CAR T Cell Therapy for Chronic Lymphocytic Leukemia: Successes and Shortcomings

Round 1

Reviewer 1 Report

The work is interesting and has a lot of detailed and well explained information. However, I believe that the presentation of the theme should be better organized into sections. The first in which the state of the art of the CAR T in CLL is presented with the reference studies. A second section which explains the problems of CAR T therapies in CLL, then a third section which lists the attempts to improve efficacy (combinations, different targets, new constructs). Rightly separate section on allogeneic CAR T and CAR NK.
Furthermore, I believe that the use of at least 2 figures that may summarize graphically, for example, the problems of the CAR T in CLL and possibly the new strategies to increase its effectiveness, may also be useful to make the reading of the paper more attractive.

Author Response

1. One more section “Resistance to CAR-T therapy in CLL and attempts to overcome it”.It is added to the revised version of the manuscript. In this section every listed problem of CAR T therapy is followed by the known attempts to improve the efficacy of the therapy.
2. Figures that summerize the problems of CAR T therapy in CLL and  the new strategies to increase its effectivenes are added (Figures 2 and 3).

Reviewer 2 Report

The paper is well written and comprehensive but very hard to read due to poor use of the English language. The language needs to be extensively edited before publication.

Also:

Table 1: how is it possible that CR rates in some studies are higher than OR rates? The Table needs to be looked at again. 

Line 108 CR range does not match with the table

Line 183 The term “cytokine storm” is not generally used for “dangerous CRS” . We would use Grade 3 or 4 CRS

Author Response

1. CR and ORR in table 1 rates are corrected.
2. CR range is corrected in 108 line.
3. Term “cytokine storm” is excluded from text and replaced with term cytokine-relase syndrome grade 3 or 4.
4. Language is edited.
5.  

Reviewer 3 Report

The review setup is overall good. I wonder if it would not be better to divide the presentation after point 2, CAR-T as promising therapy, into further sub-chapters. From line 112 on page 3 a sub-chapter could be inserted such as: Resistance to CAR-T therapy in CLL. This would make it easier to read the text.
Furthermore, at point 3 there is an imbalance between the space dedicated to the technique and the problems of allogenic CAR-T and that dedicated to NK cells. Both are technologies potentially useful in overcoming resistance to CAR-T in CLL but allogeneic CAR-T already has literature in this disease.
Finally, table 1 presents some inaccuracies on the results of the ORR and CR relating to references 31, 33, 34 and 35: the number of CR is higher than that of the ORR.

Author Response

1. Subchapter “Resistance to CAR-T therapy in CLL and attempts to overcome it” is inserted.
2. In chapter “Allogenic CAR T or CAR NK cells in CLL therapy?” more data are included regarding allogenic CAR T therapy and references are corrected.
3. CR and ORR in table 1 rates are corrected.

Reviewer 4 Report

The manuscript describes the therapy strategies using CAR T or CAR NK in patients affected by CLL. CLL is a very "strange" disease, with high rates of variability influencing the prognosis and therapy choising. 

Despite the topis is very interesting, I believe that some changes could be added:

Line 30: 100.000 or 100,000?

Line 31: 35 or 35%?

Line 34: authors should include the concept of the possible coexistence of more CLL tumor clones within a patient, that influence prognosis and therapy [e.i. PubMed ID 32483301]

No images were included, I believe that a representative workflow of the CAR T production could improve the paper. 

In section "3. Allogenic CAR T or CAR NK cells in CLL therapy?" the authors could add a summary table with the differences between T and NK, highlighting the pros and cons of each strategy. 

Author Response

1. Number in line 30 is corrected.
2. In line 31, number 35 applies to incidence 35 per 100,000 people per year.
3. We included concept of the possible coexistence of more CLL tumor clones within a patient with adequate reference.
4. Figure that summerizes CAR T cell production is added to the revised manuscript.
5. Additional table is included in the paper with advantages and disadvantages of allogenic CAR T cells and CAR NK cells.

Round 2

Reviewer 1 Report

Good pictures and ok for the re organization of the sections

Reviewer 4 Report

All suggestions are validated. I believe that the manuscript may be accepted for publication.