The Current Status and Future Perspectives of Chimeric Antigen Receptor-Engineered T Cell Therapy for the Management of Patients with Endometrial Cancer
Round 1
Reviewer 1 Report
The authors have explained status of CAR-T-cells therapy in endometrial cancer (EC). This manuscript also covers about basics of CAR-T-cells and their development from 1st generation to 5th generation. It also widely covered toxicity and clinical status of CAR-T-cells in EC.
Line#153: CARs are divided into 5 generations. If you divide this paragraph into 5 separate sections, the readers can be easily educated.
Figure 1 clearly explains CAR generations. However, 5th generation of CAR is missing in this figure. Please revise this figure with 5th generation CAR.
Is there any study being conducted in combination with other immunotherapeutic agents? If so, please include its out comes in this section
Comments for author File: 
Comments.pdf
Author Response
The authors have explained status of CAR-T-cells therapy in endometrial cancer (EC). This manuscript also covers about basics of CAR-T-cells and their development from 1st generation to 5th generation. It also widely covered toxicity and clinical status of CAR-T-cells in EC.
REPLY: We are very much thankful to the reviewer for the thorough review. We agree with all the specific comments raised and have revised our paper in light of the useful suggestions. Our responses to the specific comments/suggestions/queries given are provided below.
Line#153: CARs are divided into 5 generations. If you divide this paragraph into 5 separate sections, the readers can be easily educated.
REPLY: Thank you for your comments. Over the last three decades, CAR-T cells have advanced from their initial description to receiving FDA approval for clinical usage. With these advancements, it is important to note the new designs and molecular modifications in recent generations of CAR-T cells. In concert with the reviewer’s comments, we have divided our paragraph to 5 different section for better reading fluidity and understanding for the reader. We appreciate the reviewer’s insight.
Figure 1 clearly explains CAR generations. However, 5th generation of CAR is missing in this figure. Please revise this figure with 5th generation CAR.
REPLY: We agree with the reviewer and we have revised our manuscript with a different figure that encompasses the next generation/fifth generation of CAR-T cells. Thank you for your comments.
Is there any study being conducted in combination with other immunotherapeutic agents? If so, please include its out comes in this section.
REPLY: To our knowledge, apart from the studies we have mentioned in our manuscript, there no other ongoing trials evaluating the efficacy of CAR-T cell monotherapy or combination therapy for the treatment of endometrial cancer. This may be due to the unmatched clinical activity of immune checkpoint inhibitor therapy in endometrial cancer patients. Given the current efficacy of check point inhibitor immunotherapy, there is no clear medical or scientific rationale for testing CAR-T cell therapy as a replacement for immune checkpoint inhibitors. However, there may be a role for CAR-T therapy in treating patients who experience recurrence following treatment with immune checkpoint inhibitors in the future. Therefore, further studies are warranted to determine the optimal sequencing and combination of various immunotherapeutic strategies in endometrial cancer management. We ask for the reviewer’s understanding. Thank you for your insight and comments.
Reviewer 2 Report
Patients with metastatic or recurrent endometrial cancer (EC) have limited treatment options after unsuccessful standard treatment with chemo-and radiotherapy. Therapy with immune checkpoint inhibitors show promising results. The therapeutic benefits of CAR-T cell therapy for patients with EC are under validation. This review gives an important overview of the pros and cons of CAR-T cell therapy in EC patients. The manuscript is well-written and - organised. The references are appropriate and relevant. Figures and tables are presented in an understandable way.Author Response
Patients with metastatic or recurrent endometrial cancer (EC) have limited treatment options after unsuccessful standard treatment with chemo-and radiotherapy. Therapy with immune checkpoint inhibitors show promising results. The therapeutic benefits of CAR-T cell therapy for patients with EC are under validation. This review gives an important overview of the pros and cons of CAR-T cell therapy in EC patients. The manuscript is well-written and - organized. The references are appropriate and relevant. Figures and tables are presented in an understandable way.
REPLY: We are very much thankful to the reviewer for the thorough review. We agree with all the specific comments raised and have revised our paper in light of the useful suggestions.
Reviewer 3 Report
Ji Young Choi and Tae Jin Kim present a quality and well-written review manuscript focused on the current status and future perspectives of chimeric antigen receptor-engineered T cell therapy for the management of patients with endometrial cancer.
Authors examine CAR-T cell therapy's current use for endometrial carcinomas. They also discuss the significant adverse effects and limitations of this immunotherapeutic approach.
Authors discuss such aspects as the interaction between the female endometrium and the immune system, rationale of CAR-T cell immunotherapy for the management of endometrial cancer, molecular targets for CAR-T cells in endometrial immunotherapy, current and ongoing clinical trials for CAR-T cell immunotherapy in endometrial cancer, future directions for CAR-T cell immunotherapy for endometrial cancer, adverse events in CAR-T cell therapy.
Finally, authors conclude that they consolidated signal seeking early phase clinical trials and advancements that have shown promising results and lead to the approval of new immunotherapeutic agents for the disease.
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Overall, the manuscript is highly valuable for the scientific community and should be accepted for publication after the corrections are made.
Other comments:
1) Please check for typos throughout the manuscript.
2) With regards to CAR-T therapy against solid neoplasms – authors are kindly encouraged to cite the following article that discusses the application of CAR-T cells against solid tumor models.
DOI 10.3390/biomedicines11020626
Author Response
Ji Young Choi and Tae Jin Kim present a quality and well-written review manuscript focused on the current status and future perspectives of chimeric antigen receptor-engineered T cell therapy for the management of patients with endometrial cancer.
Authors examine CAR-T cell therapy's current use for endometrial carcinomas. They also discuss the significant adverse effects and limitations of this immunotherapeutic approach.
Authors discuss such aspects as the interaction between the female endometrium and the immune system, rationale of CAR-T cell immunotherapy for the management of endometrial cancer, molecular targets for CAR-T cells in endometrial immunotherapy, current and ongoing clinical trials for CAR-T cell immunotherapy in endometrial cancer, future directions for CAR-T cell immunotherapy for endometrial cancer, adverse events in CAR-T cell therapy.
Finally, authors conclude that they consolidated signal seeking early phase clinical trials and advancements that have shown promising results and lead to the approval of new immunotherapeutic agents for the disease.
==============================
Overall, the manuscript is highly valuable for the scientific community and should be accepted for publication after the corrections are made.
REPLY: We are very much thankful to the reviewer for the thorough review. We agree with all the specific comments raised and have revised our paper in light of the useful suggestions. Our responses to the specific comments/suggestions/queries given are provided below.
Other comments:
1) Please check for typos throughout the manuscript.
REPLY: We have revised our manuscript and have checked for misspelled words and grammatical errors. Thank you for your comments and suggestions.
2) With regards to CAR-T therapy against solid neoplasms – authors are kindly encouraged to cite the following article that discusses the application of CAR-T cells against solid tumor models.
DOI 10.3390/biomedicines11020626
REPLY: Over the past 30 years, there have been great advances and breakthroughs in the development of CAR-T cells. However, therapeutic efficacy and potential benefit have been observed in hematological malignancies, and increasing the treatment benefit of CAR-T cells in the clinical setting of non-hematologic solid tumors is still an ongoing scientific challenge. With the clinical findings of the aforementioned study, the potential usage of CAR-T cells as a treatment modality for solid tumors is gaining clinical evidence and scientific rationale. In light with the reviewer’s suggestion, we have edited our manuscript to add this information. Thank you for your insight.
