conclusion that “increased NK cell activity and reduced numbers of regulatory T-cells that inhibit 360 tumor immunity” here?

4.      In line 109-124 in Introduction section, the authors seem to discuss the combined use of immunotherapy and radiotherapy, However, the main body of the article only discusses the application of lymphocyte activation in tumors. These two parts seem inconsistent. The authors should discuss them together if they have contained both immunotherapy and radiotherapy in Introduction section and title.

5.      The authors' title only mentioned “combined” and “immunotherapy” separately but did not mention radiotherapy, so how to reflect “Combined Treatment” in this title?

Minor concerns:

1.      In line 149, it should be “CD4 positive cells” or “positive CD4+ cells” but not “positive CD4 cells”.

2.      In line155, there is an extra period after “mutations in NSCLC tumors..”.

 

Author Response

REVIEWER #2

The review titled “Prospects for Combined Treatment of Non-Small Cell Lung Cancer Using Autologous Activated Lymphocytes” discussed activating lymphocytes in lung cancer therapy. This review is informative, but here are some concerns that need to be addressed:

Major concerns:

1. In line 50, where does the “85%” conclusion come from? There seems to be a lack of references here. The same question is for “25-30%” in line 53.

Authors’ response: Appropriate references were added to this text. As well, we added many new reference items in those places when it should be referred to a source.

 

2. In line 217, what group of lymphocytes are CD56+ cells here?

Authors’ response: This group with CD56+ is Natural Killer cells.

 

3. In line 358, what methods did these studies use in “T-cell activation”, and how to get the conclusion that “increased NK cell activity and reduced numbers of regulatory T-cells that inhibit tumor immunity” here?

Authors’ response: We substantially modified this text to keep the initial meaning that in-vitro preparation of T cells with cytokine cocktail(s) to be then activated within tumor microenvironment after injection to the body is used now in many studies because of the well-known role of CD8+ cells in the anti-tumor activity.

 

4. In line 109-124 in Introduction section, the authors seem to discuss the combined use of immunotherapy and radiotherapy, However, the main body of the article only discusses the application of lymphocyte activation in tumors. These two parts seem inconsistent. The authors should discuss them together if they have contained both immunotherapy and radiotherapy in Introduction section and title.

Authors’ response: We thank for this very important critical comment. Unfortunately, our initial version of the review had some important inconsistencies and confusion. In fact, we aimed to discuss combination of immunotherapy with other modalities (not only radiation therapy). In R1 version of our review, we have modified and improved both title (to focus on both NSCLC and SCLC lung cancer and to highlight combining of activated lymphocytes therapy with other various therapies) and main text (to extend and improve our review).

 

5. The authors' title only mentioned “combined” and “immunotherapy” separately but did not mention radiotherapy, so how to reflect “Combined Treatment” in this title?

Authors’ response: The purpose of the paper was to describe outcomes of using immunotherapy with activated T cells combined with other therapies like radiotherapy or chemotherapy. The title of the paper was modified accordingly to the idea. In addition, we expanded the review covering also small cell lung cancer (in contrast to the previous version where we mentioned non-small cell lung cancer only in the title while referred to studies on SCLC in the main text).

 

Minor concerns:

1. In line 149, it should be “CD4 positive cells” or “positive CD4+ cells” but not “positive CD4 cells”.
2. In line155, there is an extra period after “mutations in NSCLC tumors..”.

Authors’ response: All the suggested correction were done.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Thank you very much for making all the required corrections to the text. In its current version, the manuscript is much more readable and easier to read, while presenting many interesting scientific details. The authors responded to all my comments and suggestions.

Reviewer 2 Report

Comments and Suggestions for Authors

This manuscript has been sufficiently improved to warrant publication in ARM.