Targeting Cancers with oHSV-Based Oncolytic Viral Immunotherapy

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors conducted a comprehensive review on oncolytic viral Immunotherapy (OViT) for cancer, focusing on  oncolytic HSV-1-based OViTs, their anti-tumor mechanism of action, and efficacy data from recent clinical trials. This a valuable review to the readers.

 

Comments:

The authors could also add a Table summarizing the main mechanisms of oHSV anti-tumor activity, as described in the respective section of the manuscript.

 

Section 2. Mechanism of oHSV Anti-tumor Activity

The authors could add a Table summarizing the main mechanisms of oHSV anti-tumor activity, as described in this section of the manuscript.

 

Section 3.1. Talimogene laherparevec (T-VEC or Imlygic)

“Interestingly, a recent phase III, randomized, double-blind study [NCT02263508] showed that there was no significant benefit for the combination of T-VEC and pembrolizumab over placebo plus pembrolizumab in patients with unresectable stage IIIB/IVM1c melanoma after a median of 31 months of follow-up [40]”

The authors give a possible explanation for this finding in the Discussion section. This explanation should be provided here as well.

 

Section 4. Discussion

“The results of a phase III, randomized, double blind study using T-VEC and pembrolizumab did not show increased treatment efficacy compared to pembrolizumab alone in patients with unresectable stage IIIB/IVM1c melanoma [8, 38-40]” 

Why so many references? Should be just one reference.

Author Response

We thank the reviewers for their constructive feedback. We have thoroughly considered the comments from each reviewer and have made changes to the paper to reflect their suggestions.

Both reviewers suggested to add a figure or table for the section describing the mechanism of oHSV anti-tumor activity, and we have added a figure that visualizes the mechanisms that were described within this section. We included the role of the cGAS-STING complex in T-cell anti-tumor response and tumor lysis as well as visualizing the mechanisms by which dendritic cells recognize DAMPS and subsequently activate and initiate the activation of CD8+ T-cells.

The first reviewer mentioned to provide the possible explanation for why no significant benefit was seen in the combination of T-VEC and pembrolizumab in both the discussion and under Section 3.1. We have added a sentence was that includes the explanation that was also in the discussion.

“The results of a phase III, randomized, double blind study using T-VEC and pembrolizumab did not show increased treatment efficacy compared to pembrolizumab alone in patients with unresectable stage IIIB/IVM1c melanoma” now only has [40] as the reference.

The second reviewer mentioned to add a table summarizing the key findings from the various clinical trials, we believe that our table 1 includes the key findings from the trials mentioned in Section 3 of the manuscript.

We have also added a section in the conclusion to include the 3^rd and 4^th suggestions; the new addition is as follows, “However, there are barriers to the utilization of oHSV therapies in other types of cancers especially the metastatic ones. Optimizing an efficient delivery system is a major issue. Intratumoral inoculation is the common route of treatment that have been reported in several preclinical and clinical studies. This method allows for the OVs to by bypass blood dilution, host immune antiviral immunity and prevention of non-targeted cell injuries. Utilizing an intravenous route of OV delivery is an ideal method of treatment as it allows for broad virus distribution, which can infect both primary and metastatic tumors regardless of location. Tumor heterogeneity is another issue that may decrease the efficacy of the oHSV activities. Nevertheless, the application of oHSV therapies continue to show promising results in the treatment of metastatic tumors. For example, the FDA recently approved the oHSV, MVR-T3011 for the treatment of recurrent or metastatic head and neck squamous cell cancer. MVR-T3011 was reported to be effective in reducing the size of tumors distant from initial injection site.”

Again, we thank the reviewers for taking their time to read and critically evaluate our manuscript. We greatly appreciate their feedback and suggestions in order to improve our manuscript. We hope that the new changes to the paper reflect the suggestions made by the reviewers.

Reviewer 2 Report

Comments and Suggestions for Authors

Comment:

This manuscript provided an extensive review of oncolytic herpes simplex virus (oHSV)-based immunotherapy for cancer treatment. Firstly, it reviewed the history, development, and current state of oHSV-based immunotherapy. Then, it discussed in detail about the mechanisms by which oHSV exerted its anti-tumor effects, and evaluated the limitations and challenges associated with current oHSV therapies. Finally, it aroused extensive suggestions for oHSV therapies. The whole review offered a comprehensive analysis of oHSV therapies and was well-organized. This review is recommended to be published after addressing the following minor concerns:

 

1.     The authors are recommended to supply more visual figures when describing the works associated with oHSV therapies, especially in the section: Mechanism of oHSV Anti-tumor Activity.

2.     The discussion on clinical trials is thorough. However, no specific figure or table information connected with clinical trials provided in the review. The authors are recommended to add a table summarizing the key findings from the various trials mentioned previously.

3.     The future directions and the potential impact of new regulation advancements on oHSV therapy are recommended to discussed in detail in this review to make it to be more helpful.

4.     The review focused more on the application of oHSV therapy on melanoma. So what are the challenges for applying oHSV therapy to non-melanoma cancers, such as ovarian, pancreatic, and prostate cancers? The authors are recommended to add more discussions. 

 

Comments on the Quality of English Language

English of this manuscript is recommended to be improved further. 

Author Response

We thank the reviewers for their constructive feedback. We have thoroughly considered the comments from each reviewer and have made changes to the paper to reflect their suggestions.

Both reviewers suggested to add a figure or table for the section describing the mechanism of oHSV anti-tumor activity, and we have added a figure that visualizes the mechanisms that were described within this section. We included the role of the cGAS-STING complex in T-cell anti-tumor response and tumor lysis as well as visualizing the mechanisms by which dendritic cells recognize DAMPS and subsequently activate and initiate the activation of CD8+ T-cells.

The first reviewer mentioned to provide the possible explanation for why no significant benefit was seen in the combination of T-VEC and pembrolizumab in both the discussion and under Section 3.1. We have added a sentence was that includes the explanation that was also in the discussion.

“The results of a phase III, randomized, double blind study using T-VEC and pembrolizumab did not show increased treatment efficacy compared to pembrolizumab alone in patients with unresectable stage IIIB/IVM1c melanoma” now only has [40] as the reference.

The second reviewer mentioned to add a table summarizing the key findings from the various clinical trials, we believe that our table 1 includes the key findings from the trials mentioned in Section 3 of the manuscript.

We have also added a section in the conclusion to include the 3^rd and 4^th suggestions; the new addition is as follows, “However, there are barriers to the utilization of oHSV therapies in other types of cancers especially the metastatic ones. Optimizing an efficient delivery system is a major issue. Intratumoral inoculation is the common route of treatment that have been reported in several preclinical and clinical studies. This method allows for the OVs to by bypass blood dilution, host immune antiviral immunity and prevention of non-targeted cell injuries. Utilizing an intravenous route of OV delivery is an ideal method of treatment as it allows for broad virus distribution, which can infect both primary and metastatic tumors regardless of location. Tumor heterogeneity is another issue that may decrease the efficacy of the oHSV activities. Nevertheless, the application of oHSV therapies continue to show promising results in the treatment of metastatic tumors. For example, the FDA recently approved the oHSV, MVR-T3011 for the treatment of recurrent or metastatic head and neck squamous cell cancer. MVR-T3011 was reported to be effective in reducing the size of tumors distant from initial injection site.”

Again, we thank the reviewers for taking their time to read and critically evaluate our manuscript. We greatly appreciate their feedback and suggestions in order to improve our manuscript. We hope that the new changes to the paper reflect the suggestions made by the reviewers.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors addressed the concerns we raised accordingly. Now it is recommended to be published.