Current Status and Future Perspectives of Immunotherapy for Locally Advanced or Metastatic Urothelial Carcinoma: A Comprehensive Review
Round 1
Reviewer 1 Report
The authors have followed the comments of reviewer 1 and added the paragraphs "vaccines" and "adoptive T cell immunotherapy" in the text and arranged them appropriately. The content of the article is therefore more comprehensive.
This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.
Round 1
Reviewer 1 Report
The authors review the current treatment landscape of human urothelial carcinoma including a historical review of treatment with chemotherapy.
The first line of the abstract is misleading as it is apparent that the authors are referencing superficial bladder cancer with invasive bladder cancer. These are well known and documented to have two different etiologies. This reference/interchange between the two different forms of the disease occur twice in the manuscript. This is a serious misinterpretation.
There is nothing substantial being added by this review that doesnt already exist in literature.
Author Response
The authors review the current treatment landscape of human urothelial carcinoma including a historical review of treatment with chemotherapy.
REPLY: We are very much thankful to the reviewer for the thorough review. We agree to all specific comments addressed and have revised our paper in light of the useful suggestions. Answers to the specific comments/suggestions/queries are as follows.
The first line of the abstract is misleading as it is apparent that the authors are referencing superficial bladder cancer with invasive bladder cancer. These are well known and documented to have two different etiologies. This reference/interchange between the two different forms of the disease occur twice in the manuscript. This is a serious misinterpretation.
REPLY: We agree with the reviewer that intravesical BCG treatment is indicated for non-invasive bladder cancers and that it is beyond the main scope of our manuscript. Our objective was to raise the concept that urothelial carcinoma is an immunogenic tumor that has the potential for immune therapy. We agree that this information is misleading and removed sentences from the Abstract and the Introduction Section.
There is nothing substantial being added by this review that doesnt already exist in literature.
REPLY: We would greatly appreciate your kind understanding that this manuscript is a review article. Following the reviewer and the editor’s suggestion, we have added a section (‘Classification of Urothelial Carcinoma’) that describes histological and mRNA subtypes of urothelial carcinoma, and how these classifications may play a role in selecting patients most likely to respond to treatment with immunotherapeutic agents.
Reviewer 2 Report
The manuscript deals with a very interesting topic, immunotherapy in bladder cancer. It is also interesting because it describes all approved and experimental drugs.
Comments:
The paragraphs 3 and 4 (“Immunotherapy for the Treatment of Urothelial Carcinoma” and “Combination Therapy for Locally Advanced and Metastatic Urothelial Carcinoma”, respectively) are quite long: please reduce them. The authors merely list the studies that have led to the approval of drugs, without mentioning the role of biomolecular classification of bladder cancer. In this regard, it would be useful to cite the data presented in the article “Comprehensive molecular characterization of the muscle-invasive bladder cancer” by A. Gordon Robertson et al. (Cell, 2017), referring to the new classification of bladder cancer, specifying how this can play a role in selecting the patients most likely to respond to treatment with immunotherapeutic agents. The paragraph 6 “Biomarkers for Predicting Treatment Response” is poor: potential biomarkers in bladder cancer are not only PD-L1 or TMB. Please extend this paragraph by discussing about other biomarkers. An interesting article in this context could be the following one: Schepisi G et al. Inflammatory Biomarkers as Predictors of Response to Immunotherapy in Urological Tumors. J Oncol 2019 Page 11 line 12. In the Conclusion section, ”Cisplastin”. Please modifyAuthor Response
The manuscript deals with a very interesting topic, immunotherapy in bladder cancer. It is also interesting because it describes all approved and experimental drugs.
REPLY: We are very much thankful to the reviewer for the thorough review. We agree to all specific comments addressed and have revised our paper in light of the useful suggestions. Answers to the specific comments/suggestions/queries are as follows.
The paragraphs 3 and 4 (“Immunotherapy for the Treatment of Urothelial Carcinoma” and“Combination Therapy for Locally Advanced and Metastatic Urothelial Carcinoma”, respectively) are quite long: please reduce them.
