Advances in Immunotherapy for Hepatocellular Carcinoma (HCC)

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

       In this research, the authors reviewed the “Advances in Immunotherapy for Hepatocellular Carcinoma”. In my opinion, the current stage of this paper could meet the requirements of Current Oncology after major revisions.

My comments are as details:

1.      What’s the recent development of PD-1 or PD-L1 small molecular inhibitor in hepatocellular carcinoma and some other solid tumors?

2.      The conclusion part was too plain. An in-depth outlook or conclusion should be added.

3.      Some minor mistakes exist in the paper. The authors should carefully check it, such as xix, xx??

4.      In my opinion, more figures or tables that summarize the pre-clinical researched immunotherapy strategies should be added.

5.      In line 43-45, the recent developments of small molecular clinical or pre-clinical inhibitors used to target PD-L1, PD-1, CTLA-4, and et al. should be clearly discussed in this review. Some related research was listed as below: 10.1002/adma.202206121.

6.      Too many keywords were listed.

7.      The abbreviations should be more clearly listed.

Author Response

Dear Reviewer,

I wanted to express my gratitude for your review of our manuscript, "Advances in Immunotherapy for Hepatocellular Carcinoma." Your assessment that our paper, with major revisions, could potentially meet the requirements of Current Oncology is greatly appreciated. Your feedback has been instrumental in our efforts to enhance the quality of our work.

Your expertise in this field is invaluable, and we're committed to addressing your comments and suggestions to improve our research. Your contributions to the peer review process are commendable and crucial to advancing oncology research.

Thank you once again for your time and thoughtful review. Please see responses to your comments and revised manuscript as attached.

Warm regards,

Fuat Bicer

----------------

***Reviewer 1:   In this research, the authors reviewed the “Advances in Immunotherapy for Hepatocellular Carcinoma”. In my opinion, the current stage of this paper could meet the requirements of Current Oncology after major revisions. 

1. *What’s the recent development of PD-1 or PD-L1 small molecular inhibitor in hepatocellular carcinoma and some other solid tumors? 

We thank the reviewer for this suggestion and added a new section for small molecule inhibitors (section 6) in the revised manuscript.   

2. *The conclusion part was too plain. An in-depth outlook or conclusion should be added. 

Thank you for the suggestion and we re-vised the conclusion part with more succinct summary of the manuscript.

3. Some minor mistakes exist in the paper. The authors should carefully check it, such as xix, xx??

Thank you for pointing out this and we corrected the errors.

4. *In my opinion, more figures or tables that summarize the pre-clinical researched immunotherapy strategies should be added.

Thank you for the suggestion and we summarized the preclinical immunotherapy research strategies in new figures and tables (current figure 1, tables 1, 4, 5, 6 and 7) in the revised manuscript.

5. *In line 43-45, the recent developments of small molecular clinical or pre-clinical inhibitors used to target PD-L1, PD-1, CTLA-4, and et al. should be clearly discussed in this review. Some related research was listed as below:10.1002/adma.202206121. 

We thank the reviewed for the suggestion and we added a new section for small molecule inhibitors (section 6) in the revised manuscript and created table 4 and 5.

6. Too many keywords were listed.

Thank you for pointing this out and we removed some of the keywords.

7. The abbreviations should be more clearly listed.

Thank you for pointing this out and we spelled out the specific abbreviations clearly now.

Reviewer 2 Report

Comments and Suggestions for Authors

Hepatocellular carcinoma (HCC) is the second most common cancer-related cause of death worldwide. As many HCC cases are discovered at an advanced stage, effective systemic therapies are required for enhanced effectiveness. For advanced HCC, immune checkpoint inhibitors (ICIs) have shown promise. Due to innate or acquired resistance, only around one-third of patients benefit from ICI-based therapy. The tumor's ability to evade immune responses is caused by the environment's innate immunosuppression in the liver tumor and certain alterations in cellular signaling pathways. Genetic sequencing of tumor tissue or circulating tumor DNA may provide insights and direct novel combination treatments while helping to understand resistance mechanisms. This review includes a summary of current studies as well as key clinical trials that helped improve ICI-based therapies for advanced HCC. It studies approaches to improve immunotherapies utilizing recent findings on tumor biomarkers and genetic alterations as well as resistance mechanisms to ICIs.

