State of the Art on CAR T-Cell Therapies for Onco-Haematological Disorders and Other Conditions
Round 1
Reviewer 1 Report
Comments and Suggestions for Authors
The authors present an overview of CAR T-cell therapies. They summarize data and show where this form of therapy is used today. The paper is very brief in detail. Disadvantages of the therapy and adverse effects are briefly addressed, but not elaborated on. There is no detailed comparison with current forms of therapy on the question of costs. The presentation of the 4 generations of CAR-T cells is isolated and is not linked to the text. The level of novelty is low.
Author Response
Thank you for your comments.
The authors present an overview of CAR T-cell therapies. They summarize data and show where this form of therapy is used today.
The paper is very brief in detail.
Certainly since the aim as explained in the manuscript is to published a short review.
_ The referee comments "There is no detailed comparison with current forms of therapy on the question of costs"
The intension of the paper is to describe shortly the Status of CAR-T cells and not to compare it with other current treatment that it is out of the scope of this paper.
The referee comments that "The presentation of the 4 generations of CAR-T cells is isolated and is not linked to the text"
Thank you.
A sentence has been added (line 209-210) to shortly link the relevance of potential 4 generations of CAR-T cells
The referee mention "The level of novelty is low"
We thank the referee for his observation. This is a review more than a research paper and only described all the novelty of CAR-T including recent reference and its applications to other conditions.
Reviewer 2 Report
Comments and Suggestions for Authors
Dr. Madrigal and Dr. Crispín review in their article the use of CAR-T cell in the therapy of tumors and autoimmune disorders. They mention successful use of this type of therapy to improve high age based conditions in primates and asthma and fungal infections in mice.
CAR-T cells are engineered to bind to specific proteins present on cell membranes of cancer cells. This activates the host immune system to attack the tumour. With haematological diseases spectacular results have been achieved where other therapeutic avenues were unsuccessful. The same type of therapy is tried in the treatment of solid tumors with partial success.
Interestingly CAR-T cell therapy had been very successfully tested in several severe autoimmune disorders like lupus erythematosus, idiopathic inflammatory myositis and systemic sclerosis with astonishing effects. In all 15 cases immunosuppressive treatment could be stopped without observing a relapse of the condition.
The authors give a very informed overview of CAR-T cell therapy. They cover how the CAR-T cells were constructed in various stages of the technical development. They highlight not only the successes of the therapy but also its disadvantages, in particular availability and costs associated with the treatment. Beyond the clinical applications they describe some of the experimental use of this technology in the treatment of immunological diseases.
I think the authors describe the CAR-T cell technology well, their scientific background, the problems in the generation of sufficient cells for individualised treatment and their successes. They highlight potential use of the technology in the future. The figure displays the essential concepts of the CAR-T cell technology. The conclusion of the manuscript that the CAR-T cell therapy has already been applied very successfully to many patients and that additional experiments promise an even broader field of application is supported by the observations and the cited research within the article.
I think the article can be published as it is.
Author Response
We as authors very much appreciate the positive review of this evaluator and thank him/her for its approval to be published as stand.
Reviewer 3 Report
Comments and Suggestions for Authors
The authors have provided a comprehensive overview of CAR-T cell therapies for oncological and autoimmune conditions. While the manuscript is informative, several areas require refinement to enhance clarity, scientific rigor, and overall impact. Below are my recommendations:
1. For the figures and legend, the illustrations in this manuscript are rendered with commendable professionalism. However, the accompanying legends lack sufficient detail, which could lead to potential misinterpretations by discerning readers. It would be prudent for the authors to revisit and refine the legends accompanying these figures
2. For the clinical trials analysis, the authors effectively summarize the clinical outcomes related to CAR-T cell therapies, but the manuscript lacks a critical evaluation of these studies. The authors should incorporate a more critical assessment of the clinical trials, discussing potential biases, limitations, and areas where CAR-T cell therapies have shown variable efficacy.
3. The manuscript mentions adverse effects such as cytokine release syndrome (CRS) and neurotoxicity but does not thoroughly discuss their management strategies. A more detailed discussion on the strategies to manage these adverse effects is essential. This may include current best practices, emerging treatment protocols, and the role of combination therapies in mitigating side effects, thereby providing readers with a comprehensive understanding of how to handle these complications in clinical settings.
