Head and Neck Squamous Cell Carcinoma Vaccine: Current Landscape and Perspectives

Round 1

Reviewer 1 Report

This manuscript described the current and perspective of vaccine therapy in HNSCC, they comprehensively gather existing evidence and summarize ongoing clinical trials focused on therapeutic vaccines for HNSCC treatment. These encouraging results and ongoing experiments instill hope for potential paradigm shifts in HNSCC therapy.

1.Consider creating a figure that succinctly illustrates the current landscape and future prospects of vaccine therapy in HNSCC. This visual representation can enhance the reader's understanding.

2.It would be valuable to discuss the advantages and disadvantages of vaccine therapy in HNSCC when compared to traditional chemotherapy and other treatment modalities. Highlighting these aspects can provide a comprehensive perspective.

3.Address the issue of resistance in vaccine therapy and delve into the possible reasons behind it. Understanding resistance mechanisms is crucial for developing more effective strategies.

4.Explore ways to improve the efficacy of vaccine therapy and provide insights into the mechanisms of action behind these vaccines. This will help readers grasp the nuances of vaccine therapy in HNSCC.

5. Incorporate a section discussing Vaccine Adjuvants in HNSCC. Detailing the role and significance of adjuvants can enrich the manuscript.

6.Consider using figures or diagrams to visually represent the different types of cancer vaccines and their schemas. Visual aids can make complex information more accessible to readers.

Overall, these suggestions can enhance the manuscript's clarity, comprehensiveness, and engagement for readers interested in vaccine therapy for HNSCC.

NONE

Author Response

Dear Reviewers,

We wanted to express sincere gratitude for taking the time to review our article. We genuinely appreciate the effort you've put into reviewing and helping us improve the content.

We carefully considered each of your comments and incorporated all of them to elevate the overall quality of the article.

Changes were made using red text and a point-by-point reply as follows.

Reviewer 1

Comment 1

“This manuscript described the current and perspective of vaccine therapy in HNSCC, they comprehensively gather existing evidence and summarize ongoing clinical trials focused on therapeutic vaccines for HNSCC treatment. These encouraging results and ongoing experiments instill hope for potential paradigm shifts in HNSCC therapy.

1.Consider creating a figure that succinctly illustrates the current landscape and future prospects of vaccine therapy in HNSCC. This visual representation can enhance the reader's understanding.”

LINE 78: We designed and inserted two figures that describe the current state of trials of virus-based HNSCC vaccines (Figure 1)

LINE 134: and non-virus-based HNSCC vaccines (Figure 2).

Comment 2

“2.It would be valuable to discuss the advantages and disadvantages of vaccine therapy in HNSCC when compared to traditional chemotherapy and other treatment modalities. Highlighting these aspects can provide a comprehensive perspective.”

We inserted the following paragraph in our discussion to describe a comparison between traditional chemotherapy and therapeutic vaccines. In our opinion it is too early to make a comparison:

LINES 657-666: “It is premature to make comparisons between standard chemotherapy and vaccine therapy since no phase III trial seems to be completed now of the writing of this manuscript. For the same reason, vaccine therapy for HNSCC can’t be considered nowadays a first-line treatment. Promising results came from the combination of therapies, for example the intratumoral administration of ONYX-015 and 5-fluorouracile and cisplatin demonstrated better results than traditional chemotherapy. [37] Those promising results were not confirmed in a Phase III study that was started in 2001 with no results published after more than 20 years. The COVID-19 pandemic increased difficulties in conducting clinical trials making follow-up and experimental protocol application more challenging. It sometimes hesitated in trials suspensions (NCT03418480). “

Comment 3

“3.Address the issue of resistance in vaccine therapy and delve into the possible reasons behind it. Understanding resistance mechanisms is crucial for developing more effective strategies.”

We inserted the following paragraph in our discussion:

LINES 6207-627: The main goal of vaccine therapy is to induce an immune response against cancer cells. Researchers are still focusing their research on finding vaccines able to activate immunity against tumor-specific antigens. The activation of immune response does not mean therapeutic efficacy. Intuitively, the immune escape mechanisms adopted by cancer cells before vaccine administration could be responsible for tumor cells' survival after immunity activation against them. For this reason, several researchers are testing anticancer therapeutic vaccines in combination with immune checkpoint escape inhibitors such as Pembrolizumab. [24], [25], [42]

Comment 4

“4.Explore ways to improve the efficacy of vaccine therapy and provide insights into the mechanisms of action behind these vaccines. This will help readers grasp the nuances of vaccine therapy in HNSCC.”