Here are some suggestions for this manuescript:

1-Chimeric Antigen Receptor T-cell (CAR-T) therapy has not been extensively used or licensed for the treatment of hepatocellular carcinoma (HCC). CAR-T treatment is a kind of immunotherapy that involves altering a patient's own T cells so that they express a chimeric antigen receptor, allowing them to detect and target cancer cells with a particular antigen on their surface. The use of CAR-T treatment in solid tumors like HCC has proven to be more difficult despite the fact that it has shown exceptional effectiveness in several hematological malignancies, such as leukemia and lymphoma. The immunosuppressive tumor microenvironment and the absence of specific antigens that may be successfully addressed in HCC create particular challenges. I advise reviewing recent medical literature, clinical trial databases, or interacting with a medical expert who is informed about the most recent developments in cancer treatments  in HCC.

2- The authors also need to explain about the, local and locoregional therapies are likely to work in conjunction with immunotherapy., locoregional treatments are less invasive, image-guided procedures. These treatments deliver an antitumoral device, medication, or chemical directly into the tumor under ultrasound supervision, resulting in tumor death.

3-The antigenicity of HCC must also be explained by the author. Expression of tumor antigens is the preliminary step in the establishment of a T cell response specific for a particular tumor. Deregulated expression of oncofetal and cancer testis antigen genes during hepatocarcinogenesis may trigger a spontaneous immune response.

Comments on the Quality of English Language

No any

Author Response

Dear Reviewer,

I would like to express my heartfelt gratitude for your review of our manuscript, "Advances in Immunotherapy for Hepatocellular Carcinoma." Your insights and suggestions have been instrumental in refining our work.

Your suggestions regarding CAR-T therapy, the combination of local and locoregional therapies with immunotherapy, and HCC antigenicity are highly valuable. We will incorporate these recommendations into our manuscript, ensuring a more comprehensive and informative document.

Thank you for your time and expertise. Please see the responses to your contributions.

Sincerely,

Fuat Bicer

---------------

***Reviewer 2:  Hepatocellular carcinoma (HCC) is the second most common cancer-related cause of death worldwide. As many HCC cases are discovered at an advanced stage, effective systemic therapies are required for enhanced effectiveness. For advanced HCC, immune checkpoint inhibitors (ICIs) have shown promise. Due to innate or acquired resistance, only around one-third of patients benefit from ICI-based therapy. The tumor's ability to evade immune responses is caused by the environment's innate immunosuppression in the liver tumor and certain alterations in cellular signaling pathways. Genetic sequencing of tumor tissue or circulating tumor DNA may provide insights and direct novel combination treatments while helping to understand resistance mechanisms. This review includes a summary of current studies as well as key clinical trials that helped improve ICI-based therapies for advanced HCC. It studies approaches to improve immunotherapies utilizing recent findings on tumor biomarkers and genetic alterations as well as resistance mechanisms to ICIs.

Here are some suggestions for this manuescript:

1. Chimeric Antigen Receptor T-cell (CAR-T) therapy has not been extensively used or licensed for the treatment of hepatocellular carcinoma (HCC). CAR-T treatment is a kind of immunotherapy that involves altering a patient's own T cells so that they express a chimeric antigen receptor, allowing them to detect and target cancer cells with a particular antigen on their surface. The use of CAR-T treatment in solid tumors like HCC has proven to be more difficult despite the fact that it has shown exceptional effectiveness in several hematological malignancies, such as leukemia and lymphoma. The immunosuppressive tumor microenvironment and the absence of specific antigens that may be successfully addressed in HCC create particular challenges. I advise reviewing recent medical literature, clinical trial databases, or interacting with a medical expert who is informed about the most recent developments in cancer treatments in HCC.

We thank the reviewer for the suggestion, and we included the CAR-T cell therapy section in the revised manuscript (section 5). 

2. The authors also need to explain about the local and locoregional therapies are likely to work in conjunction with immunotherapy., locoregional treatments are less invasive, image-guided procedures. These treatments deliver an antitumoral device, medication, or chemical directly into the tumor under ultrasound supervision, resulting in tumor death.

Thank you for the suggestion and we added a section for immunotherapy with locoregional therapies (section 8).

