Mechanistic Insights into Off-the-Shelf vs. Personalized mRNA Cancer Vaccines: A Comparative Review of BNT111 and BNT122

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is an interesting, useful, and educational study that is generally well written. However, it reflects a major and common limitation in the field, namely, the insufficient consideration and underestimation of off-target effects of mRNA-LNPs. Although the MS mentions off-target effects, it appears to be biased toward emphasizing the safety and efficacy of BNT122 versus BNT111. The MS does not mention emerging concerns about the safety of COVID-19 mRNA vaccines, leading to restriction of their clinical use in several countries, including the United States, partly due to growing awareness of adverse events. These events, although relatively rare, encompass a broad spectrum and may be linked to the systemic biodistribution of mRNA-LNPs. Such distribution can result in unintended transfection in multiple organs, potentially contributing to inflammatory conditions and, in some cases, autoimmune phenomena, even when the encoded antigen itself is not inherently immunostimulatory, as in the case of cancer vaccines. This issue is particularly relevant in the context of cancer vaccines, where whole-body distribution of immunostimulatory nanoparticles, independent of tumor targeting, may pose safety risks that could outweigh therapeutic benefits.

Unless this critical aspect is properly addressed and clarified, the manuscript risks misleading readers regarding the translational potential and safety profile of this technology. Furthermore, the reliance on prior preclinical and clinical studies that predominantly report favorable outcomes may introduce bias, especially if conflicting data or limitations are not equally discussed. Transparency regarding these aspects, including any potential conflicts of interest, is essential.

Given these concerns, I strongly recommend major revision. The authors should incorporate a balanced discussion of off-target effects, biodistribution, and associated risks, particularly in the context of systemic exposure and cancer vaccine applications. Addressing these points will significantly strengthen the manuscript and provide a more realistic and scientifically grounded perspective.

Author Response

Dear Reviewer,

Thank you for your time in reviewing our manuscript and for helping it reach its best form. Attached are our responses, and we have addressed all your comments.

Thank you very much!

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This article focuses on the background of tumor immunotherapy and delves into two core strategies of mRNA cancer vaccines (off-the-shelf / personalized), with BNT111 and BNT122 as representative models. It clearly sets out the research purpose of a comparative analysis, presenting a logical framework and a clear academic orientation. The topic is of both theoretical value and clinical reference significance. However, there is still room for improvement in terms of content depth, the rigor of argumentation and structural integrity, and targeted optimization is needed.

1. In section 2, When introducing non-replicating and self-amplifying mRNA vaccines, only describe the core differences. Whether they contain a viral replication mechanism can be supplemented with the advantages and disadvantages of both types, such as the self-amplifying mRNA vaccine having a high antigen expression level but the safety needs further verification, while the non-replicating type has good safety but limited expression level. To enhance the depth of the content, the authors can refer to the relevant literature “Engineered extracellular vesicles as a next-generation vaccine platform. Matter, 2024, 7(12): 4180-4205. (This paper systematically reviews the loading strategies of RNAs into EVs, and the application of EV vaccines in fighting cancers and infectious diseases. The discussion of EVs as a novel vaccine delivery platform may provide additional insight into this article.)”.
2. When analyzing the limitations, it is advisable to briefly add the specific reasons for the easy degradation of mRNA molecules, such as being susceptible to degradation by nucleases, rather than merely mentioning "poor stability". There are different kinds of mRNA vaccine delivery systems, which could improve the delivery efficiency of mRNA in vivo. The authors can refer to and discuss the relevant paper “Extracellular vesicle-based mRNA therapeutics and vaccines. Exploration, 2025, 0: 20240109”.
3. In section 2.2.1, when referring to the use of BNT111 in combination with PD-1 inhibitors, it is possible to add a couple of pieces of preliminary efficacy data from clinical studies, such as how much the objective response rate of patients increased after the combined treatment, thereby enhancing the persuasiveness of the advantages of the combined therapy.
4. In section 3.1, when explaining the reason for the "moderate" nature of the BNT111 immune response, specific mechanisms can be added.
5. In section 3.2, when explaining that TAAs vaccines may damage normal tissues, a simple example such as "Some TAAs are expressed at low levels in normal tissues, which may trigger an autoimmune response" can be provided to make the risk description more specific.
6. In section 5.3, when introducing the applicable scenarios of BNT122, it is advisable to briefly add "the specific population for postoperative adjuvant treatment", such as "patients with high-risk melanoma after surgery", to clearly define its clinical positioning.

Author Response

Dear Reviewer,

Thank you for your time in reviewing our manuscript and for helping it reach its best form. Attached are our responses, and we have addressed all your comments.

Thank you very much!

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have addressed the comment.

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have addressed the comment.