4. While the manuscript touches on future challenges, the discussion lacks depth regarding emerging innovations in CAR-T cell therapy. The authors should expand this section by exploring technologies such as CRISPR-based gene editing for optimizing CAR-T cells, the development of CAR-NK cells, and novel targets for CAR-T cell therapy in solid tumors. Additionally, discussing the potential of combining CAR-T cells with other modalities, such as immune checkpoint inhibitors, could provide insights into overcoming current limitations and offer a more forward-looking perspective.
5. The high cost and accessibility issues associated with CAR-T cell therapies are acknowledged, but the manuscript does not explore these challenges in depth. The authors may provide a more comprehensive review of the economic barriers to CAR-T cell therapy, discussing cost-effectiveness, insurance coverage, and strategies for improving accessibility, particularly in low- and middle-income countries.
Author Response
We very much appreciate the substantial number of recommendation of the evaluator. But given the limitations of the space recommended for the type of manuscript and for the Journal as well as that it was agree that the paper as mentioned in the manuscript is:
"In this review, without pretending to cover all the current areas of treatments with CAR-T cells, we offer a brief summary of some of the most relevant aspects of the use of CAR-T cells for some of these conditions”
the referee comments: "For the figures and legend, the illustrations in this manuscript are rendered with commendable professionalism. However, the accompanying legends lack sufficient detail, which could lead to potential misinterpretations by discerning readers. It would be prudent for the authors to revisit and refine the legends accompanying these figures"
We thank the Referee however the figure aims to be clear and simple as well as the accompanying legends. However, the manuscript elaborate more in the text the nature of the CAR-Ts and we believed it is not necessary due to the extent of the paper to add more into the legend.
The referee comments; "For the clinical trials analysis, the authors effectively summarize the clinical outcomes related to CAR-T cell therapies, but the manuscript lacks a critical evaluation of these studies. The authors should incorporate a more critical assessment of the clinical trials, discussing potential biases, limitations, and areas where CAR-T cell therapies have shown variable efficacy."
We thank the Referee for the recommendation however the description is clear and cover the data of the paper, it is not the intension to review the paper that were already published in highly peer journals but to make a summary of them in a coherent way.
The referee comments: " The manuscript mentions adverse effects such as cytokine release syndrome (CRS) and neurotoxicity but does not thoroughly discuss their management strategies. A more detailed discussion on the strategies to manage these adverse effects is essential. This may include current best practices, emerging treatment protocols, and the role of combination therapies in mitigating side effects, thereby providing readers with a comprehensive understanding of how to handle these complications in clinical settings"
We thank the Referee for the recommendation however the description is clear and cover the data of the paper, it is not the intension to review the paper that were already published in highly peer journals but to make a summary of them in a coherent way.
The referee comments "While the manuscript touches on future challenges, the discussion lacks depth regarding emerging innovations in CAR-T cell therapy. The authors should expand this section by exploring technologies such as CRISPR-based gene editing for optimizing CAR-T cells, the development of CAR-NK cells, and novel targets for CAR-T cell therapy in solid tumours. Additionally, discussing the potential of combining CAR-T cells with other modalities, such as immune checkpoint inhibitors, could provide insights into overcoming current limitations and offer a more forward-looking perspective."
We thank the Referee for the recommendation however the description is clear and cover the data of the paper, it is not the intension to review the paper that were already published in highly peer journals but to make a summary of them in a coherent way. In addition, there are some recent references that were mention in relation to future of forward-looking perspectives
the referee comments: "The high cost and accessibility issues associated with CAR-T cell therapies are acknowledged, but the manuscript does not explore these challenges in depth. The authors may provide a more comprehensive review of the economic barriers to CAR-T cell therapy, discussing cost-effectiveness, insurance coverage, and strategies for improving accessibility, particularly in low- and middle-income countries"
We thank the Referee for the recommendation however the description is clear and cover the data of the paper, it is not the intension to review the paper that were already published in highly peer journals. The economic analysis of costs and the comparative accessibility from different countries is out of the scope of this short review.
Round 2
Reviewer 1 Report
Comments and Suggestions for Authors
Thank you for considering my remarks.