3. The antigenicity of HCC must also be explained by the author. Expression of tumor antigens is the preliminary step in the establishment of a T cell response specific for a particular tumor. Deregulated expression of oncofetal and cancer testis antigen genes during hepatocarcinogenesis may trigger a spontaneous immune response.

Thank you for the suggestion and we expanded the discussion as noted in line 70-76 in section 1.1.

Reviewer 3 Report

Comments and Suggestions for Authors

The article discusses advances in immunotherapy for advanced HCC. It emphasizes the potential of immune checkpoint inhibitors (ICIs) as novel therapies, but notes limited response rates due to inherent or acquired resistance. The review highlights the importance of identifying resistance mechanisms through genomic analysis and biomarkers to optimize immunotherapy approaches. 

Regrettably, numerous articles resembling this topic exist in the literature. An exemplary instance of the current state is PMID: 36933770. Significantly enhancing its value demands substantial revisions. The provided comments address various aspects of the manuscript and suggest improvements for each point: 

1) The manuscript's main focus is on HCC, but the introduction discusses liver cancer in a broader context. To enhance the consistency and relevance, it's important to ensure that the introduction specifically introduces HCC and its significance within the broader landscape of research.

2) "Error! Bookmark not defined."  Clean up the text and improve its professional appearance, these placeholders need to be located and replaced with the appropriate content or citations.

3) The study mentioned between line 140-160 has been identified as having clinical significance. To better present the findings, it's recommended to organize the information in a table. Tables provide a structured and concise way to display data, making it easier for readers to understand and compare the results.

4) Section A, "The Role of the Tumor Microenvironment in HCC," would greatly benefit from the inclusion of an illustrative visual aid to enhance understanding.

5) In lines 271-274, a study is cited as a reference for a classification of drug-resistance mechanisms. However, upon reviewing the provided PMID (34295561), it appears that the direct connection between the study and the mentioned classification might not be clear. A re-evaluation is suggested to ensure that the reference supports the classification being discussed.

6) Section 5 of the manuscript appears to lack clarity or sufficient depth. To enhance this section, it's recommended to conduct a thorough analysis of ICI resistance mechanisms. Additionally, providing an illustration or diagram that explains the fundamental principles of ICI resistance could aid in visualizing complex concepts.

7) The absence of Section 7 needs to be addressed. It's important to determine the intended content of this missing section and either complete it or provide an explanation for its omission.

8)Section 6 is currently only a paragraph in length. To improve the presentation, this section can be expanded by adding more content or, alternatively, integrating its content into another relevant section of the manuscript. This decision should be based on the coherence and flow of the overall document.

9)The manuscript lacks a dedicated Discussion section, which is crucial for interpreting the findings in the context of existing literature. Given the growing body of evidence concerning immunotherapy's role in HCC, it's important to thoroughly discuss this topic. The provided PMID references (36933770, 37345131) can serve as valuable sources for this discussion.

10) Section 8 would benefit from being presented using tables to improve its readability. Tables offer a concise way to present data, and they can help readers quickly grasp the key points being made in this section.

Overall, addressing these comments will contribute to the clarity, cohesiveness, and overall quality of the manuscript, making it more engaging and informative for readers.

Comments on the Quality of English Language

The language of the manuscript was readable. No significant issues were detected.

Author Response

Dear Reviewer,

I want to extend my sincere gratitude for your thorough review of our manuscript, "Advances in Immunotherapy for Advanced HCC: Overcoming Resistance Mechanisms." Your insightful feedback and suggestions are immensely appreciated.

We have taken note of your comments and are fully committed to addressing each of them to enhance the quality and clarity of our manuscript. Your guidance on specific sections and improvements significantly contributed to the overall impact of our work.

Your dedication to advancing the field of immunotherapy for HCC is evident, and your expertise is invaluable.

Please see the responses to your recommendations.

Thank you for your time and invaluable input.

Warm regards,

Fuat Bicer

------------------

***Reviewer 3: The article discusses advances in immunotherapy for advanced HCC. It emphasizes the potential of immune checkpoint inhibitors (ICIs) as novel therapies but notes limited response rates due to inherent or acquired resistance. The review highlights the importance of identifying resistance mechanisms through genomic analysis and biomarkers to optimize immunotherapy approaches. 

