Radiotherapy and Immunotherapy—A Future Partnership towards a New Standard

Round 1

Reviewer 1 Report

The authors summarize current developments in the field of radio-immunotherapy. It is well written and gives a good overview about the topic.

Author Response

Dear Reviewer,

We thank you for the time and effort given to evaluate the manuscript. At the recommendation of the other reviewers, We completed the manuscript, all additions to the document being marked in yellow and new references added with in red.

Kind Regards,

Camil Mirestean

Reviewer 2 Report

I do not think giving the references at the end of each paragraph is not correct. Please give each reference just after the related sentence.

The manuscript can be strengthened with more specific KEYNOTE and CHECKMATE trials of different tumor regions.

 

Introduction

1.      ‘ab-scopal’ is not the correct use. Please use ‘abscopal’ in the text.

2.      ‘Metastatic malignant melanoma, a disease with a severe prognosis...’ Please switch ‘severe’ to ‘dismal’.

3.      ‘Also, the metastatic stage malignant melanoma is the tumor associated with most cases of abscopal effect, a systemic response being induced by an association of immunotherapy with hypofractionated palliative radiotherapy’. I could not understand this sentence. I think there is a typo somewhere. Please go through that sentence again. Also, ‘hypofractionated palliative radiotherapy’; please omit ‘palliative’.

 

Tumor immune phenotype - a classification with therapeutic implications

4.      ‘Both of these categories show a reduced mutational load and a lower expressions of PL-L1.’ Please revise ‘expressions’ as ‘expression’.

5.       ‘Blocking of T-lymphocyte action, …’; please revise as either ‘Blocking T-lymphocyte action,’ or ‘The blockage of T-lymphocyte action,’

 

Radiotherapy and immunotherapy: ab-scopal and “in situ” vaccination effect

6.      The impact of radiotherapy (RT) fraction dose and irradiated field size should be added to this paragraph. Otherwise, it can mislead the reader that every kind and dose of RT could induce immune stimulation. Also, sparing the LNs form the irradiated field is crucial. Please add these data with related references, e.g. preclinical trials by Morisada et al., Buchwald et al.

 

Table 2

7.      What is RIL? Please write it in the open form under the table. Also, please add all the abbreviations in the long form.

8.      The column ‘Radiation dose/regimen’ is not correlated with what is under. Please rearrange the table as so.

 

Conclusions

9.  No need to write the open form TME again.

Author Response

Dear Reviewer,

We thank you for the time and effort given to evaluate the manuscript. We went through the recommendations and proceeded with all the proposed minor changes and introduced preclinical data recommended in the two articles and references to the KEYNOTE AND CHECKMATE trials. Also, at the recommendation of another reviewer, We completed the manuscript, all changes being marked in yellow and new references added with red.

 

Kind Regards,

Camil Mirestean

Reviewer 3 Report

- Abstract is confusing and writing can be improved. Is also too general not precise enough. 

-  References are missing in the introduction paragraph. More recent and higher impact references will be appreciated. 

- Each sentence should be validated by the corresponding reference. The paragraphs are long and no reference is attributed until the end. This should be changed in the whole manuscript. 

- The last part of the second point "Tumor immune phenotype" seems unfinished. Important information is missing regarding anti- CTLA-4 mechanism of action and Treg cells for example. The same for anti-PD1/PDL1 mechanistic. 

- In the 3rd point "radiotherapy and immunotherapy" important information about the induction of immunogenic cell death (ICD) by radiotherapy is missing. This should be compare to the ICD induced by chemotherapy and the a discussion about the differences could improve the relevance. 

- When the authors mentioned the reports about the association of the immunotherapy and radiotherapy other relevant examples are missing. If this is in part the aim of the text, this have to be extended. 

- In the 4th point " radiotherapy and immunotherapy" is important to describe the mechanisms by which the immunotherapy and the radiotherapy can have synergistic effects. 