We believe that the easiest strategy to improve efficacy of HNSCC therapeutic vaccines is to combine medications. We have treated this subject in our discussion with the following paragraph:

LINES 597-619: In our opinion, this observation pushes the future frontiers of research towards the study of combinations of drugs that prove to be individually effective to create a therapy that is as strong in generating immunogenicity and as complete in the antigenic pool. The combination approach also makes sense with the increased action of immunotherapy against immune checkpoints. The action of drugs such as pembrolizumab is limited by the poor immune response they generate, despite their action against the tumor's immune escape mechanisms. Enhancement of cytotoxic lymphocyte activity by the combination of immune checkpoint inhibitors and therapeutic vaccines is promising, as suggested by the combination of PDS0101 and Pembrolizumab which has demonstrated such efficacy as to have received Fast Track designation from the FDA in the treatment of HNSCC HPV16+. [24], [25]  Furthermore, we should consider that having an effective drug in monotherapy does not mean that it is more effective than those already on the market. For example, T-VEC was tested in combination with pembrolizumab and the data itself was positive, but the authors who studied the effectiveness of the drug had the foresight to compare the association with the historical data of pembrolizumab alone and showed that there were no significant differences. [42] Consequently, there appears to be no apparent benefit to adding T-VEC to pembrolizumab therapy, and the therapeutic efficacy measured in the trial could be that of pembrolizumab alone. Starting from this data, we can make two important considerations: 1) The demonstration of in vivo efficacy of an immune response against the tumor does not equate to a response in therapeutic terms, and it does not mean that the drug is effective in curing the disease. 2) No less critical is then to compare these drugs with the current therapeutic gold standard and understand whether they are comparable to the therapies already in use.

Comment 5

“5. Incorporate a section discussing Vaccine Adjuvants in HNSCC. Detailing the role and significance of adjuvants can enrich the manuscript.”

LINES 628-632: A vaccine to be effective needs to induce an immune response. Adjuvant molecules are extensively used to increase immune activation. Several examples can be done such as Candida Skin Test reagent in PepCan Vaccine [31], [32], Montanide ISA 51 and GM-CSF in LY6K [44], [47], [58], AlloStimTM in AlloVax. Their impact on T cell activation may be helpful in increase vaccine efficacy.

Comment 6

“6.Consider using figures or diagrams to visually represent the different types of cancer vaccines and their schemas. Visual aids can make complex information more accessible to readers.”

“Overall, these suggestions can enhance the manuscript's clarity, comprehensiveness, and engagement for readers interested in vaccine therapy for HNSCC.”

LINE 78: We inserted a new Figure 1 to visually represent different vaccine platforms;

 LINE 128: and kept Table 1 for their pros and cons.

Author Response File: Author Response.pdf

Reviewer 2 Report

This review article named” Head and neck squamous cell carcinoma vaccine: current landscape and perspective” focus on therapeutic vaccine for head and neck squamous cell carcinoma, and summarized current evidence and ongoing studies in this field. The article is well written. There only one suggestion for it:

1.     The majority of this article from subtitle “3.5 Virus infection-based cancer vaccine” to subtitle “3.12 mRNA vaccine” integrate most current development and evidence of the therapeutic vaccine for head and neck squamous cell carcinoma. With the large content, a summarized table (s) for those vaccine will helpful for reader and reviewer to understanding the key points of the article more easily.

The English in this article is fluent.  Little mistake was noted as following:  

1.     Pleas correct the following abbreviation: (high light in bold)

Line 55: ... for the development of HSCC are smoking...

Line 277: ... to patients affected by HSCC who achieved remission...

Line 365: ... overexpression in typical of HOV-HNSCC...

Line 437: ...observed in HOV+sub-population....

Line 500: .... observed that HSCC can be divided into three group...

2.     Please showed the complete word of following: : (high light in bold)

Line 372: ...locally advanced, or recurrent OSCC.

Line 509: ...improvement in chemo and ....

