Delayed Effect of Dendritic Cells Vaccination on Survival in Glioblastoma: A Systematic Review and Meta-Analysis

Round 1

Reviewer 1 Report

The article “Delayed Effect of Dendritic Cells Vaccination on Survival in Glioblastoma: A systematic review and meta-analysis” presents available data regarding the efficacy of DC vaccination in an organized manner. I have some questions/comments that I believe will additionally improve the manuscript:

1. I think the authors should add a paragraph in the Introduction section underlining the novelty of the analysis – in which way does the manuscript contribute to current knowledge? This is particularly important since there are several other articles already published that have addressed the same issue. Also, I think the authors should also add some information regarding why GBM is more difficult to treat with immunotherapy than other types of solid tumors.
2. There are several English issues that I think would be best addressed by a native English speaker. Some examples are provided below:

Introduction – “Thus, this progressive and invasive behavior necessitates the development of novel treatments with the goal of limiting its progression, inhibiting recurrences or even metastasis5 and ultimately enhances patients’ long-term survival.”, “Such capacity for anticancer immunotherapy has been discovered in treating different malignant tumors especially in their metastatic setting”, “Overall, immunotherapy is mainly applied in two approaches (...)”

Discussion – “According to the evidence sourced from both animal and human studies, the immune system can potentially recognize malignant cells and thus can destroyed such cells efficiently”, “In this regard, DCV against GBM, has found a special role and the results on its efficacy were associated with relevant expectations.”, “Based on these findings we can hypothesize that DCV to be effective against GBM would require more time (...)”

3. Figure 3 contains some very important information, but reading it is quite difficult due to subpar quality and extremely small size.
4. The association between Temozolamide and DC vaccination versus DC vaccination alone should be analyzed in more detail and discussed accordingly. Also, more detail should be provided regarding different treatment strategies used in the clinical trials that were included in the analysis.

Author Response

Thank you so much for your nice comments. We have edited the manuscript accordingly, as it comes below. please find the edited manuscript to see the details of these changes.

1. I think the authors should add a paragraph in the Introduction section underlining the novelty of the analysis – in which way does the manuscript contribute to current knowledge? This is particularly important since there are several other articles already published that have addressed the same issue. Also, I think the authors should also add some information regarding why GBM is more difficult to treat with immunotherapy than other types of solid tumors.

 

The introduction is revised substantially and the mentioned issues are seriously considered as you can find in the newly submitted revised manuscript.

 

2.There are several English issues that I think would be best addressed by a native English speaker. Some examples are provided below:

Respectfully, we admit some grammatical errors. We have corrected the mentioned examples and also, we performed a second look edition on the whole manuscript.

3.Figure 3 contains some very important information, but reading it is quite difficult due to subpar quality and extremely small size.

 

Thank you for mentioning this issue. I have replaced it with a higher quality image so that it can be zoomed in.

4.The association between Temozolamide and DC vaccination versus DC vaccination alone should be analyzed in more detail and discussed accordingly. Also, more detail should be provided regarding different treatment strategies used in the clinical trials that were included in the analysis.

Temozolomide is the standard of care for primary glioblastoma and it is hard to find a study on primary glioblastoma in which temozolomide is not administered to the patients. Information regarding temozolomide was not available for Chang 2011, Leplina 2007, Muller 2015,Yamanaka 2005 and Yu 2004.  So, the sign “-” in the table should be “not available”. So, an analysis could not be done because of the lack of enough information.

Instead, more information about different treatment strategies is added to the table 1.

 

Author Response File: Author Response.docx

Reviewer 2 Report

The authors performed a meta-analysis to investigate survival outcome of patients enrolled in clinical trials of dendritic vaccine. Out of 157 screened studies, 15 studies were selected for the meta-analysis. PFS, OS, 1- and 2-year OS were superior in patients who received in DCV vs. control. This is an important question and the findings are interesting. The article would benefit from the following clarification:

1- The article would benefit from English Language editing

2- The introduction should focus more on different types of DCV as opposed to general explanation of immune-oncology 

3- The description of study selection is not clear. particularly #3, line 89. "unclear" and "irreproducible" need to be defined. 

4- line 148 would benefit from further clarification. 

5- line 202-210 describes prior meta-analysis regarding DCV trials. The studies are described but the authors should share their opinion regarding these studies and why the results differ from the authors' results. 

6- The authors should describe the type of "control" in each study. Were any of these historical controls? or are they all contemporary controls?

Author Response

Thank you so much for your nice comments. We have edited the manuscript accordingly, as it comes below. please find the edited manuscript to see the details of these changes.

 

1- The article would benefit from English Language editing

I agree with this comment. The whole manuscript was edited for language errors.

2- The introduction should focus more on different types of DCV as opposed to general explanation of immune-oncology :

The introduction is revised substantially and the mentioned issues are seriously considered as you can find in the newly submitted revised manuscript.

3- The description of study selection is not clear. particularly #3, line 89. "unclear" and "irreproducible" need to be defined. 

The methodological reproducibility was defined for studies for which data was available and repeating the experiment with the same data and same methods and tools led to the same results. Therefore a study is called irreproducible if there are noticeable methodological problems or some errors in data analysis. Unclear studies are referred to those not reporting the required outcomes or the outcomes are not clear. The necessary corrections were made in the manuscript.

4- line 148 would benefit from further clarification. 

The requested correction was made in the manuscript along with other language errors and ambiguities.

5- line 202-210 describes prior meta-analysis regarding DCV trials. The studies are described but the authors should share their opinion regarding these studies and why the results differ from the authors' results. 

Vatu’s study is focused on viral therapy, while our study is focused on the time at which the effect is becomes significant. Also, there is some information about side effects in our study. Our study includes 1081 cases (452 cases and 629 controls) while Vatu’s study included 1020 cases (308 cases and 712 controls). Overall, 40% overlap is present between the final analyzed studies. The second study, Artene et al, included a much lower number of patients relative to ours. They have included both primary and recurrent GBM patients and they have not reached a significant improvement in PFS, probably because of the limited number of patients. The third study, Cao et al, also has included a lower number of patients and did not analyze the start time for DCV’s effect.  

Overall, there are differences in inclusion/exclusion criteria, the included studies, and the outcome measures. Our study is the biggest one in terms of patients’ number, especially patients in the experimental arm. Our study is focused in the first time point that the effect of DCV can be seen which is not the case in other studies. Some explanations are added to the discussion.

 

6- The authors should describe the type of "control" in each study. Were any of these historical controls? or are they all contemporary controls?

Thank you for this very good point. I added the control type to table 1.

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

Thank you for addressing my concerns.