- In the conclusion more detail information about the TME complexity is expected as well as more detail information about the influence of the combinatory therapy on the effector cells, that are not mentioned here either. 

Author Response

Dear Reviewer,

We thank you for the time and effort given to evaluate the manuscript. At the recommendation of the other reviewers, I completed the manuscript, all additions to the document being marked in yellow and new references added with in red.

Kind Regards,

Camil Mirestean

Round 2

Reviewer 2 Report

Thank you for the revision. However, some points were missed and were not revised. I would kindly ask you to read the following comments and revise them as so.

 

Introduction

1.      Also, the metastatic stage malignant melanoma is the tumor associated with most cases of abscopal effect, a systemic response being induced by an association of immunotherapy with hypofractionated palliative radiotherapy’. I could not understand this sentence. I think there is a typo somewhere. Please go through that sentence again. Also, ‘hypofractionated palliative radiotherapy’; please omit ‘palliative’.

 

Tumor immune phenotype - a classification with therapeutic implications

2.      ‘Both of these categories show a reduced mutational load and a lower expressions of PL-L1.’ Please revise ‘expressions’ as ‘expression’.

3.      ‘Blocking of T-lymphocyte action, …’; please revise as either ‘Blocking T-lymphocyte action,’ or ‘The blockage of T-lymphocyte action,’

4.       ‘Due to the competi-tive competition for these ligands…’; please revise as ‘Due to the competition for these ligands…’ Also, at the end of this sentence please revise ‘in-hibition’ as ‘inhibition’.

5.       Thank you for adding references 25 and 26 and the related paragraphs. But again, please do not give the references at the end of the paragraph but right after the related sentence.

 

Table 2

6.      What is RIL? Please write it in the open form under the table. Also, please add all the abbreviations in the long form.

7.      The column ‘Radiation dose/regimen’ is not correlated with what is under. Please rearrange the table as so.

8.      Please erase the brackets following ‘RIL’ under the column ‘toxicity reported’.

Author Response

Dear Reviewer,
Thank you for your patience and time given to evaluate the manuscript. At the suggestion of another reviewer, we made minor corrections. The phrase related to melanoma and ab-scopal was rewritten "Ab-scopal effect related metastatic malignant melanoma was reported early and frequently in the literature, a systemic response being induced by an association of immunotherapy with hypofractionated palliative radiotherapy'." all minor corrections requested they were marked in the manuscript with yellow and where they were made over the previous correction, we marked them with light brown. The two introduced references were discussed and summarized in detail so that the majority of the paragraph refers to this topic. Where there is also a general discussion mentioned references. RIL was mentioned without abbreviation in the first insert (in the text above the table), the previously unexplained abbreviations in the table were also explained, we tried to correct the alignment and mentioned in parentheses the reference for each correlation. We hope you will appreciate this version of the manuscript.

Kind regards,

Camil Mirestean 

Reviewer 3 Report

Many thanks for having adresses the comments and suggestions I mentioned. I think that the reading of the paper improved significantly and the information gained in scientific soundness. 

Author Response

Dear Reviewer,
Thank you for your patience and time given to evaluate the manuscript. At the suggestion of another reviewer, we made minor corrections. The phrase related to melanoma and ab-scopal was rewritten "Ab-scopal effect related metastatic malignant melanoma was reported early and frequently in the literature, a systemic response being induced by an association of immunotherapy with hypofractionated palliative radiotherapy'." all minor corrections requested they were marked in the manuscript with yellow and where they were made over the previous correction, we marked them with light brown. The two introduced references were discussed and summarized in detail so that the majority of the paragraph refers to this topic. Where there is also a general discussion mentioned references. RIL was mentioned without abbreviation in the first insert (in the text above the table), the previously unexplained abbreviations in the table were also explained, we tried to correct the alignment and mentioned in parentheses the reference for each correlation. We hope you will appreciate this version of the manuscript.

Kind Regards,

Camil Mirestean