Regrettably, numerous articles resembling this topic exist in the literature. An exemplary instance of the current state is PMID: 36933770. Significantly enhancing its value demands substantial revisions. The provided comments address various aspects of the manuscript and suggest improvements for each point: 

Thank you for your review and recommendations. We revised the manuscript substantially and we hope that our additions, edits, and clarifications meet the reviewer`s expectations.

The manuscript's main focus is on HCC, but the introduction discusses liver cancer in a broader context. To enhance the consistency and relevance, it's important to ensure that the introduction specifically introduces HCC and its significance within the broader landscape of research.

Thank you for pointing this out. We have revised the introduction accordingly.

1. "Error! Bookmark not defined."  Clean up the text and improve its professional appearance, these placeholders need to be located and replaced with the appropriate content or citations.

Thank you for pointing this out. We fixed these errors throughout the manuscript, removed and reinserted the corresponding references.

2. The study mentioned between line 140-160 has been identified as having clinical significance. To better present the findings, it's recommended to organize the information in a table. Tables provide a structured and concise way to display data, making it easier for readers to understand and compare the results.

Thank you for the suggestion. We added a table summarizing the molecular correlates reported by Zhu et al. (Table 1)

3. Section A, "The Role of the Tumor Microenvironment in HCC," would greatly benefit from the inclusion of an illustrative visual aid to enhance understanding.

Thank you for the suggestion. We added Figure 1 to the manuscript as an illustrative visual aid to enhance understanding.

4. In lines 271-274, a study is cited as a reference for a classification of drug-resistance mechanisms. However, upon reviewing the provided PMID (34295561), it appears that the direct connection between the study and the mentioned classification might not be clear. A re-evaluation is suggested to ensure that the reference supports the classification being discussed.

Thank you for your recommendation. It appears we misplaced this reference. We used this reference to strengthen the argument that although many preclinical studies have shown a positive correlation of TMB and prognosis, there are few inconsistencies in the literature (line 280-281). We have moved it to the paragraph below.

5. Section 5 of the manuscript appears to lack clarity or sufficient depth. To enhance this section, it's recommended to conduct a thorough analysis of ICI resistance mechanisms. Additionally, providing an illustration or diagram that explains the fundamental principles of ICI resistance could aid in visualizing complex concepts.

Thank you for the recommendation. We added more specifics on the mechanisms and included some important findings from the reference (https://0-doi-org.brum.beds.ac.uk/10.1038/s41591-022-01868-2). We organized this section to provide more clarity and added a table to go along with it. We emphasized the biomarker findings that were validated in the paper by Zhu et al. (https://0-doi-org.brum.beds.ac.uk/10.1038/s41591-022-01868-2). We also added Table 7 to help visualize the two main resistance categories.

6. The absence of Section 7 needs to be addressed. It's important to determine the intended content of this missing section and either complete it or provide an explanation for its omission.

Unfortunately, we think section 7 was omitted in the PDF version. The number was just skipped over, but all content was there. It is included in the document version. We have reformatted the numbers as new information has been added based on reviewer recommendations. All numbers are included.

7. Section 6 is currently only a paragraph in length. To improve the presentation, this section can be expanded by adding more content or, alternatively, integrating its content into another relevant section of the manuscript. This decision should be based on the coherence and flow of the overall document.

We agree with the reviewer. We revised the manuscript extensively and moved this topic to the newly added section 7.

8. The manuscript lacks a dedicated Discussion section, which is crucial for interpreting the findings in the context of existing literature. Given the growing body of evidence concerning immunotherapy's role in HCC, it's important to thoroughly discuss this topic. The provided PMID references (36933770, 37345131) can serve as valuable sources for this discussion.

We thank the reviewed for the suggestion. We revised the manuscript substantially, expanded the topics as suggested and provided a succinct summary discussion in each section.

9. Section 8 would benefit from being presented using tables to improve its readability. Tables offer a concise way to present data, and they can help readers quickly grasp the key points being made in this section.

We than the reviewer for the suggestion and we summarized the findings in Table 7 in the revised manuscript.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have addressed all of the issues and suggestions put forward by the reviewers.

Comments on the Quality of English Language

No any

Reviewer 3 Report

Comments and Suggestions for Authors

The authors have adequately addressed all the points I raised.