Moving towards the Future of Radio-Immunotherapy: Could We “Tailor” the Abscopal Effect on Head and Neck Cancer Patients?

Round 1

Reviewer 1 Report

Abscopal tumor regression remains a rare phenomenon. However, in the last years calibrated radiotherapy administered in combination with stimulators of the immune system to induce systemic abscopal response gave interesting results, opening interesting and fertile fields for investigation in cancer therapy.

The work presented by De Felice et al., summarizes pathogenetic and clinical implication of combined therapies for cancer treatment, focusing on Head and Neck tumors.

The review is scientifically well-conceived and well-organized.

 

While biological effects of radiotherapy on cancer and immune cells are well described, I will suggest dedicating more space in the introduction to better define and describe abscopal general aspects, otherwise cited only in the abstract.    

Might also be useful for the reader to see a table citing the “state of art” of clinical trials (some of them described in text) combining RT with immunomodulators.

In summary, I believe that this manuscript can be accepted with minor revision.

Author Response

We sincerely thank Reviewer 1 for his constructive comments about our work. Following first consideration, we have tried to modify the introduction in such a way as to give greater emphasis to the description of abscopal effect. Therefore we think we could give a broader view about what will be later discussed.

We greatly appreciated the second suggestion about the lack of a summary table citing the “state of art” of clinical trials about radio-immunotherapy combinations, so we thought it appropriate to add it (Table 2). In this way it becomes clearer how it is a "hot" topic.

In conclusion we think that his comments have allowed us to improve our work and we would like to thank the reviewer again for taking the time to critically read our manuscript.

Reviewer 2 Report

In the manuscript “Back to the future of radio-immunotherapy: could we “tailor” the abscopal effect on head and neck cancer patients”, authors have written abstract in well convincing manner. A good attempt is made by writing introduction and discussion with relevant background. However following points need to be addressed.

1. Flow of review article is not proper as per title, it is confusing for reader. It should be written as per title for gaining interest of reader.
2. Many references (Doi: 10.1016/j.intimp.2020.106663. Epub 2020 Jun 7. PMID: 32521494, Doi: 10.1016/S1470-2045(15)00054-6) are not referred which describe the abscopal effect and radioimmunotherapy.
3. References numbering is duplicate in reference section.
4. Many abbreviations are not abbreviated.
5. Spelling and grammar need to be checked in entire manuscript.

Author Response

First of all, we would like to sincerely thank Reviewer 2 for constructively reading our work, providing interesting suggestions, which we will try to individually analyze.

• "Flow of review article is not proper as per title, it is confusing for reader. It should be written as per title for gaining interest of reader". The goal of our review is to try tailoring abscopal effect (AbE) in an extremely heterogeneous and prognostically unfavorable population, such as HNSCC patients.  Nowadays long-term effective weapons are lacking, especially in metastatic disease, therefore there is no doubt that achieving  abscopal effect is very ambitious, although difficult to reproduce. And how it could be achieved? First of all we should begin from the tumor-microenvironment (TME), deus ex machina for the regulation of the local and abscopal immune response to the tumor. RT may potentially shift TME from "cold" or immunosuppressive to "hot" or immunostimulatory, and the synergism with Immune-checkpoint inhibitors (ICIs) could activate and maintain the response for a long time. The greater the stimulation, the more likely it may be local and remote shrinkage. Therefore it is initially necessary to identify  the most radiosensitive and potentially immune-stimulable primary tumor and metastatic sites too, with particular attention to draining nodal stations; integrating low-dose RT with high-dose hypofractionated RT  for two different targets might be a winning choice in obtaining abscopal effect, however the dose, the fractionation and the right volume of irradiation might be tailored for each patient. So we are moving towards the future of radio-immunotherapy, through which we could more simply reach AbE in HNSCC. We are confident that the title of the review is in accordance with what is written.
• "Many references (Doi: 10.1016/j.intimp.2020.106663. Epub 2020 Jun 7. PMID: 32521494, Doi: 10.1016/S1470-2045(15)00054-6) are not referred which describe the abscopal effect and radioimmunotherapy". We really appreciated the two proposed references: the first one is a rewiew explaining the cellular and molecular mechanisms behind abscopal effect by radiotherapy and evaluating the molecular targets which induce potent anti-tumor immunity, therefore mentioned and integrated in our work ( reference n.8); the second one is a proof-of-principle trial that explores the pro-immunogenic effects of radiotherapy with granulocyte-macrophage colony-stimulating factor, as a prototype of immunotherapy, resulting in abscopal responses among patients with metastatic cancer, likewise cited in our review (reference n.62).  We thank Reviewer 2 for his interesting considerations that allowed us to complete our work.
• "References numbering is duplicate in reference section". We apologise for the duplications. We have taken steps to eliminate them.
• "Many abbreviations are not abbreviated". Thanks for the consideration, we think we have made the necessary and requested changes, as marked up by "track changes" in our manuscript.
• "Spelling and grammar need to be checked in entire manuscript". Our work previously shew syntax and punctuation mistakes, therefore we believe we have done now a good job of revision. 

Reviewer 3 Report

Although the authors address an important issue in the field, it is difficult to interpret their intention in the manuscript because of poor writing.  The style is not organized and there are numerous typos and gramatical errors.  The authors need to rewrite the entire manuscript.

Author Response

We are very sorry and also a little surprised by this very negative comment. In our view, the work has been conceived in an organic and structural way, concretely addressing the preclinical principles underlying the abscopal effect, the important role played by the combination of radiotherapy and immunotherapy and how clinical management of HNSCC could be influenced. The prognosis in these patients is very severe and the attempt to induce abscopal effect is a potentially viable therapeutic option. Surely the style and grammar needed to be improved; we hope that the extensive review carried out may partly change the mind of the Reviewer 3.

Round 2

Reviewer 2 Report

Authors have addressed all comments satisfactory except first one means flow of review article is still not as per title, authors should discuss abscopal effects immediately after introduction to attract reader.

Author Response

We are happy to have satisfactorily  responded to all the comments proposed. We have a bit amended the second paragraph and its title, in order to give greater prominence to the discussion of the abscopal effect, before proceeding to the analysis of the underlying immunological mechanisms. We thank Reviewer 2 for the great suggestions and for guiding us through the review process.

Reviewer 3 Report

The revised version is much improved in organization and readable.  

Minor issues

1) It is better to include the information about patient populations in Table 2.

2) Ref. 44 has two manuscripts.  Needs to be corrected.

Author Response

We would like to sincerely thank Reviewer 3 for his scientific sensitivity and transparency. We are glad that he appreciated the changes we have made to our work and the efforts produced. Surely the revised version is more complete and organized, overall the quality in writing and the form has improved. By the way, we  removed the duplicated reference n.44 and completed the table with the study population of each trial in such a way as to give a more complete view of the current state of the art. Thanks again to the Reviewer 3 for his suggestions and we apologize for the mistakes made, trusting that we have completed our work.