Author Response

Reviewer 2

Comment 1

“This review article named” Head and neck squamous cell carcinoma vaccine: current landscape and perspective” focus on therapeutic vaccine for head and neck squamous cell carcinoma, and summarized current evidence and ongoing studies in this field. The article is well written. There only one suggestion for it:

1. The majority of this article from subtitle “3.5 Virus infection-based cancer vaccine” to subtitle “3.12 mRNA vaccine” integrate most current development and evidence of the therapeutic vaccine for head and neck squamous cell carcinoma. With the large content, a summarized table (s) for those vaccine will helpful for reader and reviewer to understanding the key points of the article more easily.”

Thank you for your suggestions, we inserted two figures (Figures 2 and 3) with a table reassuming the current state of HNSCC therapeutic vaccine experimentation on humans.

Comment 2

“The English in this article is fluent.  Little mistake was noted as following:  

1. Pleas correct the following abbreviation: (high light in bold)

Line 55: ... for the development of HSCC are smoking...

Line 277: ... to patients affected by HSCC who achieved remission...

Line 365: ... overexpression in typical of HOV-HNSCC...

Line 437: ...observed in HOV+sub-population....

Line 500: .... observed that HSCC can be divided into three group...

2. Please showed the complete word of following: (high light in bold)

Line 372: ...locally advanced, or recurrent OSCC.

Line 509: ...improvement in chemo and ....”

We corrected all the typos suggested. Thank you.

Author Response File: Author Response.pdf

Reviewer 3 Report

In this MS, the authors are delving into the advancements of non-surgical therapies for HNSCC, particularly anti-cancer vaccines; they discuss the main risk factors for the development of HNSCC, such as smoking, alcohol, and HPV infection. The manuscript also mentions the use of vaccines for both prevention and therapeutic purposes; therapeutic vaccines for HNSCC are still under investigation and aim to induce immunogenicity against HNSCC cells using various mechanisms.

Major Comments

The MS is difficult to follow, therefore a schematic diagram with all the steps of the study would be welcomed for readers.

The introduction doesn't offer a broad enough context for the problem, it mentions existing treatments, but  it doesn't adequately address why a new treatment like vaccines is needed. The claim that immunotherapy has significantly improved HNSCC treatment is not backed up with sufficient data or references.

The Results section discusses various aspects such as risk factors and mechanisms but doesn't go into sufficient detail; the section lacks a comparative analysis of the efficacy of different vaccines or therapeutic approaches.

There are several typographical and formatting errors, which reduce the readability and overall quality of the manuscript.

The manuscript does not discuss the limitations of the current studies or the review itself, which is a critical component of any scientific paper.  The manuscript could improve by including more up-to-date references, as well as by providing a more comprehensive list of citations to back its claims.

Consider revising accordingly!

minor English language corrections

Author Response

Reviewer 3

Comment 1

“In this MS, the authors are delving into the advancements of non-surgical therapies for HNSCC, particularly anti-cancer vaccines; they discuss the main risk factors for the development of HNSCC, such as smoking, alcohol, and HPV infection. The manuscript also mentions the use of vaccines for both prevention and therapeutic purposes; therapeutic vaccines for HNSCC are still under investigation and aim to induce immunogenicity against HNSCC cells using various mechanisms.

Major Comments

The MS is difficult to follow, therefore a schematic diagram with all the steps of the study would be welcomed for readers.”

LINE 78: We inserted Figure 1 as a schematic diagram with our review process.

Comment 2

“The introduction doesn't offer a broad enough context for the problem, it mentions existing treatments, but it doesn't adequately address why a new treatment like vaccines is needed. The claim that immunotherapy has significantly improved HNSCC treatment is not backed up with sufficient data or references.” 

We improved the rationale of the article making the scope of our review clearer inserting the following paragraph in our introduction:

LINES 34-47: “In situations where surgical intervention is not viable, chemotherapy and radiation therapy are used. However, results are not optimal, particularly for recurrent or metastatic malignancies. The introduction of immunotherapy has improved those outcomes. Currently approved drugs for the treatment of HNSCC are pembrolizumab (KEYTRUDA, Merck and Co., Rahway, New Jersey, USA) and nivolumab (OPDIVO, Bristol Myers Squibb, New York, New York, USA), which have improved traditional chemotherapy results.  Checkmate-141, Keynote-040 and Keynote-048 trials are milestones in HNSCC treatment and set a new standard of results for non-surgical therapy. However, they still are not satisfactory with long-term efficacy in 20 to 30% of patients only. The discussion of resistance mechanisms to immune checkpoint inhibitors is beyond the scope of this manuscript, but we can state that solutions need to be found in order to reach a better performance from therapies. [2]–[4]

In this scenario, the advancement of novel non-surgical therapies appears to be imperative…”

Comment 3

“The Results section discusses various aspects such as risk factors and mechanisms but doesn't go into sufficient detail; the section lacks a comparative analysis of the efficacy of different vaccines or therapeutic approaches.”

