Harnessing the Potential of Chimeric Antigen Receptor T-Cell Therapy for the Treatment of T-Cell Malignancies: A Dare or Double Dare?
Round 1
Reviewer 1 Report
The manuscript is clear and relevant for the field. It's well-structured and the study design is reproducible.
Author Response
Thank you for the review and comments to our manuscript titled “Harnessing the Potential of Chimeric Antigen Receptor T-cell Therapy for the Treatment of T-cell malignancies: A Dare or Double Dare?” that we submitted for consideration for publication to Cells. We found the comments from the reviewers very insightful and valuable.
Reviewer 2 Report
Very well written and structured review.
Remark 1:
Line108 to 110:"The interactions between scFv and its ligand occur with greater affinity and avidity compared to that of TCR-ligand interactions, likely generating a more potent immune synapse than is seen with the use of a mAb".
The TCR, do my understanding, is able to recognized one antigen per cell (sensitivity). However, so far for CAR-T, we more in the range of 100 target per cells needed at best. Therefore, in the range of 1 to 100 target the comment above (i.e. avidity) is very relevant. The reason may be why some research groups have/are investigating CAR construct based on “TCR skeleton”.
In the previous sentence you compare scFv (CAR-T construct) to TCR but in the next sentence you compare the strength of the immune synapse to monoclonal antibody. Not sure to really capture the meaning of what you want to say.
Maybe you can rephrase the sentence to make it clearer.
Author Response
Thank you
This was meant to be a completion of this idea presented in lines 97-99:
Unlike normal T-cells that operate through TCR-based ligand recognition, CAR-T cells recognize and eliminate unprocessed tumor antigens independently of the human leukocyte antigen (HLA) complex.
However, we removed it from the updated manuscript to avoid any confusion to the reader
Reviewer 3 Report
The review article titled Harnessing the Potential of Chimeric Antigen Receptor T-cell Therapy for the Treatment of T-cell malignancies: A Dare or Double Dare? by Assi and Sulman is an interesting article discussing various approaches to enhance CAR T cell efficacy, mainly targeting (or restrict targeting) of various specific antigens by CAR T cells. I really enjoyed reading this review article. The only minor concern is that the authors need to include a section on inherent or acquired resistance of tumors that renders them unresponsive to CAR T cells therapy.
Author Response
The review article titled Harnessing the Potential of Chimeric Antigen Receptor T-cell Therapy for the Treatment of T-cell malignancies: A Dare or Double Dare? by Assi and Sulman is an interesting article discussing various approaches to enhance CAR T cell efficacy, mainly targeting (or restrict targeting) of various specific antigens by CAR T cells. I really enjoyed reading this review article. The only minor concern is that the authors need to include a section on inherent or acquired resistance of tumors that renders them unresponsive to CAR T cells therapy.
Thank you
We thank the reviewer for this valuable insight and therefore added a small paragraph (line 187, page 5), further expanding on the challenges to implement and bring to success the CAR-T therapy in T-cell malignancies:
As seen in B-cell malignancies, therapeutic failure of CAR-T therapy in T-cell malignancies also seems to sequester around two major patterns: inherent resistance signaling the absence of significant disease response after therapy, or acquired resistance in which patients enjoy a transient response followed by disease recurrence. All models of CAR-T failure appear to stem from tumor-intrinsic evasion mechanisms that are either antigen-dependent (loss of antigen expression, fratricide, etc.) or independent. Additionally, pre- and/or post-exposure T cell dysfunction could occur, leading to resistance to CAR-T therapy and/or disease relapse.