REPLY: Thank you for this comment. We had mostly focused on this section since the main scope of this review is on antigens and cancer. We agree with the reviewer that the lengths of paragraphs 3 and 4 are long. We have edited and removed redundant and repetitive sentences.
The authors merely list the studies that have led to the approval of drugs, without mentioning the role of biomolecular classification of bladder cancer. In this regard, it would be useful to cite the data presented in the article “Comprehensive molecular characterization of the muscle-invasive bladder cancer” by A. Gordon Robertson et al. (Cell, 2017), referring to the new classification of bladder cancer, specifying how this can play a role in selecting the patients most likely to respond to treatment with immunotherapeutic agents.
REPLY: We thank the reviewer for providing information regarding the new molecular classification of bladder cancer. We noted from the suggested reference, that the Cancer Genome Atlas (TCGA) analysis for muscle-invasive bladder cancer identifies five mRNA subtypes: 1) luminal-papillary, 2) luminal-infiltrated, 3) luminal, 4) basal/squamous, and 5) neuronal. This classification has the potential to be utilized to stratify patients for a specific treatment regimen. For instance, relatively higher mutational burden and higher antigen load are identified in the MSig1 cluster, characterized by favorable patient survival outcomes. Improved survival outcomes observed in these patients infers the presence of a natural host immune reaction to the high antigen load that may have inhibited tumor growth and metastasis. Indeed, this presumption warrants confirmation in clinical trials, preferably involving immune checkpoint inhibitors. Furthermore, the validation of this subtype as a prognosticator for the response to immunotherapy may support the use of immunotherapy in the neoadjuvant setting since a higher load of tumor antigens would be present if the primary tumor is still in-situ. In accordance with the reviewer’s suggestion, we have added a section (‘Classification of Urothelial Carcinoma’), including the information above, describing mRNA subtypes of urothelial carcinoma and how these classifications may play a role in selecting patients most likely to respond to treatment with immunotherapeutic agents.
The paragraph 6 “Biomarkers for Predicting Treatment Response” is poor: potential biomarkers in bladder cancer are not only PD-L1 or TMB. Please extend this paragraph by discussing about other biomarkers. An interesting article in this context could be the following one: Schepisi G et al. Inflammatory Biomarkers as Predictors of Response to Immunotherapy in Urological Tumors. J Oncol 2019 Page 11 line 12.
REPLY: We appreciate the reviewer’s insight and comments. To keep the paper readable and logically fluent, we have added information to the sections: “the rationale for immunotherapy in urothelial carcinoma” and “biomarkers for predicting treatment response”. From the suggested reference, we have noted that the CTLA-4 and PD-1/PD-L1 immune pathways are currently the most studied and well known. However, immune molecules such as TIM-3, LAG-3, and the B7-H3, H4 proteins are still under investigation as future candidates for immune checkpoints and biomarkers. Despite recent findings in genetics and molecular alterations in UC, the prognostic and clinical impact of these biomarkers are still under investigation. In accordance with the reviewer’s suggestion, we have added updated information regarding these molecules to “the rationale for immunotherapy in urothelial carcinoma” section. Furthermore, in addition to PD-L1 and TMB, we have added information to the “biomarkers for predicting treatment response” section regarding the mismatch repair (MMR) mechanism and DNA damage response (DDR) and repair pathways which are under investigation as potential biomarkers for predict response to checkpoint inhibitors. Thank you for this helpful comment.
In the Conclusion section, ”Cisplastin”. Please modify
REPLY: Thank you for pointing this out. We have edited this typo in the Conclusion Section.
Round 2
Reviewer 1 Report
I have reviewed the manuscript again. The authors have made modifications to the manuscript and added information at several places. My concern with the original submission was the lack of clarity regarding making distinction between superficial and invasive bladder cancer and treating them as one disease. This has been addressed by removing the sentences I had refereed to, and objected. The authors have also included a summary of the recent publication listing the histologic variants and the subtypes as described by TCGA. I am still not convinced this article is adding anything new to the existing review articles on this subject.
Reviewer 2 Report
The changes made by the authors have considerably improved the article, which deserves to be published in the present form