We agree with your observation but now it is not possible to compare HNSCC vaccines since most of the trials are phase I or II. We better discussed some observation such as the possibility of combining more than one vaccine or association with immune checkpoint inhibitors or adjuvant molecules in the discussion section.

LINES 597-619: “In our opinion, this observation pushes the future frontiers of research towards the study of combinations of drugs that prove to be individually effective to create a therapy that is as strong in generating immunogenicity and as complete in the antigenic pool. The combination approach also makes sense with the increased action of immunotherapy against immune checkpoints. The action of drugs such as pembrolizumab is limited by the poor immune response they generate, despite their action against the tumor's immune escape mechanisms. Enhancement of cytotoxic lymphocyte activity by the combination of immune checkpoint inhibitors and therapeutic vaccines is promising, as suggested by the combination of PDS0101 and Pembrolizumab which has demonstrated such efficacy as to have received Fast Track designation from the FDA in the treatment of HNSCC HPV16+. [24], [25]  Furthermore, we should consider that having an effective drug in monotherapy does not mean that it is more effective than those already on the market. For example, T-VEC was tested in combination with pembrolizumab and the data itself was positive, but the authors who studied the effectiveness of the drug had the foresight to compare the association with the historical data of pembrolizumab alone and showed that there were no significant differences. [42] Consequently, there appears to be no apparent benefit to adding T-VEC to pembrolizumab therapy, and the therapeutic efficacy measured in the trial could be that of pembrolizumab alone. Starting from this data, we can make two important considerations: 1) The demonstration of in vivo efficacy of an immune response against the tumor does not equate to a response in therapeutic terms, and it does not mean that the drug is effective in curing the disease. 2) No less critical is then to compare these drugs with the current therapeutic gold standard and understand whether they are comparable to the therapies already in use.

[…]

LINES 626-630: A vaccine to be effective needs to induce an immune response. Adjuvant molecules are extensively used to increase immune activation. Several examples can be done such as Candida Skin Test reagent in PepCan Vaccine [31], [32], Montanide ISA 51 and GM-CSF in LY6K [44], [47], [58], AlloStimTM in AlloVax. Their impact on T cell activation may be helpful in increasing vaccine efficacy.”

Comment 4

There are several typographical and formatting errors, which reduce the readability and overall quality of the manuscript.

The manuscript does not discuss the limitations of the current studies or the review itself, which is a critical component of any scientific paper.  The manuscript could improve by including more up-to-date references, as well as by providing a more comprehensive list of citations to back its claims.

Consider revising accordingly!

-We corrected the typo and formatting errors we noticed and the ones according to other reviewers' observations.

-We inserted a deeper discussion about the limitations of the current landscape of trials about HNSCC therapeutic vaccines. We also introduced several new discussion sections, one of which is the conclusive one:

LINES 657-668: “It is premature to make comparisons between standard chemotherapy and vaccine therapy since no phase III trial seems to be completed now of the writing of this manuscript. For the same reason, vaccine therapy for HNSCC can’t be considered nowadays a first-line treatment. Promising results came from the combination of therapies, for example, the intratumoral administration of ONYX-015 and 5-fluorouracil and cisplatin demonstrated better results than traditional chemotherapy. [37] Those promising results were not confirmed in a Phase III study that was started in 2001 with no results published after more than 20 years. COVID-19 pandemic increased difficulties in conducting clinical trials making follow-up and experimental protocol application more challenging. It sometimes hesitated in trial suspensions (NCT03418480).

The prospects must concern not only the conventional efficacy of parenteral administrations but also the study of new administration routes. The NCT04180215 trial is studying, for example, the efficacy of intratumoral administration associated with systemic administration.”

Thank you again for your comments.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Thanks for addressing all my concerns, the manuscript looks good now and I have no other questions.

None

Author Response

We appreciate for Editors/Reviewers’ warm work and really hope that our modification of this paper can get your precious recognition, which is of great significance to us.

Reviewer 3 Report

I endorse publication in its current form.

Author Response

We appreciate for Editors/Reviewers’ warm work and really hope that our modification of this paper can get your precious recognition, which is of great significance to us.