CAR-T State of the Art and Future Challenges, A Regulatory Perspective

Round 1

Reviewer 1 Report

The reviewed article “CAR-T state of the art and future challenges, a regulatory 2 perspective” provides a comprehensive overview of CAR-T therapy development in Europe, highlighting potential advancements and limitations.

Overall, the article serves as an informative resource for researchers, clinicians, and regulatory agencies, providing an overview of CAR-T therapy development in Europe.

The authors analyze the regulatory landscape, drawing on scientific literature, clinical trial databases, and EMA sources. The article offers valuable insights, there are certain areas that could be further explored and improved upon and for this reason, in my opinion could be accepted for publication once made minor points:

-     It would be beneficial for the article to delve deeper into the ethical issues related to gene editing, as this is an important aspect of CAR-T therapy that should be explored in further detail.

Exploring the current ethical concerns associated with gene editing and their implications for CAR-T therapy would contribute to a more well-rounded analysis.

-        Providing information would be useful more concrete recommendations on how regulatory approaches can be improved to promote the adoption of these therapies.

-        I suggest authors to correct the structure of the text, in particular the numbering of the paragraphs and the images presented.

Author Response

Dear Reviewer 1,

We are thankful for the comments provided, and we appreciate the time and efforts dedicated for the improvement of the manuscript.

1. We agree with the statement that ethical issues need to be addressed, particularly when we approach gene editing in CAR-Ts due to its great interest from a safety perspective as well as ethical. We also think that this analysis would deserve a specific dissertation, ranging from clinical development to legal implications which are not currently covered by our review. From a technical perspective, we added in the conclusions the concept that further research on safety is needed and, in parallel, the global legal framework should be shaped to avoid any ethical concerns, without impacting access to these innovative treatments (lines 673 to 676).
2. Thank you for pointing out the need of proposing new regulatory approaches. Indeed, under section 2.1, this concept was discussed with reference to the PRIME scheme, by suggesting earlier interactions with developers to address issues from different perspectives (safety quality, efficacy), in an iterative manner (see lines173 to 175). In addition, we have now highlighted that the future proposal of European pharmaceutical legislation will take advantage of previous experience with this scheme, which is thus proposed to be maintained and expanded (lines 212-215).
3. We thank you for highlighting the mismatched numbering. Paragraphs have been re-numbered and clarifications of pictures were given. Moreover, one new picture was added (Figure 1), according to Reviewer 2 request.

Reviewer 2 Report

Dear authors

The work submitted for review comprehensively presents the current state of knowledge regarding CAR-t therapy. The work presents currently registered preps in the European Union, and worldwide. It also discusses and compares the use of the therapy in Italy in the hospital exception. The work also analyzes the legal status based on European Union regulations. Of particular note is Figure 4, which shows the advantages of decentralizing CAT-t therapy. Kindly complete the paper:

1. a diagram on the principle of CAR-t therapy. The publication can be a valuable source of knowledge not only for those who deal with cellular therapies on a daily basis.

2. please expand the information on the application of therapy in gliomas.

Author Response

Dear Reviewer 2,

We thank you for the valuable comments provided, and we appreciate the time and efforts dedicated for the improvement of the manuscript.

1. We agree with the proposal of introducing a new explanatory diagram on the general principles of the CAR-T therapy (Figure 1), which we consider extremely helpful in expanding the potential target audience of the manuscript.
2. We agree on the suggestion, and we expanded the paragraph 3.2.2 CAR-T-mediated Neurotoxicity (ICANS) (lines 455 to 461) to enrich the discussion on gliomas; this was originally omitted due to the fact that data were limited to US and China, but no information were available for EU.